CA2114156C

CA2114156C - Elucidation and synthesis of selected pentapeptides

Info

Publication number: CA2114156C
Application number: CA002114156A
Authority: CA
Inventors: George R. Pettit; Jayaram K. Srirangam
Original assignee: Arizona Board of Regents of University of Arizona
Current assignee: Arizona Board of Regents of University of Arizona
Priority date: 1993-01-26
Filing date: 1994-01-25
Publication date: 2001-01-02
Anticipated expiration: 2014-01-25
Also published as: JPH08119990A; EP0612762A1; DE69407322T2; US5780588A; EP0612762B1; ATE161270T1; DE69407322D1; CA2114156A1

Abstract

The sea hare Dolabella auricularia has yielded many structurally distinct peptides which possess antineoplastic activity. Presently the compound denominated "dolastatin 10" represents then most important of such peptides because of its demonstrated potential as an anticancer drug.
The present invention relates to the systematic creation of five unique pentapeptides by selectively coupling a tripeptide - trifluoroacetate salt with a preselected dipeptide-trifluoroacetate salt which provide active molecules capable of emulating the measured therapeutic effect of dolastatin 10. The pentapeptides hereof have the structure shown below:
wherein R is selected from the following group of substituents:

Description

2~i~~.~b ELUCIDATION AND ;aYNTHESIS OF
SELECTED PENT~1PEPTIDES
INTRODUC~1~; ION
This inv~ntion relates generaa.ly to ttxe field o~ anta.-neop:last:tc campounds, and more part:Lcularly 'to thQ elucidation and svynthesis of s~alected pentapeptides prepared by coupling dipeptide salts with the known tripeptide-trifluoroacetate salt.
More particularly, the present invention relates to :LO the synthesis of five pentapeptides by the coupling of a tri.peptide-trifluoroacetate salt with the respective dipeptide-trifluoroacetate salt, which was itself prepared by the coupling of dolaproine with the respective amino acid. This coupling results in compounds which are found to exhibit effective antineoplastic activity against various human cancerous tumor cell :Lines.
BACKGROUND OF THE INVENTTON
Ancient marine invertebrate species of the 20 Phyla Br~ozoa, Molluska, and Porifera have been well established in the oceans for over one billion years. Such organisms have undergone trillions of biosynthetic reactions in their evolutionary chemistry to reach their prEasent level of cellular organization, regulation and defense.
For example, marine sponges have changed minimally in physical appearance for nearly 500 million years. This suggests a very effective chemical resistance to evolution in response to 30 changing environmental conditions over that period of time. Recognition of the potential for utilizing this biologically potent marine animal for medicinal purposes was a.°ecorded in Egypt about 2,700 BC and by 200 BC sea hare extracts wez~e being used in Greece for their curative affect. This consideration along with the observation that marine animals, e.g. invertebrates and sharks, rarely develop cancer led to the systematic investigation of marine animal and plant anticancer compounds .
By 1~GF3 lmple cwidence had been obtaanec.~, bused on the U.S. National Dancer :Lnst3.tute's (NC:L) ltay experimenta:L cancer study systems, 'that certain marine organisms could provide new and antineoplastic and/or cytotoxic agents and might also lead to compounds which would be effective in the control and/or eradication of viral diseases.
Further, these marine organisms were believed to possess potentially useful drug candidates of unprecedented structure which had eluded discovery by other methods of medicinal chemistry.
Fortunately, these expectations have been realized, e.g, the discovery of the b:ryostatins, dolastatins and cephalostatins, many of which are now in preclinical development or human clinical studies.
Those researchers presently involved in medicinal chemistry know well the time lag between the isolation of a new compound and its introduction to the market. Often this procedure takes several years and may take decades. As a result, industry, in association with the U.S.
Government, has developed a system of testing criteria which serves two purposes. One is to eliminate those substances which are shown through testing to be economically counterproductive. The ~ second, more important purpose serves to identify those compounds which demonstrate a high likelihood of success and therefore warrant the further study and qualification, and attendant expense, necessary to meet the stringent regulatory requirements which control the ultimate market place.
The current cost to develop the necessary data approaches ten million dollars per compound. As such, economics dictate that such a huge investment will be made only when there is a reasonable opportunity for it to bye recovered. Absent such opportunity, there will be no investment and the research involving the discovery of these potentially life saving compounds will cease. Only two hundred years ago many diseases ravaged mankind. Many of these now have been controlled or eradicated. During the advancement of'means to treat or eliminate these diseases, work with appropriate animals was of critical importance.
Current research in,the control of cancer in the United States is coordinated by the National Cancer Institute (NCI). To determine whether a substance has anti-cancer properties, the NCI has established a systematic protocol. This protocol, which involves the testing of a substance against a _.--- standard sell line panel containing 60 human tumor cell lines, has been verified and has been accepted in scientific circles. The protocol, and the established statistical means for analyzing the results obtained by the standardized testing are fully described in the literature. See: Boyd, Dr.
Michael R., ,rincigles & Practice of Oncology, PPO
Updates, Volume 3, Number 10, October 1989, for an in depth description of the testing protocol; and Paull, K. D., "Display and Analysis of Patterns of Differential Activity of Drugs Against Human Tumor Cell Lines. Development of Mean Graph and COMPARE
- 30 Algorithm", Journal of the National Cancer Institute Reports, Vol. 81, No. 14, Page 1088, July 14, 1989 for a description of the methods of statistical analysis.
Numerous substances have been discovered which demonstrate significant antineoplastic or tumor inhibiting characteristics. As stated above, many of these compounds have been extracted, albeit with great difficulty, from marine animals such as the sponge and sea hare. Once isolation and testing of these compounds has been accomplished, a practical question remains, namely how to produce commercially significant quantities of the desired substance.
Quinine, which is available in practical quantities from the bark of the cinchona plant, differs from the compounds which are extracts of marine creatures possessing antineoplastic l0 qualities. The collection and processing of these later compounds from their natural sources ranges from grossly impractical,to the utterly impossible.
Ignoring the ecological impact, the population of these creatures and the cost of collection and extraction make the process unworkable. Artificial synthesis of the active compounds is the only possible solution.
Therefore, the elucidation of the structure of these antineoplastic compounds is essential. After 20 the structure has been determined, then a means of synthesis must be determined. This is often a long and arduous procedure due to the idiosyncratic complexity of these naturally occurring, ~- evolutionary modified compounds. In addition, research is necessary to determine whether any portion of the naturally occurring compound is irrelevant to the desired properties, so that focus can be on the simplest structure having the perceived properties.

