Synthesis and structure-activity relations of bestatin analogs, inhibitors of aminopeptidase B

Abstract

Stereoisomers and analogues of bestatin, [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine [from Streptomyces olivoreticuli], were synthesized and tested for aminopeptidase B and leucine aminopeptidase inhibiting activity. Among the 8 stereoisomers, the 2S stereoisomers exhibited strong activity. In a series of compounds in which the L-leucine residue of bestatin was substituted with other amino acids, only the one containing isoleucine showed more activity than bestatin. Norleucine, norvaline, methionine, valine, serine, glutamine, phenylalanine, glutamic acid, proline and lysine analogues gave, in that order, decreasing activity. Alkyl and phenyl substitution for the benzyl group of bestatin decreased the activity markedly. p-Methyl-,p-chloro- and p-nitrobestatins showed greater activity than bestatin.