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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

1981; Wiley; Volume: 18; Issue: 1 Linguagem: Inglês

10.1111/j.1399-3011.1981.tb02038.x

0367-8377

Daniel H. Rich, Megumi Kawai, Hedda L. Goodman, John W. Suttie,

Blood Coagulation and Thrombosis Mechanisms

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 0‐benzyl groups were removed either by treatment with anhydrous hydrogen fluoride or hydrogen bromide in trifluoroacetic acid to give the cyclic hexapeptide disulfides, R 1 ‐Cys‐Leu‐Glu‐Glu‐Pro‐Cys‐OR 2 where R 1 , = H or Ac and R 2 = H or CH 3 . 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.