CA2423806A1 - Modified carbocyanine dyes and their conjugates - Google Patents

Modified carbocyanine dyes and their conjugates Download PDF

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CA2423806A1
CA2423806A1 CA 2423806 CA2423806A CA2423806A1 CA 2423806 A1 CA2423806 A1 CA 2423806A1 CA 2423806 CA2423806 CA 2423806 CA 2423806 A CA2423806 A CA 2423806A CA 2423806 A1 CA2423806 A1 CA 2423806A1
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alkyl
sulfo
amino
independently
compound
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CA2423806C (en
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Wai-Yee Leung
Ching-Ying Cheung
Stephen Yue
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Molecular Probes Inc
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Molecular Probes, Inc.
Wai-Yee Leung
Ching-Ying Cheung
Stephen Yue
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Abstract

Chemically reactive carbocyanine dyes incorporating an indolium ring moiety that is substituted at the 3-position by a reactive group or by a conjugated substance, and their uses, are described. Conjugation through this position results in spectral properties that are uniformly superior to those of conjugates of spectrally similar dyes wherein attachment is at a different position. The invention includes derivative compounds having one or more benzo nitrogens.

Claims (42)

1. A compound of the formula:
and its salts, wherein R3 is -L-R x; or -L-S c; and R4 is independently -L-R x; or -L-S c; or a C1-C22 alkyl or C7-C22 arylalkyl, each alkyl portion of which optionally incorporates up to six hetero atoms, selected from N, O and S, and each alkyl portion of which is optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxy, sulfo, phosphate, amino, sulfate, phosphonate, cyano, nitro, azido, C1-C6 alkoxy, C1-C6 alkylamino, or C2-C12 dialkylamino, or C3-C18 trialkylammonium; or R3 and R4 taken in combination complete a five- or six-membered saturated or unsaturated ring that is substituted by -L-R x; or -L-S c; and L is a single covalent bond, or a covalent linkage that is linear or branched, cyclic or heterocyclic, saturated or unsaturated, having 1-16 nonhydrogen atoms selected from the group consisting of C, N, P, O, and S, such that the linkage contains any combination of ether, thioether, amine, ester, amide bonds; or single, double, triple or aromatic carbon-carbon bonds; or phosphorus-oxygen, phosphorus-sulfur, nitrogen-nitrogen, nitrogen-oxygen, or nitrogen-platinum bonds; or aromatic or heteroaromatic bonds;
R x is a reactive group;
S c is a conjugated substance;

Y represents the atoms necessary to form one to two fused aromatic rings having 6 atoms in each ring, which atoms are selected from -CH, -C, -CR1, and -N(R2).beta., where each .beta. is 0 or 1, and each R1 is independently -L-R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;
each R2, when present (where .alpha. or .beta. is 1), is independently -L-R x;
or -L-S c; or a C1-C22 alkyl or C7-C22 arylalkyl, each alkyl portion of which optionally incorporates up to six hetero atoms, selected from N, O and S, and each alkyl portion of which is optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxy, sulfo, phosphate, amino, sulfate, phosphonate, cyano, nitro, azido, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, or C3-C18 trialkylammonium;
.alpha. is 0 or 1, and .alpha. + all .beta. = 1; and W represents the atoms necessary to form one to two fused aromatic rings having 6 atoms in each ring, which atoms are selected from -CH, -C, -CR1', and -N(R12).beta.', where each .beta.' is 0 or 1, and each R1' is independently -L-R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;
each R12, when present (where .delta. or .beta.' is 1), is independently -L-R
x; or -L-S c; or is a C1-C22 alkyl or C7-C22 arylalkyl, each alkyl portion of which optionally incorporates up to six hetero atoms, selected from N, O and S, and each alkyl portion of which is optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxy, sulfo, phosphate, amino, sulfate, phosphonate, cyano, nitro, azido, C1-C6 alkoxy, C1-alkylamino, C2-C12 dialkylamino, or C3-C18 trialkylammonium;
.delta. is 0 or 1, and .delta. + all .beta.' = 1;
Z is O, S, or CR13R14;

