US20090214436A1 - Dichromic fluorescent compounds - Google Patents
Dichromic fluorescent compounds Download PDFInfo
- Publication number
- US20090214436A1 US20090214436A1 US12/370,758 US37075809A US2009214436A1 US 20090214436 A1 US20090214436 A1 US 20090214436A1 US 37075809 A US37075809 A US 37075809A US 2009214436 A1 US2009214436 A1 US 2009214436A1
- Authority
- US
- United States
- Prior art keywords
- compound
- group
- hydrocarbyl
- acid sequence
- dichromic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 235
- 238000000034 method Methods 0.000 claims abstract description 45
- 230000008569 process Effects 0.000 claims abstract description 11
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 92
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 150000007523 nucleic acids Chemical group 0.000 claims description 28
- -1 amino, carboxyl Chemical group 0.000 claims description 27
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000004122 cyclic group Chemical group 0.000 claims description 22
- 125000004429 atom Chemical group 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 229910052717 sulfur Chemical group 0.000 claims description 19
- 239000011593 sulfur Chemical group 0.000 claims description 19
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 229910052710 silicon Inorganic materials 0.000 claims description 17
- 239000010703 silicon Chemical group 0.000 claims description 17
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 16
- 229910052698 phosphorus Inorganic materials 0.000 claims description 16
- 239000011574 phosphorus Chemical group 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 238000000862 absorption spectrum Methods 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 238000012544 monitoring process Methods 0.000 claims description 11
- 230000001268 conjugating effect Effects 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 150000003573 thiols Chemical class 0.000 claims description 9
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 239000010452 phosphate Substances 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 150000001345 alkine derivatives Chemical class 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 20
- 150000002431 hydrogen Chemical class 0.000 claims 14
- 239000000975 dye Substances 0.000 description 42
- GRAVJJAQKJDGPM-UHFFFAOYSA-N 3-[2-[7-[3-(2-carboxyethyl)-1,1-dimethylbenzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]propanoic acid;bromide Chemical compound [Br-].OC(=O)CCN1C2=CC=C3C=CC=CC3=C2C(C)(C)\C1=C/C=C/C=C/C=C/C1=[N+](CCC(O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C GRAVJJAQKJDGPM-UHFFFAOYSA-N 0.000 description 33
- 0 [1*]C1=C(*C2CC([1*])C([3*])C2[2*])CC([5*])C1[6*] Chemical compound [1*]C1=C(*C2CC([1*])C([3*])C2[2*])CC([5*])C1[6*] 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 23
- 230000005284 excitation Effects 0.000 description 22
- 239000000758 substrate Substances 0.000 description 22
- 108090000397 Caspase 3 Proteins 0.000 description 20
- 102000003952 Caspase 3 Human genes 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 235000002639 sodium chloride Nutrition 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 150000001413 amino acids Chemical group 0.000 description 15
- 239000007850 fluorescent dye Substances 0.000 description 15
- 238000003384 imaging method Methods 0.000 description 15
- 230000026731 phosphorylation Effects 0.000 description 15
- 238000006366 phosphorylation reaction Methods 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- 229960004657 indocyanine green Drugs 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- 125000005647 linker group Chemical group 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 230000003595 spectral effect Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- HIYWOHBEPVGIQN-UHFFFAOYSA-N 1h-benzo[g]indole Chemical group C1=CC=CC2=C(NC=C3)C3=CC=C21 HIYWOHBEPVGIQN-UHFFFAOYSA-N 0.000 description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 229940126214 compound 3 Drugs 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 210000005069 ears Anatomy 0.000 description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 230000000875 corresponding effect Effects 0.000 description 7
- 230000004001 molecular interaction Effects 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 108010010919 Casein Kinase II Proteins 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000002376 fluorescence recovery after photobleaching Methods 0.000 description 6
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 108010088751 Albumins Proteins 0.000 description 5
- 102000009027 Albumins Human genes 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 230000031018 biological processes and functions Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 230000009977 dual effect Effects 0.000 description 5
- 238000000295 emission spectrum Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 5
- 238000002372 labelling Methods 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 230000035945 sensitivity Effects 0.000 description 5
- 235000004400 serine Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 102000007469 Actins Human genes 0.000 description 4
- 108010085238 Actins Proteins 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000562 conjugate Substances 0.000 description 4
- 230000021615 conjugation Effects 0.000 description 4
- 150000004696 coordination complex Chemical class 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 238000011503 in vivo imaging Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000012634 optical imaging Methods 0.000 description 4
- 238000006862 quantum yield reaction Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 231100000765 toxin Toxicity 0.000 description 4
- 108700012359 toxins Proteins 0.000 description 4
- 102000052052 Casein Kinase II Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229930194542 Keto Natural products 0.000 description 3
- 102000002151 Microfilament Proteins Human genes 0.000 description 3
- 108010040897 Microfilament Proteins Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000000298 carbocyanine Substances 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 238000005100 correlation spectroscopy Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 230000003436 cytoskeletal effect Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- SLPJGDQJLTYWCI-UHFFFAOYSA-N dimethyl-(4,5,6,7-tetrabromo-1h-benzoimidazol-2-yl)-amine Chemical compound BrC1=C(Br)C(Br)=C2NC(N(C)C)=NC2=C1Br SLPJGDQJLTYWCI-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 238000000799 fluorescence microscopy Methods 0.000 description 3
- 238000002189 fluorescence spectrum Methods 0.000 description 3
- 125000000468 ketone group Chemical group 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000000863 peptide conjugate Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- QWYZFXLSWMXLDM-UHFFFAOYSA-M pinacyanol iodide Chemical class [I-].C1=CC2=CC=CC=C2N(CC)C1=CC=CC1=CC=C(C=CC=C2)C2=[N+]1CC QWYZFXLSWMXLDM-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- ZMZRKOASUWINDA-VEABSNGSSA-N (4s)-4-[[(2s)-2-amino-3-carboxypropanoyl]amino]-5-[[(2s)-1-[[(2s)-1-carboxy-3-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid Chemical compound OC(=O)C[C@@H](C=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O ZMZRKOASUWINDA-VEABSNGSSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 2
- KBMPCHWHYBINMX-UHFFFAOYSA-O CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+]2=C1/C=C/C=C/C=C/C=C1\N(CCC(=O)NCNC(=O)CC2)C2=C(/C3=C(C=CC=C3)\C=C/2)C1(C)C Chemical compound CC1(C)C2=C(C=CC3=C2C=CC=C3)[N+]2=C1/C=C/C=C/C=C/C=C1\N(CCC(=O)NCNC(=O)CC2)C2=C(/C3=C(C=CC=C3)\C=C/2)C1(C)C KBMPCHWHYBINMX-UHFFFAOYSA-O 0.000 description 2
- YHTIQAJCFQKZJB-UHFFFAOYSA-N CC1(C)C2=C(C=CC3=CC=CC=C32)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)O)C2=C(C3=CC=CC=C3C=C2)C1(C)C Chemical compound CC1(C)C2=C(C=CC3=CC=CC=C32)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCC(=O)O)C2=C(C3=CC=CC=C3C=C2)C1(C)C YHTIQAJCFQKZJB-UHFFFAOYSA-N 0.000 description 2
- NECOWJWPFRXWOU-UHFFFAOYSA-N CC1(C)C2=C(C=CC3=CC=CC=C32)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCN)C2=C(C3=CC=CC=C3C=C2)C1(C)C Chemical compound CC1(C)C2=C(C=CC3=CC=CC=C32)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCN)C2=C(C3=CC=CC=C3C=C2)C1(C)C NECOWJWPFRXWOU-UHFFFAOYSA-N 0.000 description 2
- ADBHZRJKOYYAIN-UHFFFAOYSA-N CCCN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=[N+](CCCCC(=O)O[O-])C2=C(C3=CC=CC=C3C=C2)C1(C)C Chemical compound CCCN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=[N+](CCCCC(=O)O[O-])C2=C(C3=CC=CC=C3C=C2)C1(C)C ADBHZRJKOYYAIN-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000003960 Ligases Human genes 0.000 description 2
- 108090000364 Ligases Proteins 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 108010051758 aspartyl-glutamyl-valyl-aspartal Proteins 0.000 description 2
- 150000001555 benzenes Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 238000004061 bleaching Methods 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 230000009087 cell motility Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 210000003850 cellular structure Anatomy 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000004624 confocal microscopy Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 230000009881 electrostatic interaction Effects 0.000 description 2
- 239000003344 environmental pollutant Substances 0.000 description 2
- 230000007071 enzymatic hydrolysis Effects 0.000 description 2
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000002060 fluorescence correlation spectroscopy Methods 0.000 description 2
- 238000001917 fluorescence detection Methods 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000005283 ground state Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002390 heteroarenes Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 2
- 238000001161 time-correlated single photon counting Methods 0.000 description 2
- 238000000492 total internal reflection fluorescence microscopy Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000028973 vesicle-mediated transport Effects 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- AOUOVFRSCMDPFA-QSDJMHMYSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-carboxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylbutanoyl]amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O AOUOVFRSCMDPFA-QSDJMHMYSA-N 0.000 description 1
- GGXRLUDNGFFUKI-ORGXJRBJSA-N (4s)-4-[[(2s)-2-acetamido-3-carboxypropanoyl]amino]-5-[[(2s)-1-[[(2s)-3-carboxy-1-(4-nitroanilino)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid Chemical compound OC(=O)C[C@H](NC(C)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)NC1=CC=C([N+]([O-])=O)C=C1 GGXRLUDNGFFUKI-ORGXJRBJSA-N 0.000 description 1
- ALZSTTDFHZHSCA-RNVDEAKXSA-N (4s)-4-[[(2s)-2-acetamido-3-carboxypropanoyl]amino]-5-[[(2s)-1-[[(2s)-3-carboxy-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC1=CC(=O)OC2=CC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(C)=O)C(C)C)=CC=C21 ALZSTTDFHZHSCA-RNVDEAKXSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- VEUMANXWQDHAJV-UHFFFAOYSA-N 2-[2-[(2-hydroxyphenyl)methylideneamino]ethyliminomethyl]phenol Chemical compound OC1=CC=CC=C1C=NCCN=CC1=CC=CC=C1O VEUMANXWQDHAJV-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 1
- XBNVWXKPFORCRI-UHFFFAOYSA-N 2h-naphtho[2,3-f]quinolin-1-one Chemical compound C1=CC=CC2=CC3=C4C(=O)CC=NC4=CC=C3C=C21 XBNVWXKPFORCRI-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- NNMALANKTSRILL-LXENMSTPSA-N 3-[(2z,5e)-2-[[3-(2-carboxyethyl)-5-[(z)-[(3e,4r)-3-ethylidene-4-methyl-5-oxopyrrolidin-2-ylidene]methyl]-4-methyl-1h-pyrrol-2-yl]methylidene]-5-[(4-ethyl-3-methyl-5-oxopyrrol-2-yl)methylidene]-4-methylpyrrol-3-yl]propanoic acid Chemical compound O=C1C(CC)=C(C)C(\C=C\2C(=C(CCC(O)=O)C(=C/C3=C(C(C)=C(\C=C/4\C(\[C@@H](C)C(=O)N\4)=C\C)N3)CCC(O)=O)/N/2)C)=N1 NNMALANKTSRILL-LXENMSTPSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 description 1
- QGMGHALXLXKCBD-UHFFFAOYSA-N 4-amino-n-(2-aminophenyl)benzamide Chemical compound C1=CC(N)=CC=C1C(=O)NC1=CC=CC=C1N QGMGHALXLXKCBD-UHFFFAOYSA-N 0.000 description 1
- 125000005274 4-hydroxybenzoic acid group Chemical group 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- PQJUJGAVDBINPI-UHFFFAOYSA-N 9H-thioxanthene Chemical compound C1=CC=C2CC3=CC=CC=C3SC2=C1 PQJUJGAVDBINPI-UHFFFAOYSA-N 0.000 description 1
- 108010021160 Ac-aspartyl-glutamyl-valyl-aspartyl-aminomethylcoumarin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OAMLVOVXNKILLQ-BQBZGAKWSA-N Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O OAMLVOVXNKILLQ-BQBZGAKWSA-N 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- HBNVQFNJHMUIAD-BPYSPYHTSA-N CC1(C)/C(=C/C=C/C=C/C=C/C2=N(CCC(=O)NC(CO)C(=O)O)/C3=C(/C4=C(C=CC=C4)\C=C/3)C2(C)C)N(CCC(=O)NC(CO)C(=O)O)C2=C\1C1=C(C=CC=C1)/C=C\2.CC1(C)/C(=C/C=C/C=C/C=C/C2=N(CCC(=O)NC(CO)C(=O)O)/C3=C(/C4=C(C=CC=C4)\C=C/3)C2(C)C)N(CCC(=O)NC(COP(=O)(O)O)C(=O)O)C2=C\1C1=C(C=CC=C1)/C=C\2 Chemical compound CC1(C)/C(=C/C=C/C=C/C=C/C2=N(CCC(=O)NC(CO)C(=O)O)/C3=C(/C4=C(C=CC=C4)\C=C/3)C2(C)C)N(CCC(=O)NC(CO)C(=O)O)C2=C\1C1=C(C=CC=C1)/C=C\2.CC1(C)/C(=C/C=C/C=C/C=C/C2=N(CCC(=O)NC(CO)C(=O)O)/C3=C(/C4=C(C=CC=C4)\C=C/3)C2(C)C)N(CCC(=O)NC(COP(=O)(O)O)C(=O)O)C2=C\1C1=C(C=CC=C1)/C=C\2 HBNVQFNJHMUIAD-BPYSPYHTSA-N 0.000 description 1
- WCEAIQMDJQFJMN-UHFFFAOYSA-P CC1(C)/C2=C/C=C/C=C/C=C/C3=[N+](CCC(=O)NCNC(=O)CCN2C2=C\1C1=C(C=CC=C1)/C=C\2)/C1=C(/C2=C(C=CC=C2)\C=C/1)C3(C)C.CNC(=O)CCN1/C(=C\C=C\C=C\C=C\C2=[N+](CCC(=O)NC)\C3=C(\C4=C(C=CC=C4)/C=C\3)C2(C)C)C(C)(C)/C2=C1/C=C\C1=C2C=CC=C1 Chemical compound CC1(C)/C2=C/C=C/C=C/C=C/C3=[N+](CCC(=O)NCNC(=O)CCN2C2=C\1C1=C(C=CC=C1)/C=C\2)/C1=C(/C2=C(C=CC=C2)\C=C/1)C3(C)C.CNC(=O)CCN1/C(=C\C=C\C=C\C=C\C2=[N+](CCC(=O)NC)\C3=C(\C4=C(C=CC=C4)/C=C\3)C2(C)C)C(C)(C)/C2=C1/C=C\C1=C2C=CC=C1 WCEAIQMDJQFJMN-UHFFFAOYSA-P 0.000 description 1
