Novel actinomycins formed by biosynthetic incorporation of cis- and trans-4-methylproline

Abstract

Streptomyces parvulus (Streptomyces parvullus) normally produces actinomycin D; in the presence of cis-4-methylproline, this species synthesizes two additional actinomycins, designated K(1c) and K(2c), in which one and two proline sites, respectively, are occupied by cis-4-methylproline. Analogously, actinomycins K(1t) and K(2t) are formed in the presence of trans-4-methylproline. Both mixtures were separated chromatographically, and the four novel actinomycins were obtained in crystalline form. Their biological activities were compared with that of actinomycin D in respect to inhibition of ribonucleic acid, deoxyribonucleic acid, and protein synthesis and antimicrobial potency. In all cases examined, the order of activity D > K(1t) > K(1c) > K(2t) > K(2c) was observed, and the same sequence prevailed in a spectroscopic measure of their binding to deoxyribonucleic acid. In addition, proton nuclear magnetic resonance studies revealed that the replacement of proline by cis-4-methylproline alters the conformation of the antibiotic molecule.