R13 and R14 are independently -L-R x ; or -L-S c ; or a C1-C22 alkyl or C7-C22 arylalkyl, each alkyl portion of which optionally incorporates up to six hetero atoms, selected from N, O and S, and each alkyl portion of which is optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxy, sulfo, phosphate, amino, sulfate, phosphonate, cyano, nitro, azido, C1-C6 alkoxy, C1-C8 alkylamino, or C2-C12 dialkylamino, or C3-C18 trialkylammonium; or R13 and R14 taken in combination complete a five- or six-membered saturated or unsaturated ring that is optionally substituted by -L-R x; or -L-S c;
n is 1, 2 or 3; and each R21, R22, and R23 is independently H, F, Cl, C1-C6 alkyl, C1-C6 alkoxy, aryloxy, a nitrogen heterocycle, an iminium ion, -L-R x, or -L-S c; or any two adjacent substituents of R21, R22, R23, when taken in combination, forms a 4-, 5-, or 6-membered saturated or unsaturated hydrocarbon ring that is optionally substituted one or more times by C1-C6 alkyl, halogen, or a carbonyl oxygen; or R21 taken in combination with R4 forms a 6-membered ring that is optionally substituted by C1-C6 alkyl; or one of R23, whichever is adjacent to Z, taken in combination with one of R13 and R14 forms a 6-membered ring that is optionally substituted by C1-C6 alkyl.
2. A compound, as claimed in Claim 1, wherein the atoms of Y are selected from -CH, -C, and -CR1, where each R1 is independently -L-R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C8 alkyl, C1-C8 alkoxy, C1-C6 alkylamino, dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;
.alpha. is 1;
the atoms of W are selected from -CH, -C, -CR1', and -N(R12).beta.', where each .beta. is 0 or 1, and each R1' is independently -L-R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;

each R2 and R12 is independently -L-R x; or -L-S c; or a C1-C22 alkyl, which optionally incorporates up to six hetero atoms, and is optionally substituted;
.delta. is 0 or 1, and .delta. + all .beta.'= 1; and .delta. is 1 only if W
does not contain any ring nitrogen atoms;
Z is CR13R14.
3. A compound, as claimed in Claim 2, wherein the atoms of W are selected from -CH, -C, -CR1', and -N(R12).beta.', where .beta.' is 1, but no more than one of the atoms in W is -N(R12).beta.', and each R1' is independently -L-R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;
and .delta. is 0.
4. A compound, as claimed in Claim 2, wherein the atoms of W are selected from -CH, -C, and -CR1', and each R1' is independently -L-R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;
.delta. is 1.
5. A compound, as claimed in Claim 2, wherein R3 is -L-R x; or -L-S c; and R4 is independently a C1-C6 alkyl, which is optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxy, sulfo, or amino;
the atoms of Y are selected from -CH, -C, and -CR1, where each R1 is independently -L-R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;

the atoms of W are selected from -CH, -C, -CR1', and -N(R12).beta.', where each .beta.' is 0 or 1, but no more than one of such atoms is -N(R12).beta.', and each R1' is independently -L-R x;
or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;

R2 and R12 are independently -L-R x; or -L-S c; or is a C1-C6 alkyl, which is optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxy, sulfo, or amino;
one of R13 and R14 is a C1-C6 alkyl and the other of R13 and R14 is -L-R x; or -L-S c ; or a C1-C22 alkyl, which is optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxy, sulfo, phosphate, amino, sulfate, phosphonate, cyano, nitro, azido, alkoxy, C1-C6 alkylamino, or C2-C12 dialkylamino;

each of R21, R22, and R23 are H; or any two adjacent substituents of R21, R22, R23, when taken in combination, forms a 4-, 5-, or 6-membered saturated or unsaturated hydrocarbon ring that is optionally substituted one or more times by C1-C6 alkyl, halogen, or a carbonyl oxygen.
6. A compound, as claimed in Claim 1, wherein R3 is -L-R x; and R4 is independently a C1-C22 alkyl, which optionally incorporates up to six hetero atoms, and is optionally substituted; or R3 and R4 taken in combination complete a five- or six-membered saturated or unsaturated ring that is substituted by -L-R x; and each R x is a reactive group that is independently an acrylamide, an activated ester of a carboxylic acid, an acyl azide, an acyl nitrile, an aldehyde, an alkyl halide, an anhydride, an aniline, an aryl halide, an azide, an aziridine, a boronate, a carboxylic acid, a diazoalkane, a haloacetamide, a halotriazine, a hydrazine (including hydrazides), an imido ester, an isocyanate, an isothiocyanate, a maleimide, a phosphoramidite, a reactive platinum complex, a sulfonyl halide, a thiol group, or a photoactivatable group;