- KAOCYPYDXIHEBN-FMENPOGGSA-L CC1(C)C2=C(C=CC3=CC=CC=C32)N(CCCCS(=O)(=O)[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)O)C2=C(C3=CC=CC=C3C=C2)C1(C)C.[2H]C(=O)CCN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=N(CCC(=O)[O-])C2=C(C3=CC=CC=C3C=C2)C1(C)C Chemical compound CC1(C)C2=C(C=CC3=CC=CC=C32)N(CCCCS(=O)(=O)[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCCS(=O)(=O)O)C2=C(C3=CC=CC=C3C=C2)C1(C)C.[2H]C(=O)CCN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=N(CCC(=O)[O-])C2=C(C3=CC=CC=C3C=C2)C1(C)C KAOCYPYDXIHEBN-FMENPOGGSA-L 0.000 description 1
- NGGIMASZWFJRLZ-QBXKYUFNSA-M CC1(C)C2=C(C=CC3=CC=CC=C32)N(CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCN)C2=C(C3=CC=CC=C3C=C2)C1(C)C.[2H]C(=O)CCN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=N(CCCCS(=O)(=O)O)C2=C(C3=CC=CC=C3C=C2)C1(C)C Chemical compound CC1(C)C2=C(C=CC3=CC=CC=C32)N(CCCCSOO[O-])=C1/C=C/C=C/C=C/C=C1/N(CCCN)C2=C(C3=CC=CC=C3C=C2)C1(C)C.[2H]C(=O)CCN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=N(CCCCS(=O)(=O)O)C2=C(C3=CC=CC=C3C=C2)C1(C)C NGGIMASZWFJRLZ-QBXKYUFNSA-M 0.000 description 1
- VSVBXYDFPXWMBZ-UHFFFAOYSA-N CC1(C)C2=C(C=CC3=CC=CC=C32)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/NC1=CC=CC=C1.CC1=NC2=C(C3=CC=CC=C3C=C2)C1(C)C.CC1=[N+](CCCCSOO[O-])C2=C(C3=CC=CC=C3C=C2)C1(C)C.CC1=[N+](CCCN)C2=C(C3=CC=CC=C3C=C2)C1(C)C.[Br-] Chemical compound CC1(C)C2=C(C=CC3=CC=CC=C32)[N+](CCCCSOO[O-])=C1/C=C/C=C/C=C/NC1=CC=CC=C1.CC1=NC2=C(C3=CC=CC=C3C=C2)C1(C)C.CC1=[N+](CCCCSOO[O-])C2=C(C3=CC=CC=C3C=C2)C1(C)C.CC1=[N+](CCCN)C2=C(C3=CC=CC=C3C=C2)C1(C)C.[Br-] VSVBXYDFPXWMBZ-UHFFFAOYSA-N 0.000 description 1
- NBMLFEYNGCBRRW-BKCQADLWSA-N CCCN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=N(CCCCC(=O)OO)C2=C(C3=CC=CC=C3C=C2)C1(C)C Chemical compound CCCN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=N(CCCCC(=O)OO)C2=C(C3=CC=CC=C3C=C2)C1(C)C NBMLFEYNGCBRRW-BKCQADLWSA-N 0.000 description 1
- PARNPWGHDNMVOG-UHFFFAOYSA-N CN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=[N+](C)C2=C(C3=CC=CC=C3C=C2)C1(C)C Chemical compound CN1C2=C(C3=CC=CC=C3C=C2)C(C)(C)/C1=C\C=C\C=C\C=C\C1=[N+](C)C2=C(C3=CC=CC=C3C=C2)C1(C)C PARNPWGHDNMVOG-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-YMDCURPLSA-N D-galactopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-YMDCURPLSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 238000003720 Kinase-Glo Luminescent Kinase Assay Methods 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 239000012901 Milli-Q water Substances 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920002274 Nalgene Polymers 0.000 description 1
- 229930192627 Naphthoquinone Natural products 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- YFPSDOXLHBDCOR-UHFFFAOYSA-N Pyrene-1,6-dione Chemical compound C1=CC(C(=O)C=C2)=C3C2=CC=C2C(=O)C=CC1=C32 YFPSDOXLHBDCOR-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102000028391 RNA cap binding Human genes 0.000 description 1
- 108091000106 RNA cap binding Proteins 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 108010038407 acetyl-aspartyl-glutamyl-valyl-aspartic acid p-nitroanilide Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 108010092854 aspartyllysine Proteins 0.000 description 1
- 238000005311 autocorrelation function Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- BHPNXACHQYJJJS-UHFFFAOYSA-N bacteriochlorin Chemical compound N1C(C=C2N=C(C=C3NC(=C4)C=C3)CC2)=CC=C1C=C1CCC4=N1 BHPNXACHQYJJJS-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical compound C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- AXMKEYXDFDKKIO-UHFFFAOYSA-N bilane Chemical compound C=1C=C(CC=2NC(CC=3NC=CC=3)=CC=2)NC=1CC1=CC=CN1 AXMKEYXDFDKKIO-UHFFFAOYSA-N 0.000 description 1
- 239000003809 bile pigment Substances 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000009141 biological interaction Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000000701 chemical imaging Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- SURLGNKAQXKNSP-DBLYXWCISA-N chlorin Chemical compound C\1=C/2\N/C(=C\C3=N/C(=C\C=4NC(/C=C\5/C=CC/1=N/5)=CC=4)/C=C3)/CC\2 SURLGNKAQXKNSP-DBLYXWCISA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 150000004039 corphins Chemical class 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- WUPRCGRRQUZFAB-DEGKJRJSSA-N corrin Chemical compound N1C2CC\C1=C\C(CC/1)=N\C\1=C/C(CC\1)=N/C/1=C\C1=NC2CC1 WUPRCGRRQUZFAB-DEGKJRJSSA-N 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000021953 cytokinesis Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 238000009543 diffuse optical tomography Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 238000006212 diphosphorylation reaction Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000005274 electronic transitions Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000695 excitation spectrum Methods 0.000 description 1
- 230000005281 excited state Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 238000012632 fluorescent imaging Methods 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000004770 highest occupied molecular orbital Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 210000003963 intermediate filament Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000004768 lowest unoccupied molecular orbital Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000004776 molecular orbital Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 150000002791 naphthoquinones Chemical class 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007110 pathogen host interaction Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 1
- 108060006184 phycobiliprotein Proteins 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 238000005316 response function Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 150000003355 serines Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000007046 spindle assembly involved in mitosis Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000031068 symbiosis, encompassing mutualism through parasitism Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000001551 total correlation spectroscopy Methods 0.000 description 1
- 238000012582 total correlation spectroscopy experiment Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
Abstract
Description
- This application claims the priority of U.S. provisional application No. 61/029,412, filed Feb. 18, 2008, and U.S. provisional application No. 61/029,644, filed Feb. 19, 2008, each of which is hereby incorporated by reference in its entirety.
- The present invention was supported by NIBIB Grant No. R01 EB1430, and NCI Grant Nos. R01 CA109754 and R21 CA12353. The United States Government has certain rights in this invention.
- The present invention generally relates to dichromic compounds. In particular, the invention provides dichromic fluorescent compounds, process for producing dichromic fluorescent compounds, and methods of using dichromic fluorescent compounds to monitor biological events.
- Fluorescent materials that provide high detection sensitivity of molecular processes are central to advances in biochemical assays, molecular sensor technologies, and molecular optical imaging. In biological optical imaging, the low autofluorescence of tissues and the deep penetration of light at wavelengths between 650 and 900 nm allow the use of near infrared (NIR) fluorescent dyes as contrast agents in heterogeneous systems. The ease of synthesis, biocompatibility, tunable spectral properties, and exceptionally high molar absorptivity of NIR fluorescent carbocyanines provide added incentive for their use in cellular and in vivo imaging applications.
- Despite the multitude of advantages, NIR fluorescent dyes are used for narrow applications in biological sciences and medicine because of poor sensitivity of NIR fluorescence intensity to changes in molecular processes. A traditional approach for using these dyes involves labeling biological molecules with the dyes along with the assumption that clearance from the nontarget process will allow detection of the targeted molecular event. For in vivo studies, this requires a method to remove nonspecific interactions, which is often difficult and cumbersome. Elimination of nonspecific targets in vivo, therefore, presents a major hurdle that can only be solved by sophisticated algorithms or via passive elimination that could take several days to achieve.
- Another level of difficulty with fluorescence methods relates to quantification of the signal. Fluorescence intensity measurements are generally influenced by many factors that complicate quantitative analysis. An approach to solve this problem involves the use of ratiometric methods. Unfortunately, only a few molecules have the ability to generate two emission bands for this purpose, and there are no available NIR fluorescent probes with this capacity. Thus to overcome this challenge, two or more NIR dyes are typically attached to the same molecule for ratiometric analyses.
- Yet another unsolved problem with NIR fluorescent imaging is the difficulty in detecting molecular interactions. Optical methods are particularly attractive for detecting molecular interactions because selective activation of light emission by fluorescence resonance energy transfer (FRET) or related methods using a variety of fluorescent dyes or proteins allows the detection of molecular interactions with high sensitivity and specificity. Unfortunately, most FRET or FRET-like methods rely on the use of two or more fluorophore systems to pre-quench the fluorescence efficiently before activation by the target biomolecule. In addition to the costs of developing two dyes and the potential cumulative toxicity, the approach also requires careful selection of the donor-acceptor dye pairs, stringent positioning of the dyes (because this may affect the interactions), and distance-dependent separation of the cleaved dye from cellular milieu to detect the fluorescence. Meeting these requirement is particularly challenging for developing NIR FRET probes that would be useful for deep tissue imaging. There is a need, therefore, for dual emitting NIR probes in which the ratio of the two fluorescence bands would change in response to biological events, such that the fluorescent signal could be quantified using a ratiometric analysis.
- Among the various aspects of the present invention is the provision of a dichromic compound comprising:
-
A-L-B -
- wherein:
- A and B are each either structurally symmetrical moieties, or are each structurally asymmetrical moieties; and L is a linker comprising a chromophore.
The compound further comprises R1 and R2, wherein R1 and R2 are structurally distinct groups that are each either conjugated to the compound comprising structurally symmetrical A and B moieties in a manner that yields asymmetry such that the compound has two distinct fluorescence lifetimes at two different emission wavelengths; or R1 and R2 are each conjugated to the compound comprising structurally asymmetrical A and B moieties in a manner that yields symmetry such that the compound has two distinct fluorescence lifetimes at two different emission wavelengths.
- A and B are each either structurally symmetrical moieties, or are each structurally asymmetrical moieties; and L is a linker comprising a chromophore.
- wherein:
- Another aspect of the present invention encompasses a method for monitoring a biological event in a subject. The method comprises administering a dichromic compound to the subject and detecting whether the structural symmetry of the compound changes, thereby indicating the biological event. The dichromic compound comprises:
-
A-L-B -
- wherein:
- A and B are each either structurally symmetrical moieties, or are each structurally asymmetrical moieties; and L is a linker comprising a chromophore.
The compound further comprises R1 and R2, wherein R1 and R2 are structurally distinct groups that are each either conjugated to the compound comprising structurally symmetrical A and B moieties in a manner that yields asymmetry such that the compound has two distinct fluorescence lifetimes at two different emission wavelengths; or R1 and R2 are each conjugated to the compound comprising structurally asymmetrical A and B moieties in a manner that yields symmetry such that the compound has two distinct fluorescence lifetimes at two different emission wavelengths.
- A and B are each either structurally symmetrical moieties, or are each structurally asymmetrical moieties; and L is a linker comprising a chromophore.
- wherein:
- A further aspect of the present invention provides a process for producing a dichromic compound comprising:
-
A-L-B -
- wherein:
- A and B are either structurally symmetrical moieties or are each structurally asymmetrical moieties; L is a linker comprising a chromophore; and the compound further comprises R1 and R2.
The process comprises conjugating R1 and R2, which are structurally distinct groups, to the compound comprising structurally symmetrical A and B moieties in a manner that yields asymmetry such that the compound has two distinct fluorescence lifetimes at two different emissions wavelengths; or conjugating R1 and R2 to the compound comprising structurally asymmetrical A and B moieties in a manner that yields symmetry such that the compound has two distinct fluorescence lifetimes at two different emissions wavelengths.
- A and B are either structurally symmetrical moieties or are each structurally asymmetrical moieties; L is a linker comprising a chromophore; and the compound further comprises R1 and R2.
- wherein:
- Other aspects and iterations of the invention are described more thoroughly below.
- The application file contains at least one photograph executed in color. Copies of this patent application publication with color photographs will be provided by the Office upon request and payment of the necessary fee.