BRIEF SUMMARY OF THE INVENTION
The synthesis of potentially useful peptides presents one of the most essential and promising approaches to new types of anticancer and immunosuppressant drugs. The Dolastatins, an unprecedented series of linear and cyclic antineoplastic and/or cytostatic peptides isolated from Indian Ocean sea hare Dolabe» a au i >>a is represent excellent leads for synthetic modification. The very productive sea hare Dolabe~~a auriculariA has produced a number of structurally distinct peptides with .excellent antineoplastic activity. Presently Dolastatin 10, a linear pentapeptide represents the most important member and is a potentially useful antineoplastic agent. Dolastatin 10 shows one of the bast antineoplastic activity profiles against various cancer screens presently known.
This research has led to an effective method ~) i !R ~ ~~
da ~ ~'-for the synthesis of new and very potent anti-cancer pentapeptides related in structure to Dolastat:in 10. ~l'he presea~t :i.nventi.on involves the s'truc'ture and synthesis of :f:ive such pen ta,pe,ptides as shown below, I_I Cth ttsC
\N Co-N oo_N N ~c:o-R
CHI III , ( ~ OCf I3 CIh UCFI~ O
3(a-e) ,',' I;
\ c) R .= N COOCH3 ~) R =
~N COOCEI~ II3C CEt~
F-I d) R=
-N COOCIIs H
\ CH3 ~) R= ~ S
e) R=
-N CONC-i~

I-I
Accordingly, the primary object of the subject invention is the synthesi;~ of five pentapeptide derivatives of dolastat9_n 10 which exhibit effective antineoplastic activity against various human cancerous tumor cell lines.
Another obj ect of the :>ubj ect inventic>n is the synthesis of pentapeptide derivatives of dolastatin 10 through the coupling o:E respective tripeptide and dipeptide trifluoroacetate salts, whe:re.i.n the dipeptide salt was prepared by the coug~ling of dolaproine and the respective amino acid.
These and still further objects as shall .
hereinafter appear are readily fulfilled by the present invention in a remarkably unexpected manner as will be readily discerned from the fol:Lowing detailed description of an exemplary embodiment thereo:E .
DESGRIF'!,'ION OF THE PREFERRED EMBODIMEINT
The synthesis of potentially useful peptides presents one of the most ~assential and promising approaches to new types of anticancer and immunosuppressant drugs. The Dolastatins, an unprecedented series of linear and cyclic antineoplastic and/or cyto:;tatic peptides isolated from Indian Ocean sea hare Dolabella auricularia represent excellent leads fox synthetic modification. The very productive sea hare Dolabella auricularia has produced a number of structurally distinct peptides with esccellent antineoplastic activity. Presently Dolastatin 10, a linear pentapeptide represents the most important member and is a potentially useful antineoplastic agent. Dolastatin 10 shows one of the best antineoplastic activity profiles against various cancer screens presently known. Recently the total synthesis and absolute configuration of 'this structurally unique and bio:Logically active peptide was reported. This compound has been tested in vivo and demonstrated significant activity, as shown below.

Experimental Anticancer Acaivity of Dolastatin 10 in Murine in vivo Systems, T/C (~tg/kg) P388 L~ym~phocytic Leukemia Human Mammary Xenograph tC)X:LC (13.U) Ntlde MousQ
155 and 17% cures (6.5) Toxic (26) 146 anel 17% cures (3.25) 137 (13) 137 (1.63) 178 (6.25) T.1210 OVCAR-3 Human Ovary Xenograph Lymphocytic Leukemia 10152(13) Nude Mouse 135 (6.5) 300 (40) 139 (3.25) 120 (1.63) MX-1 Human Mammary Xenograft B16 Melanoma (Tumor Regression) 238 and 40% cures (11.11) 14 (52) 182 (6.67) 50 (26) 205 (4.0) 67. (13) 171 (3.4) 69 (6.25) 142 (1.44) 20M5076 Ovarv Sarcoma toxic (26) 166 (13) 142 (6.5) 151 (3.25) LOX Human Melanoma Xenograph to (Nude Mouse) toxic (52) 301 and 67% cures (26) 309. and 50% cures (13) 30206 and 33% cures (6.5) 170 and 17% cures (3.25) LOX in separate experiments 340 and 50% cures (43) 181 and 33% cures (26) 192 (15) 138 and 17% cures (9.0) ~~ ~~t~
Dolastatin 10 has also been tested against a minipanel from the NCt Primary screen. These results appear below, showing the amount of Dolastatin 10 required to attain GISO in ygJml, against 'the cell lines set forth below.
. 5 x:10 7 . 5 x:l2 . 5 x10' 3 . h x10-"
KM20L2 (E) SK-MEL-5 ~.7 x10 7.~ x10'a l0 From the foregoing, it can be seen that the in vitro activity of dolastatin 10 in the primary screen has been confirmed by in vivo animal tests.
For the compounds disclosed i.n this application, the in vitro tests disclosed above are reasonably accurate predictors of anticancer activity, and not mere indicators of the desirability for further testing.
These newly discovered pentapeptide Compounds (~a-3a), related to Dolastatin l0, are formed by 20 the coupling of the respective dipeptide fluoroacetate salts (2a-2e) with the known tripeptide-trifluoroacetate salt (.4). The dipeptides (1a-~.~) were in turn prepared by coupling dolaproine (5) with the respective amino acids. All compounds were characterized (physical and spectroscopic data) and tested against the marine lymphocytic P388 leukemia cell line as well as six major human cancer cell lines. The remarkable cancer cell growth inhibitory data are 30 shown in Table 1.

~~~4~'~~
'I'nblc 1. Intent inhibitinn of f:nnccr cell IIItes by I)entnpeptidcs :In-c 'ffl5'fCl.:!.1~'I'YI'L(:L'L,L.I.INIi~ 1'I'sN'fr\1'I:1''CIU!:
-StR/nti~ 3 :S ;) J 3 a a b c rl ~usoMouse L-EUKGbIfAP3R8 O.U6ti')O.Ol9S11.00880.0004410.11110389 ~

OvarianOVCr\R-:S<(l,Il0010.0076<0.0001<O.UU()l<(1.0001 .

CNS SF-29S<0.00(Il11,00085<0.1100)<O,OOOI<O,OOU1 OI-50Rcnai A-498 <O.U0010.00_097<O.OOOI<O.DOUI<0.0(lOl Lure-NSCNCI-II~460<O.OOOI0.000095<11,U001<O.OOUI<0,0001 Colon KM20L2<0.11001<0,(1(101<O.OOUI<0.0(lOt<0.0(10l MclanotnaSK-MEL-3<0.00010.00017<(1.0001<0.0001<0.0001 OvarianOVCAR-3U.DOII0.()077<O.OOOI<O.OOOI<0.0001 C~VS 29S 0.000170.049 0.(10240.17 (1.OS6 SP- -'COIRennl A498 0.0029O.U062(1.0054<0.0001>l Lunc-NSCNCI-11460O.Ol1O.OII 0.00130.0110890.13 Colon KM20I.211.00110.11190.0022<(1.OOOl0.00015 McinnomnSK-MEL-3(1.00068O.Ol2 <O,OUOI<0.0001>l OvnrinnOVC;1R-3>l 0.066 >l 0.043>1 (J1S SF-295>I >l >1 >l >l ' LC-50Renal A498 >l >I >l >l >l Lane-NSCNCI-H460>l >I >1 >i >I

Colon KM20L2>l O.OR3 >.l >l >i MelanomaSK-MEL-3>I >1 >l >I >l The human cancer cell lines results shown for pentapeptides 3a-a in Table I illustrate remarkably patent and selective activity against human ovary, CNS (brain), kidney, lung, colon and melanoma type cancers. In this respect, each compound parrots a pattern previously discovered for Dolastatin 10 and as such is reasonably expected to generate pn vivo data results comparable to those reported above for Dolastatin 10. .
The scheme and structures of these penta-peptides appear below:

~~~~~~.1 I-I CH3 H CI.I3 COOII Amino acid salt ~ \ TTIIfn0InilCCtiC
N ~ i . CO-l2 acid COQIInt OCI~Ig c OCEI
COOl3n L(n-e) I-I CI~I3 1 II~C
\N~ CO-N CO-N COON
CO-R III
/ ,\ ,,, CF~C00' Cf-I3 HI CII~ OCH3 Ei H
CF3C00' OCH3 ~
2(n~e) II CHI
H3C~ ,~
N 'CO-R
CO-i CO-N

CH3 H ~H3 OCI-h O OCI-I
3(a.e) s ~ 1, I3 c) R = N ~COOCH3 a) R = a ~N COOCH3 FI3C' \CII
H
R=
/ ~ ~N,r H COOCHj v b) R= ~ /CH3 S
e) R=
~,N~ CONI-IZ
s H SCIICMr I ~ I COOCFI3 21:x. 4 ~.
General Procedure for the Synthesis of Di;psptides (1a-9.e) To a solution of dolapro:ine tfa salt (:Lmmol) and 'the amino ac:Ld salt (lmmol) in dry dichloro-methane (2m1) , cooled to ice-bath temperature under an argon atmosphere was added dry triethy:lamine (3rnmo1) followed by diethylcyanophophonate ( 1. lmmol ) . The solution Hras stirred at the same ice bath temperature for 1.-2 hr. The salts that precipitated were collected, the solvent was evaporated (under reduced pressure) and the residue chromatographed over a SILICA GEL column with solvents noted to obtain the respective dipeptides.
i) Hoa-Dap-Phe-OCH3 (la):
Chromatographic separation on a SThICA GEL
column with 3:1 hexane-acetone as the eluent .resulted in the required dipeptide as a thick oil.
Crystallization from ether-hexane gave sparkling crystals of the pure compound (la, 96%) ~ m.p. -125°Cp [a]p 5 - -15.1° (c 0.41, CHC13) ; IR(~thin film): 3314, 2974, 2934, 2878, 1748, 1692, 1663, 1537, 1456, 1400, 1366, 1173, 1101 and 700; ~H NMR
(300MHz, CDC13): 1.163(d, J=7.OHz, 3H, CH3), 1. 4316 (s, 9H, t-Bu) , 1. 624-1. 850 (m, 4H, 2 x CHz) , 2.25-2.45(m, 1H, CHCO), 3.045(dd, J=13.9 and 7.8Hz, 1H, 1/2 CHz-Ph) , 3. 175 (dd, J=13. 8 and 5.55Hz, 1H, 1/2 CHz-Ph), 3.3642(x, 3H, OCH3), 3.3701(s, 3H, OCH3), 3.50-3.60(m, 1H, CH-OCH3), 3.7422(m, 2H, CHZ-N) , 3 . 85 (m, 1H, pro CH-N) , 4 . 80 (m, 1FI, phe ' CH-N), 6.10, 6.75(m, 1H, NH) and 7.10-7.32(:m, 5H, Ph); MS: m/z 416[M-CH30H], 375, 316, 264, 210, 170, 114(1000 and 70. Anal. Found: H: 8.12, N: 6.20.
Cz4H36NZ06 requires H: 8.09, N: 6.25.
ii) Boa-Dap-Phs-NHz (1b):
Chromatographic purification using a STLICA
GEL column with 1:1 hexane-acetone as the eluent 2~.~.4~1~i~
gave the required dipeptide: as a crystalline solid.
Recrystallization from aicetone gave sparkling crystals of the pure compound ( ~.b, 65 0 ) ; m. p.
199-200°C (acetone); [a]p2' _ -40° (c 0.15, CHCI~);
IR(thin film): 3302, 3198, 2974, 2934, 2878, 1669, 1539, 1456, 1404, 1366, 1169, 1111 and 700; ~H NMR
(300MHz, CDC13) : 1.019 (brs, 3H, CII3) , 1.426 (s, 9H, t-Bu) , 1. 55-1. 90 (m, 4H, 2 x CFIZ) , 2 . 30 (quintFt, 1H, CFI-CO) , 3. 00-3 . 25 (m, 3H, C;HZ-N, CH-OCHj) , 3. 349 (s, 3Ii, OCH~), 3.60-3.75(m, 1H, pro CH-N), 4.60-4.80(m, 1H, phe CH-N) , 5. 30 (brs, 1H, NH) , 6. 267 (d, J=7. 2I-Iz, 1H, NH), 6.90(brm, 1H, NH) and 7.164-7.306(m, 5H, CbHs); MS: m/z 433(M+), 401(M-MeOH), 360, 301, 247, 232, 210, 170, 154, 138, 114 and 70(100%). Anal.
Found: C: 63.75, H:8.18, N:9.62. C23H35N305 requires C: 63.72, H: 8.14, N: 9.69.
iii) Boc-Dap-Pro-OCH3 (1a);;
Chromatographic sepana~tion on a SILICA GEL
column with 3:2 hexane-aceaone as the eluent gave the required dipeptide as a thick oil (1a, 92% );
[a]p5 - -101.5° (c 0,2, CHC13); IR(neat): 2974, 2880, 1748, 1692, 1647, 1398, 1366, 1171andl 1098; ~H
NMR (300MHz, CDC13): 1.222(d, J=7.OHz, 3H, CH3), 1.440(s, 9H, t-Bu), 1.65-2.20(m, 8H, 4 x CHZ), 2.60-2.70(m, 1H, CH-CO), 3.10-3.22(m, 1H, CH-OCH3), 3 . 417 (s, 3H, CH3) , 3 . 45-3 . 65 (m, 4H, 2 x CHZ-N) , 3.675(s, 3H, OCH3), 3.74-3.83(m, 1H, CH-N) and 4.447 (dd, J=8. 55 and 3 . 5Hz, 1H, CH-COOCH3) . HRFABMS:
m/z 399.24880[M+H]ø. CzoH35N206 requires 399.26951.
' iv) Boc-Dap-Ile-OCH3 (1d):
Chromatographic purification on a SILICA GEL
column with 3:2 hexane-ethyl acetate, as the eluent yielded the required dipeptide as an oily liquid 1d, 720) ; m.p. -- 76-77°C (acetone) ; Ca]D S = -28°2°
(c 0.17, CHC13) ; IR(thin film) : 3325, 2971, 2936, 2878, 1746, 1694, 1667, :L530, 1478, 1398, 1254, 1175, 1105, 868 and 774; ~H NMR (300MHz, CDC13):