no more than one of the atoms within Y is -N(R2).beta., and each R1 is independently -L-R x;
or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy; and each S c is a conjugated substance that is an amino acid, peptide, polypeptide, protein, nucleotide, oligonucleotide, nucleic acid polymer, a sugar, a polysaccharide, an oligosaccharide, a fluorescent dye, or a microsphere;
.alpha. is only 1 when Y contains no ring nitrogen atoms, no more than one of the atoms within W is -N(R12).beta.', and each R1' is independently -L--R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;
R2 and R12 are independently -L-R x; or -L-S c; or is a C1-C22 alkyl, which optionally incorporates up to six hetero atoms, and is optionally substituted;
.delta. is 1 only if W does not contain any ring nitrogen atoms;
Z is CR13R14;
R13 and R14 are independently -L-R x ; or -L-S c; or a C1-C22 alkyl, which optionally incorporates up to six hetero atoms, is optionally substituted;

or R13 and R14 taken in combination complete a five- or six-membered saturated or unsaturated ring that is optionally substituted by -L-R x; or -L-S c; and R21, R22, and R23 are independently H, F, Cl, C1-C6 alkyl, C1-C6 alkoxy, aryloxy, a nitrogen heterocycle, an iminium ion, -L-R x, or -L-S c.
7. A compound, as claimed in Claim 1, wherein R3 is -L-S c; and R4 is independently a C1-C22 alkyl, which optionally incorporates up to six hetero atoms, and is optionally substituted; or R3 and R4 taken in combination complete a five- or six-membered saturated or unsaturated ring that is substituted by -L-S c; and L is a single covalent bond, or a covalent linkage and S c is a conjugated substance that is an antibody, an amino acid, an angiostatin or endostatin, an avidin or streptavidin, a biotin, a blood component protein, a dextran, an enzyme, an enzyme inhibitor, a hormone, an IgG-binding protein, a fluorescent protein, a growth factor, a lectin, a lipopolysaccharide, a metal-binding protein, a microorganism or portion thereof, a neuropeptide, a non-biological microparticle, a nucleotide, an oligonucleotide, a peptide toxin, a phospholipid-binding protein, a small-molecule drug, a structural protein, or a tyramide;
no more than one of the atoms within Y is -N(R2).beta., and each R1 is independently -L-R x;
or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy; and -R x is a reactive group that is an activated ester of a carboxylic acid, an amine, a carboxylic acid, a halotriazine, a hydrazide, a maleimide, a reactive platinum complex; and a is only 1 when Y contains no ring nitrogen atoms, no more than one of the atoms within W is -N(R12).beta.', and each R1' is independently -L--R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;
R2 and R12 are independently -L-R x; or -L-S c; or is a C1-C22 alkyl, which optionally incorporates up to six hetero atoms, and is optionally substituted;
.delta. is 1 only if W does not contain any ring nitrogen atoms;
Z is CR13R14;
R13 and R14 are independently -L-R x; or -L-S c; or a C1-C22 alkyl, which optionally incorporates up to six hetero atoms, is optionally substituted;
or R13 and R14 taken in combination complete a five- or six-membered saturated or unsaturated ring that is optionally substituted by -L-R x; or -L-S c; and R21, R22, and R23, are independently H, F, Cl, C1-C6 alkyl, C1-C6 alkoxy, aryloxy, a nitrogen heterocycle, an iminium ion, -L-R x, or -L-S c.
8. A compound, as claimed in any of Claims 1-7, wherein L is a covalent linkage that is linear or branched, cyclic or heterocyclic, saturated or unsaturated, having 1-16 nonhydrogen atoms selected from the group consisting of C, N, P, O, and S, and incorporating the formula -(CH2)d(CONH(CH2)e)2'-, where d is 0-5, e is 1-5 and z' is 0 or 1, such that the linkage contains any combination of ether, thioether, amine, ester, amide bonds; or single, double, triple or aromatic carbon-carbon bonds; or phosphorus-oxygen, phosphorus-sulfur, nitrogen-nitrogen, nitrogen-oxygen, or nitrogen-platinum bonds; or aromatic or heteroaromatic bonds.
9. A compound, as claimed in any of Claims 1-8, wherein, R21, R22, and R23 are H.
10. A compound, as claimed in any of Claims 1-9, wherein S c is a conjugated substance that is an actin, an antibody or fragment thereof, an avidin or streptavidin, a biotin, a dextran, an enzyme, a fluorescent protein, a lectin, a lipopolysaccharide, a microorganism, a non-biological microparticle, a nucleotide, an oligonucleotide, a peptide toxin, a phosphotidylserine-binding protein, a protein A
or G, a small-molecule drug, or a tyramide.
11. A compound, as claimed in any of Claims 1-10, wherein the atoms of Y are selected from -CH, -C, and -CR1, where R1 is sulfo.
12. A compound, as claimed in any of Claims 1-3 and 5-11, wherein the atoms of W
are selected from -CH, -C, -CR1', and -N(R12).beta.', where each R1' is sulfo or Br.
13. A compound, as claimed in any of Claims 1-12, wherein R2 and R12 are independently a C1-C6 alkyl or C1-C6 alkyl substituted by sulfo.
14. A compound, as claimed in any of Claims 1-13, wherein, R13 and R14 are independently C1-C6 alkyl.