-
FIG. 1 illustrates the spectral properties of NIR fluorescent dyes. Absorbance (A) and dual fluorescence (B) spectra of representative dyes (compounds -
FIG. 2 presents the spectral properties ofcompound 3. Fluorescence excitation and emission scans at 695 nm (A) and 806 nm (B) in methanol. Excitation was corrected by lamp intensity (S/N). I, normalized absorbance and fluorescence intensity. -
FIG. 3 depicts the deconvolution of the broad absorbance spectra ofcompound 3 into two distinct bands. -
FIG. 4 illustrates the effects of solvent (A), albumin (B), and pH (C) on the fluorescence spectra ofcompound 3. -
FIG. 5 depicts the structural features of nonsymmetrical dichromic compounds (A) and a representative 2D TOSCY NMR (DMSO, 600 MHz) ofcompound 4 showing the seven vinyl protons in the polymethine bridge and their correlation (B). -
FIG. 6 presents normalized absorption (A) and emission (B) spectra of diserine-cypate (6) and monophosphate diserine-cypate (7) in methanol. -
FIG. 7 depicts the shifts in the fluorescence peaks of the cypate-DEVD probe before and after cleavage by caspase-3. -
FIG. 8 presents enzyme kinetics of the cypate-DEVD probe. Shown is the nonlinear fit of the initial velocity with respect to substrate concentration and the corresponding Lineweaver-Burk plot (inset). -
FIG. 9 illustrates in vivo imaging of capsase-3 activity. (A) 805 nm fluorescence intensity maps of mouse head and ears at indicated times (min) after intradermal injection of either saline or caspase-3 in left and right ears, respectively. (B) Plot of fluorescence intensity over time for the probe activation by caspase-3 starting from intravenous injection (0 min) and intradermal caspase-3 or saline injection (10 min). -
FIG. 10 depicts the detection of phosphorylation in real time. (A) Plotted is the average relative fluorescence of cypate or cypate-serine upon excitation at 633 nm or 780 nm. (B) Plotted is the ratio of relative fluorescence intensity of cypate or cypate-serine. -
FIG. 11 presents phosphorylation in A549 cells. Plotted is luminescence (which is inversely proportional to phosphorylation) as a function of concentration of casein kinase II peptide substrate (A) or cypate-diserine (6) (B). -
FIG. 12 depicts two-channel imaging of fluorescence enhancement of A549 cells incubated with cypate-diserine (6). (A) 700 nm emission (excitation at 633 nm) of untreated cells (untx) and cells treated for 2-45 min. (B) 805 nm emission (excitation at 780 nm) of untreated cells (untx) and cells treated for 2-45 min. -
FIG. 13 presents in vivo fluorescence intensity maps of mouse ears. Left panels depict ears of mice injected with indocyanine green (ICG) and right panels depict ears of mice injected with cypate-S (3). - It has been discovered that structural asymmetry of chromic compounds results in the generation of dichromic emissions that have distinct lifetimes. Because the fluorescent lifetimes of the two peaks are distinct, the information content may be multiplexed. The dichromic fluorescent compounds may advantageously be utilized for several applications including imaging, diagnostics, to monitor biological events, and for detecting and monitoring molecular processes.
- The compounds of the invention are dichromic. Stated another way, a single compound has two distinct fluorescent lifetimes at two different emission wavelengths. This dichromic property of the compound may be generated by conjugating two structurally distinct groups to a symmetrical molecule to yield an asymmetrical compound. Alternatively, the dichomic property may be generated by conjugating two structurally distinct groups to an asymmetrical molecule to yield a symmetrical compound. In the context of the present invention the term “symmetry” means that a compound is bilaterally symmetrical with respect to both the type of atoms and their arrangement (i.e., straight chain, branched, or ring) within the compound.
- In one embodiment, the dichromic compound comprises:
-
A-L-B -
- wherein:
- A and B are each either structurally symmetrical moieties, or are each structurally asymmetrical moieties;
- L is a linker comprising a chromophore; and
- the compound further comprising R1 and R2, wherein R1 and R2 are structurally distinct groups that are each either conjugated to the compound comprising structurally symmetrical A and B moieties in a manner that yields asymmetry such that the compound has two distinct fluorescence lifetimes at two different emissions wavelengths; or R1 and R2 are each conjugated to the compound comprising structurally asymmetrical A and B moieties in a manner that yields symmetry such that the compound has two distinct fluorescence lifetimes at two different emissions wavelengths.
- wherein:
- The A and B moieties, in one embodiment, are symmetrical. For this embodiment, A and B typically comprise the same group of atoms in the same arrangement. For example, if A comprises one halosubstituted benzene ring, then B comprises a halosubtituted benenze ring. Alternatively, the A and B moieties may be nonsymmetrical. For example, if A comprises a halosubstituted benzene ring, then B may comprise a benzene ring (i.e., that isn't substituted with a halogen). Irrespective of the embodiment, the atoms forming A and B may be arranged linearly, they may be within a branched chain, they may comprise one or more rings or ring systems, or they may be combinations of any of the these. The atoms forming A and B may be one or more hydrocarbyls, substituted hydrocarbyls, heteroatoms, halogens or any other suitable atoms that may come together to form a stable compound. If A and B comprise rings or ring systems, the rings may be carbocyclic, heterocyclic, or mixtures of both with any suitable degree of saturation. In general, each member ring may comprise from 4 to 8 atoms. The rings may be substituted with any suitable group including hydrocarbyls, substituted hydrocarbyls, halogens, and heteroatoms.
- The chromophore, L, is a linker that is disposed between the A and B moieties. Typically, L exists in one of two forms: a conjugated pi system or a metal complex. In conjugated pi systems, electron excitation occurs between pi orbitals spread across alternating single and double bonds. Non-limiting examples of conjugate pi chromophore moieties include acridine, anthracene, anthrapyridone, anthraquinone, aryl azo, azomethine, benzofuran, benzaopyrone, benzoxazole, benzidine, carbazole, indole, isoprenoid, naphthalene, naphthoquinone, oxazine, phenanthrene, phenazine, polymethine, pyrene, pyrenequinone, quinoline, quinazoline, stilbene, thioxanthene, triarylmethane, xanthene moieties, and derivatives thereof. Metal complex chromophores possess shared d-orbitals between transition metals (with incomplete d-shells) and ligands. Examples of metal complex chromophore moieties include bacteriochlorin, bilin (or bilane), chlorin, corphin, corrin, heme, phthalocyanine, phycobilin, porphyrin, and salen. Typically, the metal complex chromophore is complexed with an appropriate metal ion.
- R1 and R2 can and will vary depending upon whether the A and B moieties are symmetrical or nonsymmetrical. Irrespective of the embodiment, R1 and R2 are distint groups. For example, R1 may be an alkyl group substituted with a halogen and R2 may be an alkyl group substituted with a heteroatom. If the A and B moieties are symmetrical, then R1 and R2 are selected and conjugated to the compound in a manner that yields an asymmetrical compound that has two distinct fluoresence lifetimes at two different emissions wavelengths. Alternatively, If the A and B moieties are asymmetrical, then R1 and R2 are selected and conjugated to the compound in a manner that yields a symmetrical compound that has two distinct fluoresence lifetimes at two different emissions wavelengths. R1 and R2 may comprise any group that results in the formation of a dichromic compound, as described herein. Suitable examples include a hydrocarbyl, substituted hydrocarbyl, amino acid sequence, and nucleic acid sequence. In one embodiment, R1 and R2 may both be conjugated to L. In another embodiment, one of R1 or R2 may be conjugated to A and the other to B. In an additional embodiment, one of R1 or R2 may be conjugated to A and the other to L. In another embodiment, one of R1 or R2 may be conjugated to L and the other to B.
- In an additional embodiment, the dichromic compound comprises:
-
A(—CH═CH)n—CH═B -
- wherein:
- A and B are as described above; and
- n is an integer from 0 to 10. In an exemplary iteration, n is 3.
- wherein:
- In still another embodiment, the dichromic compound comprises Formula (I):
-
- wherein:
- R1 and R2 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, amino acid sequence, and nucleic acid sequence; provided that R1 and R2 are different groups;
- X is a heteroatom selected from the group consisting of nitrogen, phosphorus, silicon, and sulfur;
- X1 and X2 are atoms independently selected from the group consisting of carbon, nitrogen, phosphorus, silicon, sulfur, and oxygen;
- L is a linker comprising a chromophore; and
- R3, R4, R5, and R6 are selected from the group consisting of hydrogen, halogen, hydrocarbyl and substituted hydrocarbyl; provided that R3 and R4 and R5 and R6 may form a ring or a ring system.
- wherein:
- In an additional embodiment, the dichromic compound comprises Formula (Ia):
-
- wherein:
- R1, R2, L, X1, and X2 are as described for compounds comprising Formula (I);
- R3, R4, R5, R6, R7, R8, R9, and R10 are selected from the group consisting of hydrogen, halogen, hydrocarbyl and substituted hydrocarbyl; provided that any of R3 and R4, R4 and R5, R5 and R6, R7 and R8, R8 and R9, and R9 and R10 may form a ring or a ring system.
- wherein:
- In certain embodiments, the dichromic compound comprises Formula (Ib):
-
- wherein:
- R1 and R2 are as defined above for compounds comprising Formula (I);
- R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are each independently selected from the group consisting of hydrogen, halogen, hydrocarbyl and substituted hydrocarbyl; and
- n is an integer from 0 to 10.
- wherein:
- In one alternative embodiment, the compound comprises Formula (Ic):
-
- wherein:
- R1 and R2 are independently selected from the group consisting of hydrogen, amide, amino, carboxyl, halogen, hydroxy, phosphate, sulfonate, thiol, azido, alkyne, amino acid sequence, and nucleic acid sequence; provided that R1 and R2 are different groups;
- R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are as described for compounds comprising Formula (Ib); and
- m is an integer from 1 to 10; and
- n is an integer from 1 to 10.
- wherein:
- In another alternative embodiment, the compound comprises Formula (Id):
-
- wherein:
- R1, R2, m, and n are as described for compounds comprising Formula (Ic).
- wherein:
- In an additional embodiment, the dichromic compound comprises a polymethine chain that has a cyclic group that is centrally located within the chain. The cyclic ring may be derivatized with a hydrocarbyl or a substituted hydrocarbyl group at the meso position. The compound according to this embodiment may be a compound comprising Formula (II):
-
- wherein:
- R1, R2, R3, R4, R5, R6, X, X1, and X2 are as described for compounds comprising Formula (I);
- R19 and R20 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, amino acid sequence, and nucleic acid sequence;
- Z is a cyclic group selected from the group consisting of a carbocyclic ring and a heterocyclic ring;
- n is an integer from 1 to 3; and
- m is an integer from 1 to 3.
- wherein:
- In another embodiment, the dichromic compound comprises Formula (IIa):
-
- wherein:
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, and X2 are as described for compounds comprising Formula (Ia); and
- Z, R19, R20, m, and n are as described for compounds having Formula (II).
- wherein:
- In an additional embodiment, the dichromic compound comprises Formula (IIb):
-
- wherein:
- R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are as described for compounds comprising Formula (Ib); and
- Z, R19, R20, m, and n are as described for compounds having Formula (II).
- wherein:
- In an alternative of this embodiment, the dichromic compound may comprise Formula (IIc):
-
- wherein:
- R1 and R2 are independently selected from the group consisting of hydrogen, amide, amino, carboxyl, halogen, hydroxy, phosphate, sulfonate, thiol, azido, alkyne, amino acid sequence, and nucleic acid sequence; provided that R1 and R2 are different groups
- R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 are as described for compounds comprising Formula (IIb);
- R21, R22, R23, R24, and R25 are each independently selected from the group consisting of hydrogen, halogen, hydrocarbyl and substituted hydrocarbyl;
- m is an integer from 1 to 10; and
- n is an integer from 1 to 10.
- wherein:
- In another alternative embodiment, the dichromic compound comprises Formula (IId):
-
- wherein:
- R1, R2, m, and n are as described for compounds comprising Formula (IIc);
- R26 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, amino acid sequence, and nucleic acid sequence; and
- X4 is a single bond or a heteroatom selected from the group consisting of sulfur, nitrogen, and oxygen;
- wherein:
- For each of the foregoing embodiments, the dichromic compounds of the invention may include one or more reactive groups for coupling the dye compound to a biomolecule. In one embodiment, one or both of the R1 and R2 groups may include a reactive group for coupling the dye compound to a biomolecule. In another embodiment, the R19, R20, or R26 groups may include a reactive group for coupling the dye compound to a biomolecule. In still another embodiment, one or more of any of the aforementioned groups may include a reactive group for coupling the dye compound to a biomolecule. Suitable non-limiting examples of biomolecules include antigens, steroids, vitamins, drugs, haptens, metabolites, toxins, environmental pollutants, antibodies, DNA, RNA, peptides, proteins, siRNA, miRNA, carbohydrates, lipids, and small molecules. In an exemplary embodiment, the biomolecule may be a peptide. The biomolecule may be coupled to the dye compound by methods generally known in the art or by methods described herein.
- Alternatively, R1, R2, R19, R20, and R26 may be selected to modify or optimize the physical and/or function properties of the dichromic compounds. R1 and R2 groups may be selected, for example, to modify a physical characteristic of the dye compound selected from the group consisting of water solubility, biodistribution, and spectral elongation.
- Exemplary non-limiting examples of dichromic compounds of the invention are shown in Table A.