0.882(d, J=6.9Hz, 3H, CH3-CH), 0.9012(t, J=7.4Hz, 3H, CH3-CHZ) , 1. 05-1. 24 (m, 5H, CH3, CHz-CH3) , 1.4526(s, 9H, t-Bu), 1.65-2.00(m, 5FI, x CHZ

CIA-CH2~, 2 . 30-2 . 50 (m, 1FI, CH-CO) , 3 . 18-3 . 28 (:m, 1FI, C~-OCH3) , 3. 422 (s, 3FI, OCEI3) , 3 .48-3.1H, 60 (m, pro _C~,[-N) , 3 . 699 (s, 3FI, OCFI3) , 3.72-3.1FI, 82 (m, 1/2 CFIz-N) , 3 .88-3.98 (m, 1FI, 1/2 CFIz-N) , 4.44-4 . 58 (m, 1FI, ].le CH-N) and 6. 15, 6.7 (m, 1FI, MS:
NFI) ; m/z 382(M-MeOFI), 341, 282, 245, 230, 210, 170, 114, 70(100%) and 57. Anal. Found: C: 61.06,9.25, FI: N:

6.64. CZ~H3aN206 requires C: 60.84, H: N: 6.76.
9.24, v) Boo-Dap-Met-OCH3 (le):
Chromatographic separation on a SILICA GEL
column using 3:2 hexane-acetone as 'the eluent gave the required dipeptide as a solid (le, 83%); m.p. -68-70°C; [a]pzs = -27.6° (c, 0.59, CHC13); IR(neat):
3312, 2974, 2934, 2878, 1748, 1692, 1663, 1539, 1398, 1366, 1256, 1171, 1115, 866 and 774; ~H NMR
(CDC13) : 1. 223 (brs, 3H, CH-CFI3) , 1. 441 (brs, 9H, t-Bu), 1.6-1.2(m, 6H, 3xCHz), 2.070 (s, 3H, S-CH3), 2.3--2.55(m, 3H, CHZ-S, CH-CO), 3.15-3.35 (m, 2H, N-CHZ) , 3. 420 (s, 3H, OCH3) , 3.55 (m, 1H, CFI-OCH~) , 3.716(brs, 3H, COOCH3), 3.85-4.0(m, 1FI, pro CH-N), 4.6(brm, 1H, met CH-N), 6.3(brm, 1H, NH); MS (m/z):
432 (M+), 400, 359, 258, 210, 170,114(100%). Anal.
Found: C: 55.35, H: 8.33, N: 6.53, S: 7.23. CZOH36Nz06 S requires C: 55.53, H: 8.39, N: 6.48, S: 7.41.
Synthesis of phenylalanine amide trifluoroacetate salt:
' To a solution of t-boc-phenylalanine amide (3, 80mg, 0.303mmo1) in dichloromethane (0.5m1) was added trifluoroacetic acid (lml) at ice-bath temperature and the solution was stirred at the same temperature for 1.5 hr. under argon atmosphere. The solvents were removed under reduced pressure and the residue taken into toluene and toluene also removed under. reduced pressure to obtain a white solid of the trifluoroacetate salt 2~~ l~~'~)~
(80mg, 95~); ~H NMR (DMSO-d6, 300MHz): 2.95-3.10(m, 2H, C6H5-CHZ) , 3 . 3209 (brs, 2FI, NI-IZ) , 3 . 9408 (brs, 1I-I, CH-N), 7.236-7.317(m, 5H, C6H5) and 7.528, 7.862, 8.150 (brs, 3I-I, NH~~) .
DEPROTRCTIO~Y OF DTPEPTIDES 1a-a WTT~i TRTFLUOROACETIC ACID- aENERA1G PROCEDURE:
To a solution of the Boo-protected dipeptide (lmmol) in dry dichloromethane (2m1, cooled to ice-bath temperature, under an argon atmosphere) was added trifluoroacetic acid (2m1) and the solution was stirred at the same temperature fox 1-2 hr. After removing the solvent under reduced pressure, the residue was dissolved in toluene and solvent was again removed under reduced pressure.
The latter operation was repeated to remove all the :5,:
trifluoroacetic acid. The residue was dried (in vacuo) to obtain the trifluoroacetate salts of the respective dipeptides. Wherever possible, the trifluoroacetate salts were characterized from spectral data and physical constants recorded.
Synthesis of Dap-Phe-OCH3 Tfa (2a):
After removing toluene under reduced pressure, the residue obtained as a thick oily mass was triturated with ether to obtain the trifluoroacetate salt (2a, quantitative) as a colorless crystalline solid: IR(thin film): 3275, 2928, 1744, 1674, 1541, 1456, 1202, 1132 and 72,1; ~H
NMR (300MHz, CDC13): 1.107(brs, 3H, CH3), 1.60-2.10(m, 4H, 2 x CHZ), 2.60(m, 1H, CHCO), ' 2 . 90-3. 00 (m, 2H, CHZ-Ph) , 3 .10-3 > 35 (m, 3H, CfI-OCH3, CHZ-N) , 3 . 209 (s, 3H, OCH3) , 3 . 40-3 . 55 (m, 1H, pro CH-N), 3.712(s, 3H, COOCH3), 4.75(m, 1H, phe CH-N), 7.106(m, :LH, NH), 7.124-7.324(m, 5H, Fh) and 8.7(m, 1H, NH); HRFABMS: m/z 349.21350(100%, cation);
[C~9H29N204]'" requires 349.21273.
Synthesis of Dap-Phe-NHZ Tfa (2b):