15. A compound of the formula and its salts, wherein R3 is -L-R x; or -L-S c; and R4 is a C1-C22 alkyl, and is optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxy, sulfo, phosphate, amino, sulfate, phosphonate, cyano, nitro, azido, C1-C6 alkoxy, C1-C6 alkylamino, or C2-C12 dialkylamino, or C3-C18 trialkylammonium; or R3 and R4 taken in combination complete a five- or six-membered saturated or unsaturated ring that is substituted by -L-R x; or -L-S
c; and L is a single covalent bond, or a covalent linkage that is linear or branched, cyclic or heterocyclic, saturated or unsaturated, having 1-16 nonhydrogen atoms selected from the group consisting of C, N, P, O, and S, such that the linkage contains any combination of ether, thioether, amine, ester, amide bonds; or single, double, triple or aromatic carbon-carbon bonds; or phosphorus-oxygen, phosphorus-sulfur, nitrogen-nitrogen, nitrogen-oxygen, or nitrogen-platinum bonds; or aromatic or heteroaromatic bonds;
R x is a reactive group;
S c is a conjugated substance;
R6 through R9 and R16 through R18 are independently H, -L-R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy; or any two adjacent substituents of R6 through R9 form a fused benzo ring that is optionally substituted one or more times by -L-R x; or by -L-S c; or by amino, sulfo, trifluoromethyl, or halogen; or by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;
R2 and R12 are independently a C1-C6 alkyl or C1-C6 alkyl substituted by sulfo;
R13 and R14 are independently a C1-C6 alkyl;
n is 1, 2 or 3.
16. A compound, as claimed in Claim 15, wherein R17 is H or Br, and R16 and R18 are H.
17. A compound of the formula and its salts, wherein R3 is -L-R x; or -L-S c; and R4 is a C1-C22 alkyl, and is optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxy, sulfo, phosphate, amino, sulfate, phosphonate, cyano, nitro, azido, C1-C6 alkoxy, C1-C6 alkylamino, or C2-C12 dialkylamino, or C3-C18 trialkylammonium; or R3 and R4 taken in combination complete a five- or six-membered saturated or unsaturated ring that is substituted by -L-R x; or -L-S
c; and L is a single covalent bond, or a covalent linkage that is linear or branched, cyclic or heterocyclic, saturated or unsaturated, having 1-16 nonhydrogen atoms selected from the group consisting of C, N, P, O, and S, such that the linkage contains any combination of ether, thioether, amine, ester, amide bonds; or single, double, triple or aromatic carbon-carbon bonds; or phosphorus-oxygen, phosphorus-sulfur, nitrogen-nitrogen, nitrogen-oxygen, or nitrogen-platinum bonds; or aromatic or heteroaromatic bonds;
R x is a reactive group;
S c is a conjugated substance;
R6 through R9 and R16 through R19 are independently H, -L-R x; or -L-S c; or amino, sulfo, trifluoromethyl, or halogen; or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy; or any two adjacent substituents of R6 through R9 and R16 through form a fused benzo ring that is optionally substituted one or more times by -L-R x; or by -L-S c; or by amino, sulfo, trifluoromethyl, or halogen; or by C1-C6 alkyl, alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy;
R2 and R12 are independently a C1-C6 alkyl or C1-C6 alkyl substituted by sulfo;
R13 and R14 are independently a C1-C6 alkyl;
n is 1, 2 or 3.
18. A compound, as claimed in Claim 17, wherein R17 is H, sulfo, or Br, and R16, R18, and R19 are H.
19. A compound, as claimed in any of Claims 15-18, wherein R7 is sulfo, and R6, R8, and R9 are H; or R6 and R7 combine to form a fused benzo ring that is substituted one or more times by sulfo, and R8 and R9 are H.
20. A compound, as claimed in any of Claims 1-19, wherein, L is a covalent linkage that incorporates the formula -(CH2)d(CONH(CH2)e)z,-, or -(CH2)d(CON(CH2)4NH(CH2)e)z,-, -(CH2)d(CONH(CH2)e NH2)z,-, -(CH2)d(CONH(CH2)e NHCO)-z,, where d is 0-5, e is 1-5 and z' is 0 or 1;
21. A compound, as claimed in any of Claims 1-20, wherein R4 is a C1-C6 alkyl.
22. A compound, as claimed in any of Claims 1-6 and 8-20, wherein there is only one R x on the compound and it is an activated ester of a carboxylic acid, an amine, a carboxylic acid, a halotriazine, a hydrazide, a maleimide, or a reactive platinum complex.
23. A compound, as claimed in any of Claims 1-22, where -L is -(CH2)d(CONH(CH2)e)z,-.
24. A compound, as claimed in any of Claims 1-23, wherein -Rx is a carboxylic acid, or a succinimidyl ester of a carboxylic acid, or a maleimide.
25. A compound, as claimed in any of Claims 1-4 and 6-21, wherein S c is a conjugated substance that is an antibody or fragment thereof, a fluorescent protein, a lectin, an oligonucleotide, a small-molecule drug, or a tyramide.
26. A compound, as claimed in any of Claims 1-25, where n=1.
27. A compound, as claimed in any of Claims 1-25, where n=2.
28. A compound, as claimed in any of Claims 1-25, where n=3.
29. A compound of the formula and its salts, wherein R3 is -L-R x or -L-S c; and R4, R13, and R14 are methyl;
L is a covalent linkage that is -(CH2)5(CONH(CH2)e)Z,-, e is 1-5 and z' is 0 or 1;
Rx is a reactive group that is a carboxylic acid, a succinimidyl ester of a carboxylic acid or a maleimide;
S c is a conjugated substance that is an antibody or fragment thereof, a fluorescent protein, a lectin, a nucleotide, an oligonucleotide, a peptide, a small-molecule drug, or a tyramide;
R2 and R12 are independently methyl or sulfopropyl;
R7 and R17 are sulfo, and R6, R8 , R9, R16, R18, and R19 are H; and n is 1.
30. A compound of the formula:

and its salts, wherein R3 is -L-R x or -L-Sc; and R4, R13, and R14 are methyl;
L is a covalent linkage that is -(CH2)5(CONH(CH2)e)Z; , e is 1-5 and z' is 0 or 1;
R x is a reactive group that is a carboxylic acid, a succinimidyl ester of a carboxylic acid or a maleimide;
S c is a conjugated substance that is an antibody or fragment thereof, a fluorescent protein, a lectin, a nucleotide, an oligonucleotide, a peptide, a small-molecule drug, or a tyramide;
R2 and Rl2 are independently methyl or sulfopropyl;
R7 and R17 are sulfo, and R6, R8 , R9, R16, R18, and R19 are H; and n is 2.
31. A compound of the formula:

and its salts, wherein R3 is -L-R I or -L-S c; and R4, R13, and R14 are methyl;
L is a covalent linkage that is -(CH2)5(CONH(CH2)e)Z'-, e is 1-5 and z' is 0 or 1;
R x is a reactive group that is a carboxylic acid, a succinimidyl ester of a carboxylic acid or a maleimide;

S c is a conjugated substance that is an antibody or fragment thereof, a fluorescent protein, a lectin, a nucleotide, an oligonucleotide, a peptide, a small-molecule drug, or a tyramide;
R2 and R12 are independently methyl or sulfopropyl;
R7 and R17 are sulfo, and R6, R8 , R9, R16, R18, and R19 are H;
n is 3.
32. A compound of the formula:

and its salts, wherein R3 is -L-R x or -L-S c; and R4, R13 and R14 are methyl;
L is a covalent linkage that is -(CH2)5(CONH(CH2)e)Z'-, e is 1-5 and z' is 0 or 1;
Rx is a reactive group that is a carboxylic acid, a succinimidyl ester of a carboxylic acid or a maleimide;