- The compounds of the invention, as stated above, are dichromic. In this context, as shown in the examples, a single compound has two fluorescence lifetimes at two different emissions wavelengths. The two wavelengths generally have absorption spectra ranging from about 200 to about 1200 nm, depending upon the chromophore system (i.e., L) that is utilized. In an exemplary embodiment, the absorption spectrum of each wavelength is from about 700 nm to about 900 nm. In certain embodiments, the absorption spectra of each emission is above about 705 nm, 710 nm, 715 nm, 720 nm, 725 nm, 730 nm, 735 nm, 740 nm, 745 nm, 750 nm, 755 nm, 760 nm, 765 nm, 770 nm, 775 nm, 780 nm, 785 nm, 790 nm, 795 nm, 800 nm, 805 nm, 810 nm, 815 nm, 820 nm, 825 nm, 830 nm, 835 nm, 840 nm, 845 nm, 850 nm, 855 nm, 860 nm, 865 nm, 870 nm, 875 nm, 880 nm, 885 nm, 890 nm, 895 nm, 900 nm, or greater than 900 nm. The emissions of the two fluorescence bands may be separated from about 25 to about 400 nm. More typically, the emissions of the two fluorescence bands may be separated by from about 50 to about 300 nm. In one embodiment, the emissions of the two fluorescence bands may be separated by about 100 nm. By way of non-limiting example, one emission may be at 700 nm and the other at 800 nm. Alternatively, one emission may be at 750 nm and the other at 850 nm.
- Additionally, the dichromic compounds of the present invention may exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, the racemic mixtures thereof and other mixtures thereof. Pharmaceutically acceptable salts of such tautomeric, geometric or stereoisomeric forms are also included within the invention. The terms “cis” and “trans”, as used herein, denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond (“cis”) or on opposite sides of the double bond (“trans”). Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or “E” and “Z” geometric forms. Furthermore, some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
- The dichromic compounds may be attached to a biomolecule or a ligand to form a conjugated substrate. Attachment may be, for example, by covalent bonding, ionic bonding, dative bonding, hydrogen bonding, and other forms of molecular bonding.
- Several types of biomolecules are suitable for conjugation to the dichromic compounds. For example, useful conjugated substrates of the invention include, but are not limited to, conjugates of antigens, small molecules, steroids, vitamins, drugs, haptens, metabolites, toxins, environmental pollutants, amino acids, peptides, proteins, photosensitizers, nucleotides, oligonucleotides, nucleic acids, carbohydrates, lipids, ion-complexing moieties, and non-biological polymers. In one exemplary embodiment, the conjugated substrate is a natural or synthetic amino acid; a natural or synthetic peptide or protein; or an ion-complexing moiety. Preferred peptides include, but are not limited to protease substrates, protein kinase substrates, phosphatase substrates, neuropeptides, cytokines, and toxins. Preferred protein conjugates include enzymes, antibodies, lectins, glycoproteins, histones, albumins, lipoproteins, avidin, streptavidins, protein A, protein G, casein, phycobiliproteins, other fluorescent proteins, hormones, toxins, growth factors, and the like.
- The point of attachment of the biomolecule to the dichromic compound can and will vary depending upon the embodiment. In certain embodiments, the point of attachment may be at position R1 of any of the compounds described herein. In another embodiment, the point of attachment may be at position R2 of any of the compounds described herein. In yet another embodiment, the point of attachment may be at position R19 of any of the compounds described herein. In yet another embodiment, the point of attachment may be at position R20 of any of the compounds described herein. In yet another embodiment, the point of attachment may be at position R26 of any of the compounds described herein. It is also envisioned that more than one biomolecule may be conjugated to the dichromic compounds. For example, two, three, or more than three biomolecules may be conjugated to the dichromic compound.
- Several methods of linking dyes to various types of biomolecules are well known in the art. For example, methods for conjugating dyes to a biomolecule are described in R. Haughland, The Handbook: A Guide to Fluorescent Probes and Labeling Technologies, 9th Ed., 2002, Molecular Probes, Inc. and the references cited therein; and Brindley, 1992, Bioconjugate Chem. 3:2, which are all incorporated herein by reference. By way of example, a dichromic compound may be covalently attached to DNA or RNA via one or more purine or pyrimidine bases through an amide, ester, ether, or thioether bond; or may be attached to the phosphate or carbohydrate by a bond that is an ester, thioester, amide, ether, or thioether. Alternatively, a dichromic compound may be bound to the nucleic acid by chemical post-modification, such as with platinum reagents, or using a photoactivatable molecule such as a conjugated psoralen.
- A further aspect of the invention encompasses compositions comprising the dichromic compounds or conjugates thereof. The dichromic compounds may be in the form of free bases or pharmaceutically acceptable acid addition salts. The term “pharmaceutically-acceptable salts” refers to salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt may vary, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, hydroxybutyric, salicylic, galactaric, and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of the compounds include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine-(N-methylglucamine), and procaine.
- The composition comprising the dichromic compound may be administered to subject by a number of different means that will deliver an effective dose of the compound for either detection or treatment purposes. Such compositions may be administered orally, parenterally, by inhalation spray, rectally, intradermally, transdermally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques. Formulation of pharmacologically active agents is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975), and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980).
- Injectable preparations, e.g., sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be useful in the preparation of injectables. Furthermore, dimethyl acetamide, surfactants including ionic and non-ionic detergents, and polyethylene glycols may be used. Mixtures of solvents and wetting agents such as those listed above also may be used.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compound may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation and as such may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills may additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
- Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned above for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
- The dichromic compounds of the invention may be made in accordance with methods generally known in the art. Non-limiting examples of suitable synthetic techniques are provided in the Examples herein.
- In general, the dichromic compound comprising A-L-B, wherein A, B, and L are defined in section (I), is prepared by conjugating R1 and R2, which are structurally distinct groups, to the compound comprising structurally symmetrical A and B moieties in a manner that yields asymmetry such that the compound has two distinct fluorescence lifetimes at two different emissions wavelengths; or conjugating R1 and R2 to the compound comprising structurally asymmetrical A and B moieties in a manner that yields symmetry such that the compound has two distinct fluorescence lifetimes at two different emissions wavelengths.
- The dichromic compounds of the invention are useful in many applications including those described for other fluorescent compounds in U.S. Pat. Nos. 7,172,907; 5,268,486; and U.S. Patent Publication Nos. 2004/0014981; and 2007/0042398, each of which is incorporated herein by reference. For example, fluorescent dyes may be used in imaging with techniques such as those based on fluorescence detection, including but not limited to fluorescence lifetime, anisotropy, photoinduced electron transfer, photobleaching recovery, and non-radioactive transfer. The fluorescent dichromic compounds, as such, may be utilized in all fluorescent-based imaging, microscopy, and spectroscopy techniques including variations on such. In addition, they may also be used for photodynamic therapy and in multimodal imaging. Exemplary fluorescence detection techniques include those that involve detecting fluorescence generated within a system. Such techniques include, but are not limited to, fluorescence microscopy, confocal microscopy, multiphoton microscropy, total internal reflection fluorescence microscopy (TIRF), fluorescence activated cell sorting (FACS), fluorescent flow cytometry, fluorescence correlation spectroscopy (FCS), fluorescence in situ hybridization (FISH), multiphoton imaging, diffuse optical tomography, molecular imaging in cells and tissue, fluorescence imaging with one nanometer accuracy (FIONA), free radical initiated peptide sequencing (FRIPs), and second harmonic retinal imaging of membrane potential (SHRIMP), as well as other methods known in the art.
- Alternatively, the fluorescent dichromic compounds may be used as markers or tags to track dynamic behavior in living cells. In this regard, fluorescence recovery after photobleaching (FRAP) may be employed in combination with the fluorescent dichromic compounds of the invention to selectively destroy fluorescent molecules within a region of interest with a high-intensity laser, followed by monitoring the recovery of new fluorescent molecules into the bleached area over a period of time with low-intensity laser light. Variants of FRAP include, but are not limited to, polarizing FRAP (pFRAP), fluorescence loss in photo-bleaching (FLIP), fluorescence localization after photobleaching (FLAP). The resulting information from FRAP and variants of FRAP can be used to determine kinetic properties, including the diffusion coefficient, mobile fraction, and transport rate of the fluorescently labeled molecules. Methods for such photo-bleaching based techniques are described in Braeckmans, K. et al., Biophysical Journal 85: 2240-2252, 2003; Braga, J. et al., Molecular Biology of the Cell 15: 4749-4760, 2004; Haraguchi, T., Cell Structure and Function 27: 333-334, 2002; Gordon, G. W. et al., Biophysical Journal 68: 766-778, 1995, which are all incorporated herein by reference in their entirety.
- In preferred embodiments, the dichromic compounds of the invention may be used to monitor biological events. In exemplary embodiments, the dichromic compounds may be used to monitor molecular interactions or detect single molecules in cells. In general, the methods comprise administering a dichromic compound to a subject and detecting whether the structural symmetry of the compound changes, thereby indicating the biological event. The detection and imaging of biological or molecular interactions may be conducted in vitro or in vivo. Changes in the structural symmetry of the compound may be detected as detailed below.
- The dichromic compounds generally have two peaks of emission that preferably differ by about 100 nm. Symmetrical dichromic compounds comprising benzoindole groups, which have essentially equivalent groups attached to the benzoindole N-heteroatoms, generally emit more light at the longer wavelength than the shorter wavelength. In contrast, nonsymmetrical fluorescent dichromic compounds comprising benzoindole groups, which have non-equivalent groups attached to the benzoindole N-heteroatoms, generally emit more light at the shorter wavelength that at the longer wavelength. Changes to the structural symmetry of a dye, i.e., changing a more symmetrical dye molecule into a less symmetrical dye molecule or vice versa, generally will alter the ratio of the dual emission fluorescence. Alterations in the ratio of fluorescence, therefore, provide a means to quantify the fluorescence signal by ratiometic imaging. Furthermore, the two emission peaks have distinct fluorescence lifetimes, providing another means to quantify the fluorescent signal.
- In one embodiment, the structural symmetry of a dichromic compound may be altered by the activity of an enzyme. For example, if a kinase transfers a phosphate group to one of the R1 or R2 end-groups, then a symmetrical dichromic compound molecule may be converted into a nonsymmetrical dye molecule (see Example 7). Examples of enzymes whose activity may be monitored via changes to the structural symmetry of a dichromic compound molecule include kinases, phosphatases, hydrolases, capsases (e.g., see Example 8), proteases, nucleases, polymerases, ligases, transferases, synthetases, lipases, and so forth. Those of skill in the art will be familiar with appropriate end-groups to be attached to the N-heteroatoms of the dichromic compound molecules. Non-limiting examples of suitable end-groups include hydrocarbyl groups, alkyl groups, amino acids, peptides, nucleotides, oligonucleotides, monosaccharides, oligoscaccharides, lipids, small molecule enzyme inhibitors, receptor inhibitors, metals, and chelators. The amino acids may be D or L isomers; the nucleotides may be DNA or RNA, etc.
- In one example, the end-groups of a symmetrical dye molecule (e.g., two N-linked end-groups of a molecule comprising symmetric indole or benzoindole groups) may be linked (cyclized) by an amino acid sequence such as -Lys-Asp-Glu-Val-Asp-Lys-, wherein cleavage of the peptide bond between Asp-Lys produces a nonsymmetrical dye molecule. In another example, an initially symmetric dye may comprise a first end-group comprising L amino acids and second end-group comprising the same sequence of D amino acids, wherein cleavage of the L amino acid chain produces a nonsymmetrical dye molecule. In a further example, an initially nonsymmetrical dye molecule may comprise a first end-group comprising one amino acid and a second end-group comprising five amino acids, wherein cleavage between the 1st and 2nd amino acid of the second end-group creates a symmetrical dye molecule. Those skilled in the art will appreciate that many other iterations are possible without departing from the scope of the invention.
- Thus, changes in the structural symmetry and the concomitant ratio of fluorescence may be used to examine interactions between molecules in cells. Examples of molecular interactions include protein-protein interactions, protein-nucleic acid interactions, enzyme-substrate interactions, receptor-ligand interactions, cell signaling events, host-pathogen interactions, and so forth. In one application of this embodiment, the dichromic compound may be used to monitor tumor progression or tumor responsiveness to a therapeutic treatment. The dichromic compound may be targeted to tumor cells via addition of an Arg-Gly-Asp (RGD) peptide to another reactive group of the molecule. Targeting of RGD-tagged dichromic compounds to tumor cells was detailed in US Pat. Publication No. 2009/0028788, which is herein incorporated by reference in its entirety. In another embodiment, the dichromic compounds of the invention may be used as molecule beacons to detect or image target RNA or DNA molecules. In a further embodiments, the dichromic compounds may be used to detect and quantify metals.
- In another embodiment, the structural symmetry of a dichromic compound may be used to track assembly of cellular structures in vitro or in vivo. The cellular structure may be a cytoskeletal structure, such as those formed by actin, tubulin, or intermediate filaments. Tracking cytoskeletal assembly permits the tracking of cell movement, cell motility, protein trafficking, vesicular transport, membrane vesicle transport, mitotic spindle assembly, cytokinesis, and other such cytoskeletal-mediated process. In one embodiment, the assembly of actin may be tracked by attaching an actin-binding site (such as the cap-binding protein or a fragment thereof) to one of the benzoindole N-heteroatoms and attaching a reactive group to the other benzoindole N-heteroatom of a dichromic compound comprising benzoindole groups. Upon binding of the dye to actin, the reactive group may form strong electrostatic interactions or hydrogen bonds with actin such that structural asymmetry is generated in the dichromic compound molecule. In another embodiment, the actin-binding site may be attached to another region of the dichromic compound molecule, and the benzoindole N-heteroatoms may be linked to equivalent reactive groups, wherein structural asymmetry is generated upon actin binding.
- Besides being useful for monitoring, detecting, imaging, and/or treating in humans, the dichromic compounds of the invention also may be used in companion animals, research animals, exotic animals, and farm animals, including mammals, rodents, avians, and the like. More preferred animals include rodents, horses, dogs, cats, sheep, and pigs.