r., :~. ~. .:~ ) Removal of toluene under reduced pressure left the trifluoroacetate salt (2b, 97% ) as a colorless solid.
&ynthesis of Dap-.lPro-OCH3 ~fa (20):
After removing toluene under reduced pressure, t h a residue obtained as a think oily mass was triturated with ether to obtain the trifluoroacetate salt (20, 99%) as a colorless crystalline solid: TR(thin film): 2980, 2890, 1746, 1680, 1626, 1437, 1287, 1200, 1094, 799 and 721; ~H
NMR (300MHz, CDC13): 1.307(d, J=6.9Hz, 3'H, CH3), 1. 85-2 . 30 (m, 8H, 4 x CHZ) , 2 . 85 (m, 1H, CH-CO) , 3 .20-3.40 (m, 1H, CH-OCH3) , 3. 485 (s, 3H, CHI) , 3.35-3.75(m, 3H, CH-N, CHZ-N), 3.687(s, 3H, COOOCH3) , 4 .165 (m, 2H, CHZ-N*) , 4 . 442 (m, 1FI, CH-N+) and 8.008(m, NH). HRFABMS: m/z 299.19770(100%, cation) t [C~SHZ~N204]+ requires 299.1971.
Synthesis of Dap-Il~-OCH3 Tfa (2d):
After removing toluene under reduced pressure, the residue obtained as a thick oily mass was triturated with ether to obtain the trifluoroacetate salt (2d, 97%) as a gummy mass:
IR(thin film): 3289, 2969, 2884, 1744, 16?4, 1541, 1458, 1383, 1202, 1136, 833, 799 and 721; ~H NMR
(300MHz, CDC13): 0.88(brs, 3H, CH3), 1.884(t, J=6.7Hz, 3H, CH3-CHZ) , 1. 209 (d, J=6.8Hz, CH3-CH) , 1.10-1.50(m, 2H, CHZ), 1.80-2.20(m, 5H, 2 X CHz, ' CH3-CH), 2.707(m, 1H, CH-CO), 3.10-3.41(m, 2H, CHZ-N), 3.470(s, 3H, OCH3), 3.60-3.70(M, 1H, CH-OCH3), 3.48-3.85-3.90(m, 1H, pro CH-N), 3.702(s, 3H, COOCH3), 4.43(dd, J=7.5 and 5.4Hz, 1H, ile CH-N), 6.926(d, J=7.9Hz, 1H, NH), 8.8(m, 1H, 1/2 NHz) and 10 (m, 1H, 1/2 NHZ): MS: HRFAE3: m/z 315.22890(100%. Cation) p (C~6H31N204]* requires 315.22838.

Synthesis of Dap-Met-OCH3 Tfa (2e);
Removal of toluene under reduced ;pressure left the trifluoroacetate salt (2e, quantitative) as a gummy mass.
SYNTHESIS OF PENTABEPTIDES 3a-a ~ ~3E1NERAL
PROCEDURE;
To a solution of the tripeptide tfa ;salt (4, lmmol) and the dipeptide tfa salt (lmmol) in dichloromethane (2m1, ice-bath and under argon) was added dry triethylamine (3mmol) followed by diethylcyanophosphonate (l.lmmol). The solution was stirred at the same temperature for 1-2hr.
After removing solvent under reduced pressure the residue was chromatographed on a SILICA GEL column using the solvent system given below as eluents to obtain the respective pentapeptides (3a-e).
Dov-Val-Dil-Dap-Phe-OCH3 (3a):
Chromatographic separation on a SIL~TCA GEL
column with 3:4 hexane-acetone as the eluent gave the required pentapeptide(3a, 87%); m.p. - 80-83°C
[a]p 5 = -35.3 ° (c 0.34, CHC13) ; IR(thin film) 3298, 2963, 2934, 2876, 2830, 2787, 1748, 1622, 1532, 1454, 1379, 1269, 1200, 1099, 1038, 737 arid 700; MS: m/z 759(Mi), 716, 481, 449, 433, 227, 186, 154, 128, 100(100%), 85 and 70. Anal. Found: C:
64.91, H: 9.33, N: 8.97. C4~H69N508 requires C: 64.71, H: 9.15, N: 9.22.
Dov-Val-Dil-Dap-Phe-NHZ(9b):
Chromatographic separation on a SILICA GEL
column with 1:3 hexane-acetone as the eluent resulted in the required pentapeptide as colorless powder (33~, 99 0) ; m.p. = 111-113 °C ; [a]p 5 = -42 ° (c 0.25, CHCl3) ; IR(thin film) : 3304, 3138, 3054, 2965, 2934, 2876, 2830, 2787, 1622, 1541, 1499, 1423, 1371, 1306, 1252, 1202, 1171, 1098, 1038, 756, 735 and 696; MS: m/z 744(M+), 701, 669, 519, 481, 418, 227, 206, 186, 170, 154, 128 and 114.
Dov-Val-Dil-Dap-Pro-OCH3 (3a):
Chromatographic purification using a SILICA
GEL column with 1:3 hexane-acetone as the eluent yielded the required pentapeptide as colorless powder (3a, 69%) ; m.p. = 75-77°C ; [a]p25 = _52.7° (c 0.11, CI-IC13) ; IR(thin film) : 3293, 2963, 2876, 2830, 2789, 1750, 1624, 1422, 1385, 1273, 1198, :L096, 1040 and 733; MS: m/z 709(:M"), 666, 581, 481, 449, 412, 383, 369, 297, 255, 227(100%), 199, 186, 170 and 155. Anal. Found: C: 62.51, H: 9.61, N: 9.72.
C3~H6~N508 requires C: 62.59, H: 9.51, N: 9.87.
Dov-val-Dil,-Dap-Ile-OCH3 (3~d) Chromatographic separation on a SILICA GEL
column with 1:2 hexane-acetone as the elu~ent gave the required pentapeptide .as colorless powder (3d, 80% ); m.p. - 80-82°C; [a]p25 = -39.3° (c 0.14, CHC13) ; IR(thin film) : 3300, 3050, 2965, 2878, 2830, 2787, 1746, 1622, 1530, :L454, 1383, 1267, 1120, 1099, 1038 and 735; MS: m/z 725(M+), 682, 481, 399, 227, 186, 170, 154 and 128. Anal. Found: C: 63.03, H: 10.01, N: 9.77. C38H7~N5t~8 requires C: 62.86, H:
9.86, N: 9.65.
Dov-va7.-Di1-Dap-Met-OCH3 (;De) ' Chromatographic separation using a SILICA GEL
column with 1:2 hexane-acetone as the eluent .resulted in the required pentapeptide as colorless powder (3e, 78%) ; m.p. = 63-65°C; [a]o 5 = -44.1" (C, 0.44, CHC13) ; IR(thin film) : 3297, 2963, 2934, 2876, 2830, 2787, 1750, 1620(br),. 1539, 1449, 1420, 1375, 1198 and 1098; MS (m/z) : '743 (M+) , 700, 611, 568, 481, 417, 311, 227 and 154. Anal. Found: C: 59.78, H: 9.14, N: 9.16, S: 4.39. C3~H69N5068S requires C:

,;::~
59.73, H: 9.35, N: 9.41, S: 4.31.
To further aid in the understanding of the present invezxtion, and not by way of l:Lm:i.tation, the following examples axe presented.
Example ~a - 8ynthas3s of Boc-Dap-Phe-OCH~ (:La):
The general procedure for the synthesis of dipeptides (1a-1e) was followed. The numerical identificate shown in Scheme 1 is followed herein.
Chromatographic separation on a SILICA GEL column with 3:1 hexane-acetone as the eluent resulted in the required dipeptide as a thick oil.
Crystallization from ether-hexane gave sparkling crystals of the pure compound (~.a, 96~) ; m.p. -125°C; [a]p 5 = -15.1 (c 0.41, CHC13) ; IR(thin film) 3314, 2974, 2934, 2878, 1748, 1692, 1663, 1537, 1456, 1400, 1366, 1173, 1101 arid 700; ~H NMR
(300MHz, CDC13): 1.163(d, J=7.OHz, 3H, CH3), 1. 4816 (s, 9H, t-Bu) , 1. 624-1. 850 (m, 4H, 2 x CHz) , 2.25-2.45(m, 1H, CHCO), 3.045(dd, J=13.9 and 7.8Hz, 1H, 1/2 CHz-Ph), 3.175(dd, J=13.8 and 5.55Hz, 1H, 1/2 CHz-Ph), 3.3642(s, 3H, OCH3), 3.3701(s, 3H, OCH3), 3.50-3.60(m, 1H, CH-OCH3), 3.7422(m, 2H, CHz-N), 3.85(m, 1H, pro CH-N), 4.80(m, 1H, phe CH-N), 6.10, 6.75(m, 1H, NH) and 7.10-7.32(m, 5H, Ph); MS: m/z 416(M-MeOH), 375, 316, 264, 210, 170, 114(100%) and 70. Anal. Found: H: 8.12, N: 6.20.
Cz~H3eN20s requires H: 8.09, N: 6.25.
' Example Ib - Synthesis of Boc-Dap-Phe-PIHZ (1b):
The general procedure for the synthe~;is of dipeptides (1a-1e) was followed. Chromatographic purification using a SILICA GEL column wii~h 1:1 hexane-acetone as the eluent gave the required dipeptide as a crystalline solid.
Recrystallization from acetone gave sparkling crystals of the pure compound (l.b, 65%); m.p. -2114'156 199-200°C (acetone) ; [a]pzs = -40 (c 0.15, CkiCl3) ;
IR(thin film): 3302, 3198, 2974, 2934, 2878, 1669, 1539, 1456, 1404, 1366, 11119, 1111 and 700; ~H NMR
(300MHz, CDC13) : 1. 019 (brs, 3kI, CkI3) , 1. 426 (s, 9kI, t-Eiu), 1.55-1.90(m, 4ki, 2 x CHz), 2.30(quintet, 1H, CH-CO) , 3 . 00-3. 25 (m, iii, C:FIz-N, CH-OCki3) , 3. 349 (s, Ski, OCi~I3) , 3 . 60-3 . 75 (m, 1k3, pro CkI-N) , 4. 60-4 . 80 (m, lkI, phe CH-N) , 5. 30 (brs, 1H, NFI) , 6. 287 (d,. J=7. 2kiz, lkl, NH) , 6. 90 (brm, lkI, NH) and 7. 164-7 . 306 (m, 5H, C6Hs) ; MS: m/z 433 (M*) , 401 ~;M-MeOH) , 360, 301, 247, 232, 210, 170, 154, 138, 114 and 70(1000 . Anal.
Found: C: 63.75, H:8.18, N:9.62. Cz3H3sN3Os requires C: 63.72, H: 8.14, N: 9.69.
Eacample Tc - Synthesis of lBoc-Dap-Pro-OCH~ (1c):
The general procedure for the synthesis of dipeptides was followed. Chromatographic separation on a SILICA GEL column with 3:2 hexane-acetone as the eluent gave the required dipeptide as a thick oil (7.c, 92~) ; [a]pz5 - _101.5 (c 0.2, CHC13) ; IR(neat) : 2974, 2880, 1748, 1692, 1647, 1398, 1366, 1171and. 1098; ~H NMR (300MHz, CDC13): 1.222(d, J=7.OHz, 3H, CH3), 1.440(x, 9H, t-Bu), 1.65-2.20(m, 8H, 4 x CHz), 2.60-2.70(m, 1H, CH-CO), 3.10-3.22(m, 1H, CH-OCH3), 3.417(x, 3H, CH3), 3.45-3.65(m, 4H, 2 x CHz-N), 3.675(x, 3H, OCH3), 3.74-3.83(m, 1H, CH--N) and 4.447(dd, J=8.55 and 3.5Hz, 1H, CH-COOCH3). HRFABMS: m/z 399.24880 (M+H)*; . [CZpH3sN206]* requires 399.24951.
Eacample Id - Synthesis of I3oo-Dap-ale-OOHS (sd) o The general procedurE~ for the synthesis of dipeptides (la-1e) was followed. Chromatographic purification on a SILICA. GEL column with 3:2 hexane-ethyl acetate as i~he eluent yielded the required dipeptide as an oily liquid (id, 72%);
m.p. - 76-77°C (acetone) : [a]pzs = -28.2 (c 0.17, CHC13) ; IR(thin film) : 3325,, 2971, 2936, 2878, 1746, 1694, 1667, 1530, 1478, 1398, 1254, 1175, 1105, 868 2I1i5 and 774; ~H NMR (300MHz, CDC13): 0.882 (d, J=6.9Hz, 3H, CH3-CH) , 0. 9012 (t, J=7. 4Hz, 3H, !CH;-CHZ) , 1. 05-1.24 (m, 5FI, CFI3, CHZ-CFI3) , 1, 4526 (s, 9H, t-Bu) , 1. 65-2 . 00 (m, SFI, 2 x CFIz, C~F~-CHZ) , 2 . 30-2 . 50 (m, 1FI, CFF-CO) , 3 . 18-3. 28 (m, 1FI, C~-OCFi~) , 3.422 (s, 3FI, OCFI3) , 3. 48-3. 60 (m, 1FI, pro ,~-N) , 3. 6951 (s, 3FI, OCFIj) , 3 . 72-3 .82 (m, 1FI, 1/2 CFIZ-r1) , 3 . 88-3 , 98 (m, 1FI, 1/2 CFIZ-N) , 4. 44-4 . 58 (m, 9.FI, i1e CFI-N) and 6. 15, 6.7(m, 1H, NFI); MS: m/z 382(M-MeOH), 341, 282, 245, 230, 210, 170, 114, 70(1000 and 57. Anal. Found:
C: 61. 06, H: 9. 25, N: 6. E.4. CZ~H38N206 requires C:
60.84, H: 9.24, N: 6.76.
Example Ie - Synthesis of ;Boc-Dap-Met-OCH3 (xe):
The general proaedur~a for the synthe:;is of dipeptides (1a-1e) was fo7.lowed. Chromatographic separation on a SILICA GEL column using 3:2 hexane-acetone as the eluent gave the required dipeptide as a solid (1e, 83~k) ~ m.p. - 68-70°C;
(a]pZS= -27.6 (c, 0.59, CHCl;s) ; IR(neat) : 3312, 2974, 2934, 2878, 1748, 1692, x.663, 1539, 1398, 1366, 1256, 1171, 1115, 866 anal 774; ~H NMR (CDC13):
1.223(brs, 3H, CH-CH3), 1.441(brs, 9H, t-Bu), 1.6-1.2 (m, 6H, 3xCHZ) , 2.070 (s, 3H, S-CH3) , 2.3-2.55(m, 3H, CHZ-S, CH-CO), 3.15-3.35 (m, 2H, N-CHZ) , 3. 420 (s, 3H, OCH3) , 3.55 (m, 1H, CH-°OCH3) , 3.716(brs, 3H, COOCH3), 3.85-4.0(m, 1H, pro CH-N), 4.6(brm, 1H, met CH-N), 6.3(brm, 1H, NH): MS (m/z):
432 (M+), 400, 359, 258, 210, 170, 114(100%). Anal.
Found: C: 55.35, H: 8.33, N: 6.53, S: 7.23. CZaH36N206 S requires C: 55.53, H: 8.39, N: 6.48, S: 7.41.
Example TIa - gynthesis of Dap-Phe-oCH3 Tfa~ (xa):
General procedure A was followed. After removing toluene under reduced pressure, the residue obtained as a thief oily mass was ti~trated with ether to obtain the trifluoroacetate salt (2a, quantitative) as a colorless crystalline: solid:
IR(thin film): 3275, 2928, 1744, 1674, 1541, 1456, zm4ms 1202, 1132 and 721; ~H NMR (300MHz, CDC13):