S c is a conjugated substance that is an antibody or fragment thereof, a fluorescent protein, a lectin, a nucleotide, an oligonucleotide, a peptide, a small-molecule drug, or a tyramide;
R6, R8, R9, R16, R17 and R18 are H; R7 is sulfopropyl;
R2 and R19 are independently methyl or sulfopropyl;
n is 2.
33. A compound of the formula:

and its salts, wherein R3 is -L-R x or -L-S c; and R4, R13 and R14 are methyl;
L is a covalent linkage that is -(CH2)5(CONH(CH2)e)Z'-, e is 1-5 and z' is 0 or 1;
R x is a reactive group that is a carboxylic acid, a succinimidyl ester of a carboxylic acid or a maleimide;

Sc is a conjugated substance that is an antibody or fragment thereof, a fluorescent protein, a lectin, a nucleotide, an oligonucleotide, a peptide, a small-molecule drug, or a tyramide;
R6, R8, R9, R16, and R18 are H; R7 is sulfo; R17 is Br;
R2 and R12 are independently methyl or sulfopropyl;
n is 2.
34. A compound of the formula:

and its salts, wherein R3 is -L-R x or -L-S c; and R4, R13 and R14 are methyl;

L is a covalent linkage that is -(CH2)5(CONH(CH2)e)Z'-, e is 1-5 and z' is 0 or 1;
R X is a reactive group that is a carboxylic acid, a succinimidyl ester of a carboxylic acid or a maleimide;
S c is a conjugated substance that is an antibody or fragment thereof, a fluorescent protein, a lectin, a nucleotide, an oligonucleotide, a peptide, a small-molecule drug, or a tyramide;
R6 and R7 combine to form a fused benzo ring, which benzo ring is substituted meta and para to R7 attachment site by sulfo; R8, R9, R16, and R18 are H; R17 is Br;
R2 and R12 are independently methyl or sulfopropyl;
n is 2.
35. A method of staining a biological sample, comprising:
combining a dye solution comprising any of the dyes described in Claims l-34, with a biological sample in a concentration sufficient to yield a detectable optical response under the desired conditions.
36. A method, as claimed in Claim 43, wherein the sample comprises cells.
37. A method, as claimed in Claim 43, wherein the sample comprises proteins or nucleic acid polymers in a microarray.
38. A method, as claimed in Claim 43, wherein the sample comprises a ligand that is a member of a specific binding pair, for which S c is a complementary member.
39. A method, as claimed in any of Claims 35-38, wherein the sample is contained in or on a solid or semi-solid matrix that is a membrane, an electrophoretic gel, a silicon chip, a glass slide, a microwell plate, or a microfluidic chip.
40. A kit for fluorescent labeling of a biological sample, comprising a dye solution comprising any of the compound described in Claims 1-34, or its salts;
and a buffer suitable for use with such sample.
41. A compound of the formula:

and its salts, wherein R3 is C3-C7 carboxyalkyl; and R4 is a C1-C6 alkyl;
R2 is H or a C1-C6 alkyl or C1-C6 alkyl substituted by sulfo.

R6 through R9 are independently H, amino, sulfo, trifluoromethyl, or halogen;
or C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy; or any two adjacent substituents of R6 through R9 form a fused benzo ring that is optionally substituted one or more times by amino, sulfo, trifluoromethyl, or halogen; or by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C12 dialkylamino, each of which is optionally further substituted by carboxy, sulfo, amino, or hydroxy.
42. A compound, as claimed in Claim 41, wherein R3 is C5-C6 carboxyalkyl; and R4 is methyl;
R2 is methyl or sulfopropyl;
R6 and R7 form a fused benzo ring that is optionally substituted one or more times by sulfo; or R7 is independently H or sulfo, and R6 is H; both R8 and R9 are H.
CA 2423806 2000-09-29 2001-09-28 Modified carbocyanine dyes and their conjugates Expired - Lifetime CA2423806C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US23663700P 2000-09-29 2000-09-29
US60/236,637 2000-09-29
US27687001P 2001-03-16 2001-03-16
US60/276,870 2001-03-16
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