- To facilitate understanding of the invention, several terms are defined below.
- The term “acyl,” as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R1, R1O—, R1R2N—, or R1S—, R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R2 is hydrogen, hydrocarbyl, or substituted hydrocarbyl.
- The term “acyloxy,” as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (—O—), e.g., RC(O)O— wherein R is as defined in connection with the term “acyl.”
- Unless otherwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
- Unless otherwise indicated, the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
- Unless otherwise indicated, the alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
- The terms “aryl” or “ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
- As used herein, the term “functional group” includes a group of atoms within a molecule that is responsible for certain properties of the molecule and/or reactions in which it takes part. Non-limiting examples of functional groups include, alkyl, carboxyl, hydroxyl, amino, sulfonate, phosphate, phosphonate, thiol, alkyne, azide, halogen, and the like.
- The terms “halogen” or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
- The terms “heterocyclo” or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxyl, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
- The term “heteroaromatic” as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxyl, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
- The terms “hydrocarbon” and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
- The “substituted hydrocarbyl” moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, carbocycle, aryl, heterocyclo, alkoxy, alkenoxy, alkynoxyl, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers.
- The term “linking group” includes a moiety on the compound that is capable of chemically reacting with a functional group on a different material (e.g., biomolecule) to form a linkage, such as a covalent linkage. See R. Haughland, The Handbook—A Guide to Fluorescent Probes and Labeling Technologies, 9th Edition, Molecular probes, Inc. (1992). Typically, the linking group is an electrophile or nucleophile that can form a covalent linkage through exposure to the corresponding functional group that is a nucleophile or electrophile, respectively. Alternatively, the linking group is a photoactivatable group, and becomes chemically reactive only after illumination with light of an appropriate wavelength. Typically, the conjugation reaction between the dye bearing the linking group and the material to be conjugated with the dye results in one or more atoms of the linking group being incorporated into a new linkage attaching the dye to the conjugated material.
- The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the invention. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention, therefore all matter set forth or shown in the accompanying drawings is to be interpreted as illustrative and not in a limiting sense.
- The following examples illustrate various embodiments of the invention.
- Carbodichromic compounds, such as cypate (compound 1) or indocyanine green (ICG) (compound 2), are generally safe for use in humans due to their established safety profile and known photophysical properties. The high absorption coefficient of carbocyanines in organic and aqueous solutions facilitates the enhanced detection sensitivity of optical imaging systems. Amongst several carbocyanines, heptamethine dichromic compounds are very attractive for in vivo imaging because they absorb and emit radiation in the NIR wavelengths that are suitable for imaging superficial and deep tissues. In addition, these dyes can be prepared in large quantities in pure form without HPLC purification.
- To improve the hydrophilicity of cypate (1) and minimize the potential side reactions caused by the presence of two carboxylic acid functions, a hybrid of 1 and 2 was synthesized. The new compound, cypate-S (compound 3), has only one reactive carboxylic acid and a water-solubilizing sulfonate group. Similarly, an analogous amine derivative, cypate-NH2 or ICG-NH2 (compound 4) was synthesized for labeling peptides or proteins via their activated carboxylic acid groups.
- The synthesis of these nonsymmetrical compounds as represented by 4, is shown in
reaction scheme 1. - A solution of 10 (0.35 g, 1 mmol) in MeCN was added to a refluxing mixture of glutaconic aldehyde dianiline hydrochloride (0.34 g, 1.20 mmol), Ac2O (120 μL), DIEA (600 μL) and NaOAc (78 mg) in a mixed solvent of MeCN/DCM. The resultant mixture was stirred for additional 2 h before adding excess of 9 (0.52 g, 1.50 mmol). The mixture was again refluxed for 2 h. The reaction was quenched by water and the solvent was removed by a rotary evaporator. The residue was washed sequentially with EtOAc, MeCN, EtOAc and water, and purified twice by column chromatography to afford 0.31 g (46%) of 4 compound as dark solid. 1H NMR (CD3OD, 500 MHz) δ 8.24-8.22 (m, 2H), 8.18 (d, J=8.5 Hz, 1H), 8.09-7.92 (m, 7H), 7.70-7.57 (m, 3H), 7.52 (t, J=7.5 Hz, 1H), (t, J=7.5 Hz, 1H), 6.67 (t, J=12.5 Hz, 1H), 6.57 (t, J=12.5 Hz, 1H), 6.46-6.38 (m, 2H), 4.32 (t, J=7.0 Hz, 2H), 4.22 (t, J=7.5 Hz, 2H), 4.22 (t, J=8.0 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.18-2.13 (m, 2H), 2.10-2.04 (m, 2H), 2.02-1.98 (m, 2H), 1.96 (s, 6H), 1.95 (m, 6H). MS/EI: 675.2 (MH2 +).
- A nonsymmetrical cypate-peptide conjugate (compound 5) was also synthesized essentially as described by Achilefu et al., 2005, Proc. Natl. Acad. Sci. USA, 102, 7975, which is incorporated herein by reference in its entirety.
- To further characterize these newly synthesized nonsymmetrical cypate dyes, their absorption and emission spectra were evaluated and compared to those of
cypate 1 andICG 2. Cypate was synthesized according to the method of Achilefu et al., 2000, Invest. Radiol., 35, 479. ICG was purchased from a commercial source. All of the compounds, including ICG, were further purified on a Vydac C-18 column (250×4.6 mm) (Grace Davison Discovery Sciences, Deerfield, Ill.) using gradient aqueous MeCN (0.1% TFA) solvent system for multi-milligram production. Solutions of the samples in ACN/water were lyophilized to obtain about 10 mg in each case. - The polymethine dyes and their derivatives were dissolved in 150 mL of DMSO as stock solutions. To prevent inner effect in the fluorescent measurements, aliquots (10 mL) were diluted with the solvent of interest until the absorbance at the excitation wavelength was ≦0.15. UV-Vis spectra were obtained on Beckman Coulter DU 640 UV-Vis spectrometer (Beckman Coulter, Inc., Fullerton, Calif.). Emission spectra were recorded on a Fluorolog-3 spectrofluorometer (HORIBA Jobin Yvon Inc., Edison, N.J.).
- Fluorescent spectra were recorded by using 620 nm and 720 nm excitation wavelengths. Fluorescent quantum yield was measured at 720 nm with slits width of 5 nm for both excitation and emission. The fluorescence quantum yield of ICG in DMSO (Ψ=0.12) was used as a reference standard. All measurements were conducted at room temperature. Excitation scans were performed in the range of 500-720 nm with monitoring at 735 nm fluorescence intensity, and 600-815 nm with monitoring at 830 nm. Excitation scans were corrected by lamp intensity using the equation F=S/R.
- The absorption and emission spectra of the compounds are shown in
FIGS. 1A and 1B , respectively. In addition to possessing the expected long wavelength fluorescence, thenonsymmetrical compounds - There was an excellent overlap of the absorbance spectra of the symmetrical (1 and 2) and nonsymmetrical (3, 4, and 5) compounds, with 3 and 4 exhibiting higher absorbance than other compounds at ˜700 nm (
FIG. 1A ). This trend persisted in different solvents, suggesting the peak was an inherent feature of the nonsymmetrical dyes and did not originate from H-aggregates (see solvent and pH effects below). In contrast to the absorption spectra, the emission spectral profiles of the symmetrical and nonsymmetrical compounds differed (FIG. 1B ). For example, the fluorescence of 3 at ˜700 nm was much higher than the fluorescence at ˜800 nm relative to 1 and 2 upon excitation at 645 nm. Fluorescence excitation scans ofcompound 3 at the two emission peaks (695 nm and 806 nm) resulted in calculated S0-S0 transitions corresponding to 686 nm and 796 nm, respectively (FIGS. 2A and 2B , respectively), suggesting the existence of inter-convertible isomers in the ground state of the molecules. - By combining the information from the fluorescence excitation spectra obtained at both wavelengths, the broad absorbance spectrum was deconvoluted into two distinct absorbance spectra of compound 3 (
FIG. 3 ). The result shows that each absorbance spectrum was characterized by a major peak and a shoulder. The striking similarity between the individual absorbance spectra indicate similar sets of π→π* and other transitions. - The 100 nm shift in the two emission spectra suggests that the excited state properties of the two fluorescence peaks may be different. Fluorescence lifetime (FLT) was measured using time correlated single photon counting (TCSPC) technique with excitation sources NanoLed® (HORIBA Jobin Yvon Inc.) at 700 nm and 773 nm and impulse repetition rate of 1 MHz at 900 to a R928P detector (Hamamatsu Photonics, Japan). The detector was set to either 750 nm (for
Nanoled 700 nm) or for 820 nm (for Nanoled 773 nm) with a 20 nm bandpass. The electrical signal was amplified by TB-02 pulse amplifier (HORIBA Jobin Yvon Inc.) and the amplified signal was fed to the constant fraction discriminator CFD (Philips, Netherlands). The first detected photon represented the start signal by the time-to-amplitude converter (TAC) and the excitation pulse triggered the stop signal. The multi-channel analyzer (MCA) recorded repetitive start-stop signals from the TAC and generated a histogram of photons as a function of time-calibrated channels (6.878 ps/channel) until the peak signal reached 10,000 counts. The lifetime was recorded on a 50 ns scale. The instrument response function was obtained by using Rayleigh scatter of Ludox-40 (Sigma-Aldrich, St. Louis, Mo.) (0.03% in Milli-Q water) in a quartz cuvette at either 700 nm or 773 nm emission. DAS6 v6.1 decay analysis software (HORIBA Jobin Yvon Inc.) was used for lifetime calculations. The goodness of fit was judged by X2 values and Durbin-Watson parameters and visual observations of fitted line, residuals and autocorrelation function - The fluorescence lifetime properties of
compounds -
TABLE 1 Dynamic optical properties of representative cyanine molecules in DMSO. Lifetime at Fractional Lifetime at Compound 700 nm (ns)a contribution (f %) 800 nm (ns)b 1 Weak signal 99 0.87c 2 1.50d 99 0.97c 3 1.39 92 0.86 4 1.40 90 0.90 a Excitation 650 nm;emission 700 nm;bExcitation 773 nm; emission 820 nm;cSee Berezin et al., 2007, Biophys. J. 93(8): 2892-2899; dAverage two exponential 1.26 ns (39%) and 1.59 ns (60%) - Although the 100 nm blue-shifted emission peak could indicate the elimination of a methine bond from the heptamethine structure, it is unlikely that the 700 nm emission resulted from the formation of lower homologues (tri- or penta-methines) of cypate or ICG, which typically have similar fluorescence lifetimes of cypate at 800 nm (0.86 ns in DMSO). Additionally, the steady state spectral properties of the half-dyes (a potential contaminant) used to prepare 3 and 4 is 35 nm shorter than the 700 nm peak, with a corresponding fluorescence lifetime of only 0.39 ns.
- The ratios of the 700 nm and 800 nm emission peaks were examined in different environments and simulated dilute conditions (e.g., binding to albumin). For this, the fluorescence behavior of
compound 3 was determined in different solvents (i.e., methanol, water, and DMSO), pH levels (i.e., 2.5 and 10), and in the presence of albumin (which binds the dyes in its drug binding pocket). The spectral analysis was conducted as described above in Example 2. Spectra at pH 2.5 and 10.0 were obtained by titrating 20% DMSO/water solution with diluted aqueous HCl and NaOH. - As shown in
FIG. 4 , the ratio of the fluorescence at 700 nm and 800 nm was only weakly dependent on solvent system or pH, and albumin does not significantly alter this ratio. Similarly, the absorption and fluorescence spectral profiles of the blue-shifted peaks were not affected by temperatures between 20° C. and 80° C., further confirming that aggregation was not responsible for the observed increase in the 700 nm absorption. - The nonsymmetrical nature of these compounds was further examined by 2D NMR analysis, using 4 as a representative compound (see
FIG. 5 ). This analysis was made on a Varian Inova-600 spectrometer (Varian, Inc., Palo Alto, Calif.). COSY experiments were obtained with a 5200 Hz spectral width and an 8.5 μs π/2 pulse width. A data matrix with 2048 complex point in F2 and 512 real points in F1 dimension was collected with 16 transients per t1 increment. TOCSY spectra were recorded using an MELV-17 mixing sequence of 100 ms flanked by two 2 ms trim pulses. Phase-sensitive 2D spectra were obtained by employing the hypercomplex method. A total of 2×256×2048 data matrix with 16 scans per t1 increment were collected. Gaussian and sine-bell apodization functions were used in weighting the t2 and t1 dimensions, respectively. After two-dimensional Fourier transformation, the 2048×2048 frequency domain representation was phase and baseline corrected in both dimensions. - Resonances of the indole N-substituents (H2 1-H2 3 and H3 1-H3 4) and polymethine bridge (H1 1-H1 7) were identified by the through bond spin propagation at the fragment in TOCSY experiment. The correlated proton resonances at 4.20 and 4.26 ppm were unambiguously assigned to H2 1 and H3 1, respectively. Proton connectivities were confirmed by the vicinal J-coupling in COSY experiment. All the connections between adjacent protons were observed and a continuous path indicated the segment of H2 1 and H3 1, at the vinyl bridge as well as H2 1-H2 3, H3 1-H3 4 methylene chain in indole N-substituents. Assignments of H1 1 resonance at 6.64 ppm and H1 7 at 6.32 ppm were further confirmed by the observed H1 1-H3 1 and H1 7-H2 1 NOE cross peaks. In addition, the presence of the H1 6-H4 2 and H1 2-H4 1 NOE clearly indicated a 7.9 ppm and 8.01 ppm for the H1 6 and H1 2 resonances respectively, which are consistent with the assignment in COSY spectra.