1. 107 (brs, 3H, CFI) , 1. 60-2 . 10 (m, 4H, 2 ~" CHZ) , 2 . 60 (m, 1FI, CFiCO) , 2 . 90-3 . 00 (m, 2FI, CII2-Ph) , 3. 10-3. 35 (m, 3FI, CFA-OCFI3, CHZ-N) , 3. 209 (s, 3FI, OCFI~) , 3 .40-3. 55 (m, 1II, pro CFI-N) , 3 . 712 (s, 3FI, COOCFI3) , 4 , 75 (m, 1H, phe CFI-N) , 7 .106 (m, 1FI, NFI) , 7. 124-~ 7. 324 (m, 5FI, Ph) and 8.7 (xa, 7.II, NFI) ; IiFtF~ABMS:
m/z 349.21350(100, nation) ; (G~9FI29N20~]* requires 399.21273.
Example IIb - 8ynthe~is of Dap-Ph~-NHZ Tfa (2b):
General procedure A was followed. Removal of toluene under reduced pressure left the trifluoroacetate salt (2b, 97~) as a co7.orless solid.
Exampl~ IIa - Synthesis of Dap-Pro-OCH3 Tfa (2a):
General procedure A was followed. After removing toluene under reduced pressure, residue obtained as a thick oily mass was triturated with ether to obtain the trifluoroacetate salt (20, 990) as a colorless crystalline solid: IR(thin film):
2980, 2890, 1746, 1680, 1626, 1437, 1287, 1200, 1094, 799 and 721; ~H NMR (300MHz, CDC13): 1.307(d, J=6.9Hz, 3H, CH3), 1.85-2.30(m, 8H, 4 x CHZ), 2.85(m, 1H, CH-CO), 3.20-3.40(m, 1H, CH-OCH3), 3.485(s, 3H, CH3), 3.35-3.75(m, 3H, CH-N, CHz-N), 3. 687 (s, 3H, COOOCH3) , 4. 165 (m, 2H, CFIZ-N*) , 4 .442 (m, 1H, CH-N*) and 8.008(m, NH). HRFABMS: m/z 299.19770(100%, cation) ; [C~SHZ~Nz04]* requires 299.1971.
Exaanple IId - Synthesis of >aap-Ile-OCH3 Tfa (2d) :
General procedure A was followed. After removing toluene under reduced pressure, the residue obtained as a thick oily mass was triturated with ether to obtain the trifluoro-acetate salt (2d, 970) as a gummy mass: IR(thin film): 3289, 2969, 2884, 1744, 1674, 1541, 1458, 1383, 1202, 1136, 833, 799 and 721; ~H NMR (300MHz, ~:~1~156 CDC13): 0.88(brs, 3H, CH3), 1.884(t, J=6.7Hz, 3H, CFI3-CHZ) , 1. 209 (d, J=6. 8Hz, CH3-CH) , 1. 10-1. 50 (m, 2H, CHz) , 1. 80-2. 20 (m, 5H, 2 X CFI2, CFi3-CFI) , 2 .707 (m, lFi, CFI-CO) , 3 . 10-3. 41 (m, 2FI, CFi2-N) , 3 . 470 (s, 3FI, 0CFI3) , 3 . 60-3 . 70 (M, 1FI, C~-OCFI~) , 3 . 85-3 . 90 (m, 1FI, pro ~-N) , 3.702 (s, 3FI, COOCFij) , 4. 43 (dd, J=7. 5 and 5.4Fiz, lFi, ile CFI-N) , 6.926 (d, J=7.9FIz, 1H, NH) , 8.8 (m, lFi, 1/2 NFiz) and 10 (m, 1FI, 1/2 NHz) ; MS:
HRFAB: m/z 315.22890(100. ration) ; [C,6FI31N204~*
requires 315.22838.
Example IIe - Synthesis of Dap-Mat-OCH3 Tfa (2e):
General procedure A was followed. Removal of toluene under reduced pressure left the trifluoro-acetate salt (2e~ quantitative) as a gummy mass.
Example IIIa - Synthesis o~ Dov-Val-Dil-Dap-Phs-OCIi~
(3a) Chromatographic separation on a STLICA GEL
column with 3:4 hexane-acetone as the eluent gave the required pentapeptide(3a, 87~); m.p. - 80-83°C
; [a]D 5= -35.3 (c 0.34, CHC13) ; IR(thin film) : 3298, 2963, 2934, 2876, 2830, 2787, 1748, 1622, 1532, 1454, 1379, 1269, 1200, 1099, 1038, 737 and 700;
MS: m/z 759(M+), 716, 481, 449, 433, 227, 186, 154, 128, 100(100%), 85 and 70. Anal. Found: <:: 64.91, H: 9.33, N: 8.97. C4~H69Ns08 requires C: 64.71, H:
9.15, N: 9.22.
Example IIIb - Synthesis o~ DoV-Val-Dil-Dap-Phe-iJgiz ' (3b) :
General procedure B was followed.
Chromatographic separation on a SILICA GEL column with 1:3 hexane-acetone as the eluent resulted in the: required pentapeptide as colorless powder (3b, 99~); m.p. = 111-113°C ; [a~pz5= -42 (c 0.25, CHC13);
IR(thin film): 3304, 3138, 3054, 2965, 2934, 2876, 2830, 2787, 1622, 1541, 1499, 1423, 1371, 1306, r z~~~156 1252, 1202, 1171, 1098, 1038, 756, 73°.> and 696; MS:
m/z 744 (M+) , 701, 669, 519, 481, 418, :?27, 206, 186, 170, 154, 128 and 114.
Example IIIa - synthesis of Dov-Val-Dill-Dap-pro-OCH3 (3a) s General procedure B was followed.
Chromatograph:Lc purification using a SILICA GEL
column with 1:3 hexane-acetone as the eluent yielded the required pentapeptide as co:Lorless powder (3a, 69~); m.p. = 75-77°C ; [a]p5= -52.7 (c 0.11, CHC13) ; IR(thin film) : 3293, 2963, 2876, 2830, 2789, 1750, 1624, 1422, 1385, 1273, 1198, 1096, 1040 and 733; MS: m/z 709(M+), 666, 581, 481, 449, 412, 383, 369, 297, 255, 227(1000), 199, 186, 170 and 155. Anal. Found: C: 62.51, H: 9.61, N: 9.72.
C37H67N5~a requires C: 62.59, H: 9.51, N: 9.87.
Example TIId - synthesis of Dov-Val-Dil-Dap-Ile-OCH3 (3d) General procedure B was followed.
Chromatographic separation on a SILTCA Gr~L column with 1:2 hexane-acetone as the eluent gave the required pentapeptide as colorless powder (3d, 80~); m.p. - 80-82°C ; [a]pz5= -39.3 (c 0.14, CHC13) ; IR(thin film) : 3300, 3050, 2965, 2878, 2830, 2787, 1746, 1622, 1530, 1454, 1383, 12Ei7, 1120, 1099, 1038 and 735; MS: m/z 725(M+), 682, 481, 399, 227, 186, 170, 154 and 128. Anal. Found: C: 63.03, H: 10.01, N: 9.77. C38H7~N5~08 requires C: 62.86, H:
' 9.86, N: 9.65.
Example IIIe - sgnthesis of Dov-Val-Dil-Da~u-Met-OCH3 (3e) General procedure B was followed.
Chromatographic separation using a SI:L7CCA GEL
column with 1:2 hexane-acetone as the eluent resulted in the required pentapeptide as c~o:iLorless ~~~i~s powder (3e, 78%); m.p. - 63-65°C; (a]pZS= -44.1 (c, 0.44, CHC13) ; IR(thin film) : 3297, 2963, 2934, 2876, 2830, 2787, 1750, 1620(br), 1539, 1449, 1420, 1375, 1198 and 1098; MS (m/z) : 743 (Nf~) , 700, 611, 568, 487., 417, 311, 227 and 154. Anal. T'ound: C: 59.78, I3: 9.14, N: 9.16, S: 4.39. C~~I~I69N506n8 rec~uiras C:
59.73, II: 9.35, N: 9.41, S: 4.31.
From the foregoing, it is readily apparent that a useful embodiment of the present invention has been herein described and illustrated which i fulfills all of the aforestated objectives in a remarkably unexpected fashion. It is of course understood that such modifications, alterations and adaptations as may readily occur to the artisan confronted with this disclosure are intended within the spirit of this disclosure which is limite=d only by the scope of the claims appended hereto.
i

