Studies of Peptide Antibiotics. I. Dipeptide Anhydrides as Models of Cyclic Peptide Antibiotics

Abstract

The d-d, l-l, d-l and l-d stereomers of both valyllysine anhydride and phenylalanyllysine anhydride, and the d-l and l-l stereomers of both valylornithine anhydride and phenylalanylornithine anhydride, have been synthesized in order to compare them with the cyclic peptide antibiotics, with which they possess several structural features in common. Synthesis has been achiveved by the dicyclohexylcarbodiimide-induced condensation of formyl, (or t-butyloxycarbonyl) valine (or phenylalanine) with the ω-carbobenzoxylysine (or ornithine) ester, followed by the treatment of the resulting acyl dipeptide ester with hydrogen chloride in methanol or ethyl acetate to remove the formyl- or t-butyloxycarbonylblocking group. The dipeptide ester hydrochlorides so derived have been converted by the action of ammonia to the corresponding carbobenzoxy-substituted dipeptide anhydrides and these, in turn, transformed to the desired unacylated dipeptide anhydride hydrochlorides by palladium-catalyzed hydrogenolysis. Enzymic experiments have been carried out to determine whether the dipeptide anhydride hydrochlorides are attacked by trypsin or chymotrypsin. The results indicate that no hydrolysis of any of the anhydrides occurs. In this connection, valyllysines, phenylalanyllysines and lysylphenylalanine have been synthesized for the purposes of chromatographic comparison. The effects of the dipeptide anhydride hydrochlorides on bacterial growth have been examined. The results indicate that no antibacterial activities are observed against microorganisms in a bouillon agar medium.