- In previous studies, the two gem-dimethyl groups in symmetrical cypate showed a singlet upfield (Ye et al., 2000, Photobiol., 72, 392). However, the present analysis revealed that the corresponding peak for the
nonsymmetrical compound 4 was split into two singlets. In addition, the vinyl protons at δ 6-7 ppm, which correspond to H1 1, H1 3, H1 5 and H1 7, are doublets in cypate but are distorted in 4. The ensemble of these results suggest that one of the structures responsible for the 700 nm emission consists of a preferentially localized positive charge on one of the indole N atoms at ground state, which could further be stabilized by the neighboring sulfonate anion. It is therefore likely that the long wavelength emission arises from the conventional π-π* electronic transition when the charge is transiently even distributed. These two structural dispositions could be associated with different molecular orbital diagram, resulting in different HOMO and LUMO levels. - Both the symmetrical and nonsymmetrical dichromic compounds exhibited dual fluorescence at about 800 nm and 700 nm. The
symmetrical dyes peptide conjugate 5 exhibited a 45% increase in the level of the secondary emission relative to cypate, albeit still lower than the 82% obtained withcompounds - To demonstrate the potential of monitoring the activities of kinases involved in physiological process, the symmetrical di-serine cypate (6) and the nonsymmetrical monophosphoserine/serine cypate derivative (7) were prepared. The compounds were dissolved in methanol and the molar absorption coefficients for
compounds - As shown in
FIG. 6 , the ratio of the 700/800 nm emission peaks of the nonsymmetrical, phosphorylatedcompound 7 was increased relative to that of the symmetrical compound 6 (i.e., from 0.36 to 2.5, a 7-fold increase). Such a huge increase should allow the detection of kinase activity with high sensitivity, which is not available with conventional NIR fluorescent probes. - Another application of interest is monitoring the response of tumors to treatment by detecting the onset of apoptosis through the activity of caspase-3. To test the response of the dichromic fluorescent dyes to caspase-3 activity, a macrocyclic NIR dichromic compound (12) was prepared by linking the two carboxylic acid groups of cypate with a caspase-3 peptide substrate, NH2-Asp-Glu-Val-Asp-Ala-Pro-Lys-COOH. The enzymatic hydrolysis by caspase-3 occurs at the C-terminal of aspartic acid producing a nonsymmetrical pendant molecule (13).
- Hydrolysis of the more symmetrical compound 12 by recombinant caspase-3 (CalBiochem, San Diego, Calif.) after 16 hours of incubation at 37° C. to the less symmetrical compound 13 induced structural asymmetry that was monitored by fluorescence spectroscopy (
FIG. 7 ). This enzymatic reaction led to more than 300% increase in the 700 nm emission channel and only 45% increase in the 800 nm channel using 620 nm excitation (to obtain full emission spectra). The enhancement was independent of the excitation wavelength, in accordance with Kasha-Vavilov rule, which states that quantum yield and a position of fluorescence is independent of the excitation wavelength (Birks, 1970, Photophysics of Aromatic Molecules, Wiley, New York, N.Y.). Parallel measurements of 800 nm emission using 720 nm excitation showed 35% intensity increase. Under the same conditions, the control experiment (with no enzyme added), showed a small increase in the 700/800 nm ratio, which is attributable to a slow nonspecific hydrolysis. Thus, the observed increase in the emission ratio of 700/800 nm upon enzymatic hydrolysis confirmed that the change in fluorescence pattern was caused by the change in structural symmetry. However, moderate increase in the 700/800 nm ratio of compound 13 (2-fold increase) relative to the increase of cypate-monoserine phosphate compound 7 (7-fold increase) demonstrates the need to optimize the macrocyclic structure. These preliminary data, however, reveal that substrates with symmetrical structures as determined by the low 700/800 nm emission ratio are necessary to generate highly sensitive assays for monitoring molecular processes. - To examine the kinetics, a caspase-3 substrate was prepared using the standard FRET method where the tetrapeptide Asp-Glu-Val-Asp (DEVD) was flanked by two cypate dyes (cypate-DEVD probe). Enzyme assays were performed with a fluorometer by using commercially available recombinant caspase-3 (CalBiochem). An aliquot of the cypate-DEVD probe (substrate concentrations ranged from 70 nM to 100 μM) was dissolved in DMSO and added to a buffer comprising 10 mM PIPES, pH 7.4, 2 mM EDTA, 0.1% CHAPS, and 5 mM DTT. Five units of the enzyme were added, and the assay was performed at 37° C. A control experiment under the same conditions but with no enzyme was conducted at the same time. The apparent Km for the cypate-DEVD probe for caspase-3 was calculated with the Cheng-Prusoff equation: EC50=Ki(1(+[S]/Km), where [S] is the concentration of substrate and Ki is the published inhibitory constant of DEVD-CHO. To generate EC50 values, initial rates were determined from the linear portion of substrate hydrolysis and were plotted against log-inhibitor concentration (DEVD-CHO). The apparent kcat values were calculated using the equation kcat=V(Km+[S])/[Et][S], where [S] is the concentration of substrate, [E] is the concentration of enzyme, and V is the initial rate of cleavage. To express V in units of micromolar per second, initial velocities were determined from plots of fluorescence intensity increase versus time (seconds), using only the linear portion of the curve (<40% of full hydrolysis). The slope was divided by the change in fluorescence intensity corresponding to complete hydrolysis (corrected for background fluorescence in the absence of the enzyme) and then multiplied by the substrate concentration to obtain initial velocity V (μM/s). Et was determined with known substrate (Ac-DEVD-AMC, BD Biosciences, Franklin Lakes, N.J.), wherein one unit of capsase activity equals 1 μmol substrate cleavage per minute per μg enzyme.
- Cleavage of the cypate-DEVD probe by caspase-3 produced an increase in fluorescence intensity. A non-linear fit of the data produced values of 15±3 μM and 1.02±0.06 M s−1 for μM and kcat, respectively (
FIG. 8 ). These values compare favorably with those of the standard, Ac-DEVD-pNA (KM=11 μM and kcat=2.4 M s−1). - To assess the NIR optical imaging of caspase-3 activity, 2 nmol of the pre-quenched (FRET) cypate-DEVD probe was injected intravenously in a nude mouse, followed by intradermal injection of caspase-3 solution (right pinna) or saline (left pinna). This approach provides positive and negative controls in one set of experiments. Mouse ears were imaged with Li-Cor Odyssey single-channel (805 nm) NIR imaging system (Li-Cor Biosciences, Lincoln, Nebr.). Images were captured before treatment, after injection of a probe and after intradermal injection of caspase-3 in the ear.
- The results are shown in
FIG. 9 . Measured fluorescence intensity increased in both ears at the sites of injection of saline or caspase-3 solution. The magnitude and area of increase, however, was significantly greater in the caspase-3-injected ear and increased with time relative to the saline-injected ear. - To determine whether phosphorylation could be detected in real time, cells were incubated with cypate (1) or cypate diserine (6) and changes in the ratio of 700/800 nm were detected. Cypate diserine has two serine groups that can be phosphorylated by serine kinases, whereas, the structurally symmetrical cypate does not respond to phosphorylation.
- The human non-small cell carcinoma cell line A549 was purchased from American Type Culture Collection (Manassas, Va.). A549 cells were maintained in Ham's F12K medium supplemented with 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 10% fetal calf serum, 100 units/mL penicillin, and 100 units/mL streptomycin.
- Cells were grown on LAB-TEK™ slides (Nalgene Nunc International, Rochester, N.Y.). The medium was replaced and cells were incubated for 30 min, 1 h, or 6 h at 37° C. in the presence of 1 μM cypate (1) or cypate diserine (6). At the end of the incubation, the slides were rinsed with PBS, mounted with Prolong Gold mounting medium (Invitrogen Inc, Carlsbad, Calif.) and coverslipped. For confocal microscopy, cells were visualized with an Olympus FV1000 microscope using a 60×/1.20M, 0.13-0.21 NA water immersion objective. Fluorescence emission was detected from 645-745 nm and from 805-830 nm using a 633 nm laser and a 780 nm laser for excitation, respectively. For spectral imaging, fluorescence images were collected at 10 nm increments from 645-790 nm using a 633 nm laser and images of each group of slides were acquired with the same microscope settings during a single imaging session, allowing for qualitative comparison of the relative fluorescence. Relative fluorescence was quantitated with FV1000 software. Relative fluorescence of five areas of each image was determined and the results were averaged.
- The results are presented in
FIG. 10 . After 1 h, the ratio of the 700 to 800 emission was about 0.4:1 for cypate diserine (6), suggesting the phosphorylation of at least one of the serine groups. At 6 h, the ratio increased significantly to 3.5:1, suggesting the formation of di- or tri-phosphates on the serines. These results reveal that molecular processes may be monitored in real time using dichromic fluorescent dyes. - The following example was designed to further explore the use of cypate diserine (6) to monitor the activity of endogenous kinases. A549 cells (which express casein kinase II) were incubated with a standard casein kinase II peptide substrate or compound 6 (which is not specific for casein kinase II). Kinase activity was measured with the Kinase-Glo Luminescent Kinase Assay Platform (Promega Corp., Madison, Wis.) per the manufacturer's instructions. This assay measures free ATP in the reaction mixture. As phosphorylation increases, the levels of ATP decrease, and consequently, luminescence is inversely proportional to kinase activity.
- The concentration-dependent decreases in luminescence (i.e., increased phosphorylation) for the casein kinase II peptide substrate and
compound 6 are presented inFIGS. 11A and 11B , respectively. Fluorescence spectra of the cells incubated withcompound 6 for 10 min showed a similar spectral change fromcompound 6 to the phosphorylated derivative as depicted inFIG. 6B , suggesting substrate phosphorylation and the expected change in the structural symmetry of the dye. - It was hypothesized that since cypate diserine could be phosphorylated in cells, it is possible that the initial phosphorylation of one serine (as indicated by an increase in the 700 nm channel) could be followed by phosphorylation of the second serine. Phosphorylation of both serine would afford a more symmetrical molecule that would exhibit a corresponding increase in the 800 nm channel. To test this notion, A549 cells were incubated with of 1 μM of
compound 6. It was found (seeFIG. 12 ) that the cells exhibited an early fluorescence increase in the 700 nm emission channel (i.e., 5 and 15 minutes) probably due to monophosphorylation, followed by a later (i.e., 30 and 45 minutes) fluorescence enhancement in both channels, which could correspond to diphosphorylation of the compound. - To assess the retention of dichromic fluorescence in vivo, 2 nmol of symmetrical ICG (compound 2) and nonsymmetrical cypate-S (compound 3) were each injected intravenously in a nude mouse. Mouse ears were imaged with a Li-Cor Odyssey system at two excitation (680 nm and 780 nm) and emission (700 and 800 nm) channels. The results are shown in
FIG. 13 . The blood vessels were clearly seen in both channels for the nonsymmetrical compound (3). In contrast, ICG (2) showed the blood vessels only at the 800 nm channel, with autofluorescence dominating the 700 nm channel. Thus, the dual fluorescence contrast mechanism is tenable in vivo.