Claims

1. A compound having the structural formula designated 3(a-e):
wherein R is selected from the following group of substituents:

2. A compound according to claim 1 in which R
is the substituent designated a.

3. A compound according to claim 1 in which R
is the substituent designated b.

4. A compound according to claim 1 in which R
is the substituent designated c.

5. A compound according to claim 1 in which R
is the substituent designated d.

6. A compound according to claim 1 in which R is the substituent designated e.

7. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as defined in any one of claims 1 to 6, and a pharmaceutically acceptable carrier.

8. Use of a compound as defined in any one of claims 1 to 6, for inhibiting the growth of human cancer cells responsive thereto.

9. A method of synthesizing a pentapeptide as defined in claim 1, which comprises: selecting dolaproine tfa salt;
selecting an amino acid salt; dissolving said amino acid salt in cooled dry dichloromethane and triethylamine;
adding said dolaproine tfa salt to said amino acid salt solution to produce a solution; adding diethylcyanophosphonate (DECP) to said solution; cooling said DECP-containing solution to cause precipitation in the solution;
evaporating the solvents from said precipitate-containing solution under reduced pressure to leave a residue;
chromatographing said residue over a SILICA GEL column with solvents to isolate the respective dipeptide; dissolving said dipeptide in cooled dry dichloromethane and adding trifluoroacetic acid thereto to create a second solution;
stirring said second solution, removing solvent from said second solution, under reduced pressure to provide a second residue; repeatedly dissolving said second residue in toluene and thereafter evaporating said solvent therefrom to remove all trifluoroacetic acid from said second residue; drying said second residue in vacuo thereby to obtain the trifluoroacetate salt of the respective dipeptide; admixing the respective tripeptide tfa salt to said dipeptide salt; dissolving said salts in dichloromethane in an ice-bath under an argon atmosphere to form a third solution; adding dry triethylamine to said third solution and thereafter; adding diethylcyanopho- phonate thereto to form a resultant fourth solutions stirring said fourth solution; removing solvent from said fourth solution under reduced pressure to leave a third residue; and chromatographing said third residue on a SILICA GEL column to isolate the desired pentapeptide.

10. An in vitro method for inhibiting the growth of human cancer cells in an environment which comprise administering a pharmaceutically acceptable carrier combined with an amount of an active agent which is selected from the compounds claimed in any one of claims 1 to 6 effective to inhibit the growth and effects of tumor cells in human cancer cells within the environment to which the administration is effected.

11. An in vitro method for inhibiting the growth of human cancer cells wherein said cancer is selected from the group consisting of leukemia, ovarian cancer, CNS cancer, mammary cancer, non-small cell lung cancer, renal cancer, colon cancer, and melanoma consisting of administering an active ingredient selected from the group consisting of:
Dov-Val-Dil-Dap-Phe-OCH3, Dov-Val-Dil-Dap-Phe-NH2, Dov-Val-Dil-Dap-Pro-OCH3, Dov-Val-Dil-Dap-Ile-OCH3, and Dov-Val-Dil-Dap-Met-OCH3, to said cells in a quantity sufficient to inhibit the growth of said cells.

12. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-OCH3.

13. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-NH2.

14. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Pro-OCH3.

15. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Ile-OCH3.

16. An in vitro method according to claim 11 wherein said active ingredient consists of Dov-Val-Dil-Dap-Met-OCH3.

17. An in vitro method according to claim 11 for inhibiting the growth of human cancer cells selected from the group of cell lines consisting of P388 Lymphotic Leukemia, L1210 Lumphatic Leukemia, B16 Melanoma, M5076 Ovary Sarcoma, LOX Human Melanoma, Human Mammary MX-7, and OVCAR-3, consisting of administering an active ingredient selected from the group consisting of Dov-Val-Dil-Dap-Phe-OCH3, Dov-Val-Dil-Dap-Phe-NH2, Dov-Val-Dil-Dap-Pro-OCH3, Dov-Val-Dil-Dap-Ile-OCH3, and Dov-Val-Dil-Dap-Met-OCH3, to said cells in a quantity sufficient to inhibit the growth of said cells.

18. An in vitro method according to claim 11 wherein said cancer is selected from the group of cell lines consisting of P388, OVCAR-3, SF-295, A498, NCI-H460, KM20L2, and SK-MEL-3.

19. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-OCH3.

20. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Phe-NH2.

21. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Pro-OCH3.

22. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Ile-OCH3.

23. An in vitro method according to claim 18 wherein said active ingredient consists of Dov-Val-Dil-Dap-Met-OCH3.