Synthesis of two analogs of a cyclic hexapeptide with disulfide bridge corresponding to bovine prothrombin precursor sequence 18-23. Extent of carboxylation by Vitamin K-Dependent carboxylase.

D H Rich, M Kawai, H L Goodman, J W Suttie

Index: Int. J. Pept. Protein Res. 18 , 41, (1981)

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Abstract

The synthesis of two analogs of sequence 18-23 of bovine prothrombin precursor is described. Hexapeptides Boc-Cys (Acm)-Leu-Glu(OBzl)-Glu(OBzl)-Pro-Cys (Acm)-OBzl and Ac-Cys(Acm-Leu-Glu(OBzl)-Glu(OBzl)-Pro-Cys(Acm)-OMe were synthesized in solution by stepwise addition of Boc-amino acids using dicyclohexylcarbodiimide/N-hydroxybenzotriazole as the coupling reagent. The acetamidomethyl groups were cleaved and oxidized, using iodine in methanol, to the protected cyclic disulfide in 62-69% yield. The O-benzyl groups were removed either by treatment with anhydrous hydrogen fluoride or hydrogen bromide in trifluoroacetic acid to give the cyclic hexapeptide disulfides, R1-Cys-Leu-Glu-Glu-Pro-Cys-OR2 where R1 - H or Ac and R2 = H or CH3. The cyclic hexapeptides were evaluated as substrates for vitamin K-dependent carboxylase. Both peptides are unusually poor substrates for the carboxylase, and each appears to inhibit carboxylation of Phe-Leu-Glu-Glu-Leu, a good substrate for the enzyme.