Claims (20)
A-L-B
A-L-B
A-L-B
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/370,758 US20090214436A1 (en) | 2008-02-18 | 2009-02-13 | Dichromic fluorescent compounds |
US15/090,055 US11406719B2 (en) | 2008-02-18 | 2016-04-04 | Dichromic fluorescent compounds |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2941208P | 2008-02-18 | 2008-02-18 | |
US2964408P | 2008-02-19 | 2008-02-19 | |
US12/370,758 US20090214436A1 (en) | 2008-02-18 | 2009-02-13 | Dichromic fluorescent compounds |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/090,055 Continuation US11406719B2 (en) | 2008-02-18 | 2016-04-04 | Dichromic fluorescent compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US20090214436A1 true US20090214436A1 (en) | 2009-08-27 |
Family
ID=56407007
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/370,758 Abandoned US20090214436A1 (en) | 2008-02-18 | 2009-02-13 | Dichromic fluorescent compounds |
US15/090,055 Active US11406719B2 (en) | 2008-02-18 | 2016-04-04 | Dichromic fluorescent compounds |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/090,055 Active US11406719B2 (en) | 2008-02-18 | 2016-04-04 | Dichromic fluorescent compounds |
Country Status (1)
Country | Link |
---|---|
US (2) | US20090214436A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090124792A1 (en) * | 2007-08-15 | 2009-05-14 | Washington University In St. Louis | Fluorescent polymethine cyanine dyes |
WO2011152046A1 (en) * | 2010-05-31 | 2011-12-08 | 国立大学法人千葉大学 | Fluorescent probe for imaging lymph nodes |
WO2017123052A1 (en) * | 2016-01-14 | 2017-07-20 | 한국과학기술원 | Photodegradable nanoparticles for imaging and multiple phototherapy, and uses thereof |
WO2018119476A1 (en) | 2016-12-23 | 2018-06-28 | The Board Of Trustees Of The Leland Stanford Junior University | Activity-based probe compounds, compositions, and methods of use |
WO2018183960A1 (en) * | 2017-03-30 | 2018-10-04 | The Board Of Trustees Of The Leland Stanford Junior University | Protease-activated contrast agents for in vivo imaging |
US10806804B2 (en) | 2015-05-06 | 2020-10-20 | Washington University | Compounds having RD targeting motifs and methods of use thereof |
US10904518B2 (en) | 2012-01-23 | 2021-01-26 | Washington University | Goggle imaging systems and methods |
US11406719B2 (en) | 2008-02-18 | 2022-08-09 | Washington University | Dichromic fluorescent compounds |
US11712482B2 (en) | 2019-12-13 | 2023-08-01 | Washington University | Near infrared fluorescent dyes, formulations and related methods |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102015014560A1 (en) * | 2015-11-11 | 2017-05-11 | Giesecke & Devrient Gmbh | Pigment system, luminescence color system and value document |
Citations (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4987021A (en) * | 1986-02-28 | 1991-01-22 | Olympus Optical Co., Ltd. | Optical information recording medium |
US5107063A (en) * | 1990-10-31 | 1992-04-21 | E. I. Du Pont De Nemours And Company | Aqueous soluble infrared antihalation dyes |
US5268486A (en) * | 1986-04-18 | 1993-12-07 | Carnegie-Mellon Unversity | Method for labeling and detecting materials employing arylsulfonate cyanine dyes |
US5290670A (en) * | 1991-07-19 | 1994-03-01 | Minnesota Mining And Manufacturing Company | Silver halide photographic elements |
US5508161A (en) * | 1992-03-30 | 1996-04-16 | Fuji Photo Film Co., Ltd. | Photographic silver halide photosensitive material |
US5589250A (en) * | 1993-04-12 | 1996-12-31 | Ibiden Co., Ltd. | Resin compositions and printed circuit boards using the same |
US5955224A (en) * | 1997-07-03 | 1999-09-21 | E. I. Du Pont De Nemours And Company | Thermally imageable monochrome digital proofing product with improved near IR-absorbing dye(s) |
US6027709A (en) * | 1997-01-10 | 2000-02-22 | Li-Cor Inc. | Fluorescent cyanine dyes |
US20020028474A1 (en) * | 1996-09-19 | 2002-03-07 | Daiichi Pure Chemical Co., Ltd. | Composition for immunohistochemical staining |
US6652835B1 (en) * | 1999-07-29 | 2003-11-25 | Epix Medical, Inc. | Targeting multimeric imaging agents through multilocus binding |
US20040014981A1 (en) * | 2000-09-19 | 2004-01-22 | Lugade Ananda G. | Cyanine dyes |
US6747159B2 (en) * | 2001-01-03 | 2004-06-08 | Giuseppe Caputo | Symmetric, monofunctionalised polymethine dyes labelling reagents |
US7172907B2 (en) * | 2003-03-21 | 2007-02-06 | Ge Healthcare Bio-Sciences Corp. | Cyanine dye labelling reagents with meso-substitution |
US20070042398A1 (en) * | 2005-06-30 | 2007-02-22 | Li-Cor, Inc. | Cyanine dyes and methods of use |
US20090028788A1 (en) * | 2005-01-21 | 2009-01-29 | Washington University In St. Louis | Compounds having rd targeting motifs |
US7547721B1 (en) * | 1998-09-18 | 2009-06-16 | Bayer Schering Pharma Ag | Near infrared fluorescent contrast agent and fluorescence imaging |
US20100215585A1 (en) * | 2006-08-03 | 2010-08-26 | Frangioni John V | Dyes and precursors and conjugates thereof |
US7850946B2 (en) * | 2003-05-31 | 2010-12-14 | Washington University In St. Louis | Macrocyclic cyanine and indocyanine bioconjugates provide improved biomedical applications |
US20100323389A1 (en) * | 2009-04-17 | 2010-12-23 | Li-Cor, Inc. | Fluorescent imaging with substituted cyanine dyes |
US8344158B2 (en) * | 2007-08-15 | 2013-01-01 | Washington University | Fluorescent polymethine cyanine dyes |
Family Cites Families (78)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5254852A (en) | 1992-05-28 | 1993-10-19 | Night Vision General Partnership | Helmet-mounted night vision system and secondary imager |
JPH06145539A (en) | 1992-11-04 | 1994-05-24 | Fuji Photo Film Co Ltd | Cyanine compound |
JPH0772446A (en) | 1993-09-01 | 1995-03-17 | Sharp Corp | Display system |
US5453505A (en) | 1994-06-30 | 1995-09-26 | Biometric Imaging, Inc. | N-heteroaromatic ion and iminium ion substituted cyanine dyes for use as fluorescence labels |
US5518934A (en) | 1994-07-21 | 1996-05-21 | Trustees Of Princeton University | Method of fabricating multiwavelength infrared focal plane array detector |
DE4445065A1 (en) | 1994-12-07 | 1996-06-13 | Diagnostikforschung Inst | Methods for in-vivo diagnostics using NIR radiation |
US6032070A (en) | 1995-06-07 | 2000-02-29 | University Of Arkansas | Method and apparatus for detecting electro-magnetic reflection from biological tissue |
US5959705A (en) | 1996-03-15 | 1999-09-28 | Osd Envizion, Inc. | Welding lens with integrated display, switching mechanism and method |
DE19649971A1 (en) | 1996-11-19 | 1998-05-28 | Diagnostikforschung Inst | Optical diagnostics for the diagnosis of neurodegenerative diseases using near-infrared radiation (NIR radiation) |
AU7221698A (en) | 1997-04-29 | 1998-11-24 | Nycomed Imaging As | Light imaging contrast agents |
AU7221398A (en) | 1997-04-29 | 1998-11-24 | Nycomed Imaging As | Method of demarcating tissue |
JP2000095758A (en) | 1998-09-18 | 2000-04-04 | Schering Ag | Near-infrared, fluorescent contrast medium, and its production |
US6217848B1 (en) | 1999-05-20 | 2001-04-17 | Mallinckrodt Inc. | Cyanine and indocyanine dye bioconjugates for biomedical applications |
WO2001005161A1 (en) | 1999-07-13 | 2001-01-18 | Surgivision Ltd. | Stereoscopic video observation and image magnification system |
US6944493B2 (en) | 1999-09-10 | 2005-09-13 | Akora, Inc. | Indocyanine green (ICG) compositions and related methods of use |
YU44402A (en) | 1999-12-15 | 2005-03-15 | Schering Aktiengesellschaft | Near infrared fluorescent contrast agent and fluorescence imaging |
US20110213625A1 (en) | 1999-12-18 | 2011-09-01 | Raymond Anthony Joao | Apparatus and method for processing and/or for providing healthcare information and/or helathcare-related information |
US6180085B1 (en) | 2000-01-18 | 2001-01-30 | Mallinckrodt Inc. | Dyes |
US6395257B1 (en) | 2000-01-18 | 2002-05-28 | Mallinckrodt Inc. | Dendrimer precursor dyes for imaging |
US6180086B1 (en) | 2000-01-18 | 2001-01-30 | Mallinckrodt Inc. | Hydrophilic cyanine dyes |
US6554444B2 (en) | 2000-03-13 | 2003-04-29 | Kansai Technology Licensing Organization Co., Ltd. | Gazing point illuminating device |
JP2001299676A (en) | 2000-04-25 | 2001-10-30 | Fuji Photo Film Co Ltd | Method and system for detecting sentinel lymph node |
US7345277B2 (en) | 2000-08-09 | 2008-03-18 | Evan Zhang | Image intensifier and LWIR fusion/combination system |
US6487428B1 (en) | 2000-08-31 | 2002-11-26 | Trustees Of The University Of Pennsylvania | Extravasation detection apparatus and method based on optical sensing |
US6663847B1 (en) | 2000-10-13 | 2003-12-16 | Mallinckrodt Inc. | Dynamic organ function monitoring agents |
US6673334B1 (en) | 2000-10-16 | 2004-01-06 | Mallinkcrodt, Inc. | Light sensitive compounds for instant determination of organ function |
US7556797B2 (en) | 2000-10-16 | 2009-07-07 | Mallinckrodt Inc. | Minimally invasive physiological function monitoring agents |
US6733744B1 (en) | 2000-10-16 | 2004-05-11 | Mallinckrodt Inc. | Indole compounds as minimally invasive physiological function monitoring agents |
US6585660B2 (en) | 2001-05-18 | 2003-07-01 | Jomed Inc. | Signal conditioning device for interfacing intravascular sensors having varying operational characteristics to a physiology monitor |
US20030105299A1 (en) * | 2001-10-17 | 2003-06-05 | Mallinckrodt Inc. | Carbocyanine dyes for tandem, photodiagnostic and therapeutic applications |
US6761878B2 (en) | 2001-10-17 | 2004-07-13 | Mallinckrodt, Inc. | Pathological tissue detection and treatment employing targeted benzoindole optical agents |
JP2003261464A (en) * | 2002-03-07 | 2003-09-16 | Fuji Photo Film Co Ltd | Near infrared fluorescent contrast agent and fluorescent contrast radiography |
US7134994B2 (en) | 2002-05-20 | 2006-11-14 | Volcano Corporation | Multipurpose host system for invasive cardiovascular diagnostic measurement acquisition and display |
WO2004065491A1 (en) | 2003-01-24 | 2004-08-05 | Schering Ag | Hydrophilic, thiol-reactive cyanine dyes and conjugates thereof with biomolecules for fluorescence diagnosis |
US20040215081A1 (en) | 2003-04-23 | 2004-10-28 | Crane Robert L. | Method for detection and display of extravasation and infiltration of fluids and substances in subdermal or intradermal tissue |
US8675059B2 (en) | 2010-07-29 | 2014-03-18 | Careview Communications, Inc. | System and method for using a video monitoring system to prevent and manage decubitus ulcers in patients |
US20060173351A1 (en) | 2005-01-03 | 2006-08-03 | Ronald Marcotte | System and method for inserting a needle into a blood vessel |
US20060173360A1 (en) | 2005-01-07 | 2006-08-03 | Kalafut John F | Method for detection and display of extravasation and infiltration of fluids and substances in subdermal or intradermal tissue |
US20090268983A1 (en) | 2005-07-25 | 2009-10-29 | The Regents Of The University Of California | Digital imaging system and method using multiple digital image sensors to produce large high-resolution gapless mosaic images |
US7211778B1 (en) | 2005-10-07 | 2007-05-01 | Itt Manufacturing Enterprises, Inc. | Night vision goggle with separate camera and user output paths |
US7826890B1 (en) | 2005-12-06 | 2010-11-02 | Wintec, Llc | Optical detection of intravenous infiltration |
EP2007273B1 (en) | 2006-04-07 | 2017-01-25 | Novarix Ltd. | Vein navigation device |
US9229230B2 (en) | 2007-02-28 | 2016-01-05 | Science Applications International Corporation | System and method for video image registration and/or providing supplemental data in a heads up display |
US7923801B2 (en) | 2007-04-18 | 2011-04-12 | Invisage Technologies, Inc. | Materials, systems and methods for optoelectronic devices |
US20090074672A1 (en) | 2007-09-17 | 2009-03-19 | Sri International | Tumor Boundary Imaging |
US20090093761A1 (en) | 2007-10-05 | 2009-04-09 | Sliwa John W | Medical-procedure assistance device and method with improved optical contrast, and new practitioner-safety, device-fixation, electrode and magnetic treatment and lumen-dilation capabilities |
US8849380B2 (en) | 2007-11-26 | 2014-09-30 | Canfield Scientific Inc. | Multi-spectral tissue imaging |
US20100113940A1 (en) | 2008-01-10 | 2010-05-06 | The Ohio State University Research Foundation | Wound goggles |
WO2009089543A2 (en) | 2008-01-10 | 2009-07-16 | The Ohio State University Research Foundation | Fluorescence detection system |
US20090214436A1 (en) | 2008-02-18 | 2009-08-27 | Washington University | Dichromic fluorescent compounds |
US20090242797A1 (en) | 2008-03-31 | 2009-10-01 | General Electric Company | System and method for multi-mode optical imaging |
US8840249B2 (en) | 2008-10-31 | 2014-09-23 | Christie Digital Systems, Inc. | Method, system and apparatus for projecting visible and non-visible images |
SG173567A1 (en) | 2009-02-06 | 2011-09-29 | Beth Israel Hospital | Charge-balanced imaging agents |
US20100240988A1 (en) | 2009-03-19 | 2010-09-23 | Kenneth Varga | Computer-aided system for 360 degree heads up display of safety/mission critical data |
KR101190265B1 (en) | 2009-06-30 | 2012-10-12 | 고려대학교 산학협력단 | Head mouted operating magnifying apparatus |
US8498694B2 (en) | 2009-07-13 | 2013-07-30 | Entrotech, Inc. | Subcutaneous access device and related methods |
US8586924B2 (en) | 2010-09-13 | 2013-11-19 | Lawrence Livermore National Security, Llc | Enhancement of the visibility of objects located below the surface of a scattering medium |
US9105548B2 (en) | 2011-06-22 | 2015-08-11 | California Institute Of Technology | Sparsely-bonded CMOS hybrid imager |
