UTILIZATION OF SOME NON CODED AMINO-ACIDS AS ISOSTERS OF PEPTIDE BUILDING-BLOCKS

In our study on non coded amino acids and their utilization in peptide chemistry we synthesized methylene-thio (CH2-S) and methyleneoxy (CH2 -O) group containing amino acids and pseudodipeptides which could be u sed as building blocks for the construction of peptide hormone analogu es. The (CH2-S) isoster of peptide bond exhibits increased flexibility , lipophility and resistance to proteolytic enzymes. This group exhibi ts similar properties as the isosteric disulfide bond in the side chai n of cystine residue. The (CH2-O) isoster is moreover similar in its g eometry to extended conformation of peptide bond. As a consequence, th e changed profile of biological activities could be expected for pepti de hormone analogues containing such isosteric moiety. The (CH2-S) iso sters of the peptide bond were prepared by alkylation of thiolates of 2-mercaptocarboxylic acids, the disulfide bond by alkylation of cystei ne or homocysteine. The (CH2-O) isosters were prepared by (AcO)(4)Rh-2 catalyzed addition of carbenes of alkyl diazocarboxylates to N-protec ted aminoalcohols. Pseudodipeptides H-Leu-psi (CH2-S)-Gly-NH2 and H-Le u-psi (CH2-O)-Gly-NH2 were introduced into the C-terminal part of the oxytocin molecule using solution methods of peptide chemistry. Both in serted isosteric bonds were resistant against proteolytic degradation, the first one was found to decrease an enzymic cleavage of the distan t Tyr(2)-Ile(3) bond in the corresponding analogue, too. The (CH2-S) i sosters of the disulfide bond containing an orthogonal protection of t heir alpha-amino (Fmoc) and alpha-(OAll, OH) or omega-(OBu(+), OH) car boxylic groups were applied in the solid phase synthesis of the aminot erminal 1-deamino-15-pentadecapeptide of endothelin-I which represents a strong vasoactive agent. The solid phase synthesis was carried out by the step-wise protocol on the Rink or Merrifield type resin using o rthogonally protected carba cystine building blocks.