1993 Fiscal Year Final Research Report Summary
Total Synthesis of Cyclotheonamides, Potent Inhibitors of Thrombin
| Project/Area Number |
04671303
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | Nagoya City University |
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Principal Investigator |
HAMADA Yasumasa Nagoya City University, Faculity of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (90117846)
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| Project Period (FY) |
1992 – 1993
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| Keywords | cyclotheonamide / inhibitor / thrombine / vinylogous tyrosine / alpha-keto arginine / 2,3-diaminopropionic acid |
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| Research Abstract |
Cyclotheonamides(A and B), potent andselective inhibitor of the serine protease thrombine, were isolated fron a marine sponge of the genus Theonalla. They are cyclic pentapeptides containing two, so far umknown, amino acid components, a vinylogous tyrosine and alpha-keto arginine. We have undertaken total synthesis of the interesting cyclic peptides for evaluation of their biological activities.
The preparation of the protected E-vinylogous tyrosine ester was carried out by a new one-pot reaction in high selectivity from the protected amino alclhol derived from D-tyrosine. The synthesis of the alpha-keto arginine was accomplished as alpha-hydroxy acid after homologation of L-arginine. The protected 2,3-diaminopropionic acid was synthesixed fron Z-L-asparagine according the lzumiya method.
With the three unusual amino acids in hand, toral synthesis of cyclothenamide B was set out. The dipeptide, H-Dpr-Pro-OR, and tripeptide, Boc-alpha-hydroxyArg-the-vinylTyr-OH, were coupled with our method. Thus obtained pentapeptide after deprotection was cyclized with pentafluorophenyl diphenylphosphinate to give the cyclic precursor in high yield. Oxidation of the alpha-hydroxy acid moiety to alpha-keto acid one with Dess-Martin reagent furmished the cyclotheonamide B.
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