CA2844135A1 (en) | 2011-08-01 | 2013-02-07 | Infrared Imaging Systems, Inc. | Disposable light source for enhanced visualization of subcutaneous structures |
WO2013028963A1 (en) | 2011-08-24 | 2013-02-28 | Volcano Corporation | Medical communication hub and associated methods |
EP3338617B1 (en) | 2012-01-23 | 2020-08-19 | Washington University | Goggle imaging systems and devices |
US20130317373A1 (en) | 2012-03-12 | 2013-11-28 | Ivwatch, Llc | System for Mitigating the Effects of Tissue Blood Volume Changes to Aid in Diagnosing Infiltration or Extravasation in Animalia Tissue |
US20140046291A1 (en) | 2012-04-26 | 2014-02-13 | Evena Medical, Inc. | Vein imaging systems and methods |
US20140039309A1 (en) | 2012-04-26 | 2014-02-06 | Evena Medical, Inc. | Vein imaging systems and methods |
US20140200438A1 (en) | 2012-12-21 | 2014-07-17 | Volcano Corporation | Intraluminal imaging system |
US9486143B2 (en) | 2012-12-21 | 2016-11-08 | Volcano Corporation | Intravascular forward imaging device |
WO2014099935A1 (en) | 2012-12-21 | 2014-06-26 | Volcano Corporation | System and method for multi-site intravascular measurement |
WO2014100207A1 (en) | 2012-12-21 | 2014-06-26 | Paul Hoseit | Imaging guidewire with photoactivation capabilities |
US10058284B2 (en) | 2012-12-21 | 2018-08-28 | Volcano Corporation | Simultaneous imaging, monitoring, and therapy |
US20140194704A1 (en) | 2012-12-21 | 2014-07-10 | Volcano Corporation | Intraluminal imaging system |
WO2014099942A1 (en) | 2012-12-21 | 2014-06-26 | Volcano Corporation | Display control for a multi-sensor medical device |
US20140180316A1 (en) | 2012-12-21 | 2014-06-26 | Volcano Corporation | Imaging and removing biological material |
US20140275950A1 (en) | 2013-03-13 | 2014-09-18 | Volcano Corporation | Imaging guidewire with pressure sensing |
US20140276110A1 (en) | 2013-03-14 | 2014-09-18 | Volcano Corporation | Imaging guidewire system with flow visualization |
JP2016515876A (en) | 2013-03-15 | 2016-06-02 | ボルケーノ コーポレイション | Universal patient interface module and related apparatus, system, and method |
US11001562B2 (en) | 2013-10-31 | 2021-05-11 | Beth Israel Deaconess Medical Center | Near-infrared fluorescent nerve contrast agents and methods of use thereof |
WO2016179350A1 (en) | 2015-05-06 | 2016-11-10 | Washington University | Compounds having rd targeting motifs and methods of use thereof |
US10209242B2 (en) | 2015-05-21 | 2019-02-19 | Emit Imaging, Inc. | Fluorescence histo-tomography (FHT) systems and methods |
-
2009
- 2009-02-13 US US12/370,758 patent/US20090214436A1/en not_active Abandoned
-
2016
- 2016-04-04 US US15/090,055 patent/US11406719B2/en active Active
Patent Citations (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4987021A (en) * | 1986-02-28 | 1991-01-22 | Olympus Optical Co., Ltd. | Optical information recording medium |
US5268486A (en) * | 1986-04-18 | 1993-12-07 | Carnegie-Mellon Unversity | Method for labeling and detecting materials employing arylsulfonate cyanine dyes |
US5107063A (en) * | 1990-10-31 | 1992-04-21 | E. I. Du Pont De Nemours And Company | Aqueous soluble infrared antihalation dyes |
US5290670A (en) * | 1991-07-19 | 1994-03-01 | Minnesota Mining And Manufacturing Company | Silver halide photographic elements |
US5508161A (en) * | 1992-03-30 | 1996-04-16 | Fuji Photo Film Co., Ltd. | Photographic silver halide photosensitive material |
US5589250A (en) * | 1993-04-12 | 1996-12-31 | Ibiden Co., Ltd. | Resin compositions and printed circuit boards using the same |
US20020028474A1 (en) * | 1996-09-19 | 2002-03-07 | Daiichi Pure Chemical Co., Ltd. | Composition for immunohistochemical staining |
US6027709A (en) * | 1997-01-10 | 2000-02-22 | Li-Cor Inc. | Fluorescent cyanine dyes |
US5955224A (en) * | 1997-07-03 | 1999-09-21 | E. I. Du Pont De Nemours And Company | Thermally imageable monochrome digital proofing product with improved near IR-absorbing dye(s) |
US7547721B1 (en) * | 1998-09-18 | 2009-06-16 | Bayer Schering Pharma Ag | Near infrared fluorescent contrast agent and fluorescence imaging |
US6652835B1 (en) * | 1999-07-29 | 2003-11-25 | Epix Medical, Inc. | Targeting multimeric imaging agents through multilocus binding |
US20040014981A1 (en) * | 2000-09-19 | 2004-01-22 | Lugade Ananda G. | Cyanine dyes |
US6747159B2 (en) * | 2001-01-03 | 2004-06-08 | Giuseppe Caputo | Symmetric, monofunctionalised polymethine dyes labelling reagents |
US7172907B2 (en) * | 2003-03-21 | 2007-02-06 | Ge Healthcare Bio-Sciences Corp. | Cyanine dye labelling reagents with meso-substitution |
US7850946B2 (en) * | 2003-05-31 | 2010-12-14 | Washington University In St. Louis | Macrocyclic cyanine and indocyanine bioconjugates provide improved biomedical applications |
US20090028788A1 (en) * | 2005-01-21 | 2009-01-29 | Washington University In St. Louis | Compounds having rd targeting motifs |
US20070042398A1 (en) * | 2005-06-30 | 2007-02-22 | Li-Cor, Inc. | Cyanine dyes and methods of use |
US20100215585A1 (en) * | 2006-08-03 | 2010-08-26 | Frangioni John V | Dyes and precursors and conjugates thereof |
US8344158B2 (en) * | 2007-08-15 | 2013-01-01 | Washington University | Fluorescent polymethine cyanine dyes |
US20130116403A1 (en) * | 2007-08-15 | 2013-05-09 | The Washington University | Fluorescent polymethine cyanine dyes |
US20100323389A1 (en) * | 2009-04-17 | 2010-12-23 | Li-Cor, Inc. | Fluorescent imaging with substituted cyanine dyes |
Non-Patent Citations (2)
Title |
---|
Achilefu et al. Synergistic effects of light-emitting probes and peptides for targeting and monitoring integrin expression - ARTICLE + SUPPORTING INFORMATION. PNAS 102(22) 7976-81 (2005). * |
Ito et al. Development of Fluorescence-Emitting Antibody Labeling Substance by Near-Infrared Ray Excitation. Bioorganic & Medicinal Chemistry Letters, Vol. 5, No. 22, pp. 2689-2694 (1995). * |
Cited By (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090124792A1 (en) * | 2007-08-15 | 2009-05-14 | Washington University In St. Louis | Fluorescent polymethine cyanine dyes |
US8344158B2 (en) * | 2007-08-15 | 2013-01-01 | Washington University | Fluorescent polymethine cyanine dyes |
US11406719B2 (en) | 2008-02-18 | 2022-08-09 | Washington University | Dichromic fluorescent compounds |
JP6057710B2 (en) * | 2010-05-31 | 2017-01-11 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Fluorescent probe for lymph node imaging |
WO2011152046A1 (en) * | 2010-05-31 | 2011-12-08 | 国立大学法人千葉大学 | Fluorescent probe for imaging lymph nodes |
US9302018B2 (en) | 2010-05-31 | 2016-04-05 | Eisai R&D Management Co., Ltd. | Fluorescent probe for imaging lymph nodes |
EP2579027A4 (en) * | 2010-05-31 | 2016-06-15 | Eisai R&D Man Co Ltd | Fluorescent probe for imaging lymph nodes |
US20160222211A1 (en) * | 2010-05-31 | 2016-08-04 | Eisai R&D Management Co., Ltd. | Fluorescent Probe for Imaging Lymph Nodes |
JP2017075937A (en) * | 2010-05-31 | 2017-04-20 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Fluorescent probe for imaging lymph nodes |
US9957392B2 (en) * | 2010-05-31 | 2018-05-01 | Eisai R&D Management Co., Ltd. | Fluorescent probe for imaging lymph nodes |
TWI499427B (en) * | 2010-05-31 | 2015-09-11 | Eisai R&D Man Co Ltd | Fluorescent probes for imaging lymph nodes |
CN103038629A (en) * | 2010-05-31 | 2013-04-10 | 国立大学法人千叶大学 | Fluorescent probe for imaging lymph nodes |
US10904518B2 (en) | 2012-01-23 | 2021-01-26 | Washington University | Goggle imaging systems and methods |
US11310485B2 (en) | 2012-01-23 | 2022-04-19 | Washington University | Goggle imaging systems and methods |
US11765340B2 (en) | 2012-01-23 | 2023-09-19 | Washington University | Goggle imaging systems and methods |
US11413359B2 (en) | 2015-05-06 | 2022-08-16 | Washington University | Compounds having RD targeting motifs and methods of use thereof |
US10806804B2 (en) | 2015-05-06 | 2020-10-20 | Washington University | Compounds having RD targeting motifs and methods of use thereof |
WO2017123052A1 (en) * | 2016-01-14 | 2017-07-20 | 한국과학기술원 | Photodegradable nanoparticles for imaging and multiple phototherapy, and uses thereof |
CN110023740A (en) * | 2016-12-23 | 2019-07-16 | 里兰斯坦福初级大学理事会 | Based on active probe compound, composition and its application method |
US10869936B2 (en) | 2016-12-23 | 2020-12-22 | The Board Of Trustees Of The Leland Stanford Junior University | Activity-based probe compounds, compositions, and methods of use |
JP2020515507A (en) * | 2016-12-23 | 2020-05-28 | ザ ボード オブ トラスティーズ オブ ザ リーランド スタンフォード ジュニア ユニバーシティ | Activity-based probe compounds, compositions, and methods of use |
AU2020286325B2 (en) * | 2016-12-23 | 2022-02-03 | The Board Of Trustees Of The Leland Stanford Junior University | Activity-based probe compounds, compositions, and methods of use |
EP3510380A4 (en) * | 2016-12-23 | 2020-05-27 | The Board of Trustees of the Leland Stanford Junior University | Activity-based probe compounds, compositions, and methods of use |
WO2018119476A1 (en) | 2016-12-23 | 2018-06-28 | The Board Of Trustees Of The Leland Stanford Junior University | Activity-based probe compounds, compositions, and methods of use |
AU2022202947B2 (en) * | 2016-12-23 | 2023-11-16 | The Board Of Trustees Of The Leland Stanford Junior University | Activity-based probe compounds, compositions, and methods of use |
EP4310504A2 (en) | 2016-12-23 | 2024-01-24 | The Board of Trustees of the Leland Stanford Junior University | Activity-based probe compounds, compositions, and methods of use |
CN110678460A (en) * | 2017-03-30 | 2020-01-10 | 里兰斯坦福初级大学理事会 | Protease activated contrast agents for in vivo imaging |
WO2018183960A1 (en) * | 2017-03-30 | 2018-10-04 | The Board Of Trustees Of The Leland Stanford Junior University | Protease-activated contrast agents for in vivo imaging |
US11828752B2 (en) | 2017-03-30 | 2023-11-28 | The Board Of Trustees Of The Leland Stanford Junior University | Protease-activated contrast agents for in vivo imaging |
US11712482B2 (en) | 2019-12-13 | 2023-08-01 | Washington University | Near infrared fluorescent dyes, formulations and related methods |
Also Published As
Publication number | Publication date |
---|---|
US11406719B2 (en) | 2022-08-09 |
US20160206758A1 (en) | 2016-07-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11406719B2 (en) | Dichromic fluorescent compounds | |
Yang et al. | Small-molecule fluorescent probes for imaging gaseous signaling molecules: current progress and future implications | |
Zhou et al. | An APN-activated NIR photosensitizer for cancer photodynamic therapy and fluorescence imaging | |
Martynov et al. | Synthetic fluorophores for visualizing biomolecules in living systems | |
Fan et al. | Water-soluble BODIPY and aza-BODIPY dyes: synthetic progress and applications | |
Rich et al. | Elimination of autofluorescence background from fluorescence tissue images by use of time-gated detection and the AzaDiOxaTriAngulenium (ADOTA) fluorophore | |
Izumi et al. | A simple and effective strategy to increase the sensitivity of fluorescence probes in living cells | |
Xing et al. | Recent advances in quinazolinones as an emerging molecular platform for luminescent materials and bioimaging | |
CN106929003B (en) | A kind of multi-functional near infrared fluorescent probe and its preparation method and application | |
KR20180108697A (en) | Chemiluminescent probes for diagnostic and in-vivo imaging | |
EP2686385A2 (en) | Activatable fluorogenic compounds and uses thereof as near infrared probes | |
US20090124792A1 (en) | Fluorescent polymethine cyanine dyes | |
US9745318B2 (en) | Fluorescent red emitting functionalizable calcium indicators | |
Wang et al. | Recent progress in H 2 S activated diagnosis and treatment agents | |
Patsenker et al. | Fluorescent reporters for drug delivery monitoring | |
US20090215105A1 (en) | Tetraazaporphyrin-Based Compounds and Their Uses | |
Onoe et al. | Development of photostabilized asymmetrical cyanine dyes for in vivo photoacoustic imaging of tumors | |
Qiao et al. | Small-molecule probes for fluorescent detection of cellular hypoxia-related nitroreductase | |
Karaman et al. | Xanthene dyes for cancer imaging and treatment: A material odyssey | |
US11746094B2 (en) | Small molecule photosensitizers for photodynamic therapy | |
US20210040326A1 (en) | Azacyanine dyes and use thereof | |
Jiang et al. | Chemical Approaches to Optimize the Properties of Organic Fluorophores for Imaging and Sensing | |
WO2014160671A1 (en) | Fluorescent markers and methods for imaging diseases | |
Patel et al. | Impact of Substituents in Tumor Uptake and Fluorescence Imaging Ability of Near‐Infrared Cyanine‐like Dyes | |
Hu et al. | An advanced multifunctional prodrug combining photodynamic therapy with chemotherapy for highly efficient and precise tumor ablation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF Free format text: EXECUTIVE ORDER 9424, CONFIRMATORY LICENSE;ASSIGNOR:WASHINGTON UNIVERSITY;REEL/FRAME:022481/0162 Effective date: 20090327 |
|
AS | Assignment |
Owner name: WASHINGTON UNIVERSITY, MISSOURI Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ACHILEFU, SAMUEL I., PHD;ZHANG, ZONGREN;BEREZIN, MIKHAIL Y.;REEL/FRAME:022683/0179 Effective date: 20090504 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |
|
AS | Assignment |
Owner name: NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR, MA Free format text: CONFIRMATORY LICENSE;ASSIGNOR:WASHINGTON UNIVERSITY;REEL/FRAME:042822/0684 Effective date: 20170612 |