Pyrrolo(1,4)benzodiazepine antitumor antibiotics. Comparative aspects of anthramycin, tomaymycin and sibiromycin.

Abstract

Anthramycin, sibiromycin and tomaymycin are structurally related antibiotics produced by various actinomycetes. Anthramycin was originally isolated from the fermentation broth of a thermophilic actinomycete, Streptomyces refruineus var. thermotolerans found in a compost heap in the 1950's by M. D. TENDLER1). The active compound, originally called refuin (from the Hebrew refuah meaning a medicine), was isolated as a pure crystalline antibiotic by LEIMGRUBER2, 3) in 1965. This antibiotic was subsequently shown to have antibiotic, antitumor, antiprotozoal and chemosterilant activity against houseflies. Tomaymycin, a Japanese antibiotic, produced by Streptomyces achromogenes var. tomaymyceticus, was isolated from a soil sample collected in Musashikoganei-city. The isolation and properties of this antibiotic were first reported by ARIMA and coworkers4) in 1972. The structure of tomaymycin and the structurally related but biologically inactive compound, oxotomaymycin, were reported by KARIYONE5) in 1971. Tomaymycin has been shown to have antitumor, antiviral and antibiotic activities. Sibiromycin, the most recent of the three antibiotics to be fully characterized, is produced by the actinomycete, Streptosporangium sibiricum and was first reported by GAUSE and coworkers6) at the Moscow Institute for New Antibiotics. The isolation and partial characterization of this antibiotic was published in 1972.7) However, its full structure was not published until 1974 by MESENTEV and coworkers.8) Sibiromycin has been shown to have antitumor as well as antibiotic activity. In addition to anthramycin, sibiromycin and tomaymycin, three further structurally related antibiotics have appeared in the literature, although full structural information has not been published. The first of these compounds, dextrochrysin which is produced by Streptomyces calms var. dextrochrysus9), has been demonstrated to have antiviral as well as antibiotic activity. Most recently two isomeric anthramycin-related compounds, neothramycins A and B produced by Streptomyces No. MC916-C410) have been reported. These compounds have been shown to have weak antibiotic and antifungal activity as well as antitumor activity. Reviews on the mechanism of action of anthramycin11, 12) and sibiromycin have appeared.13-15)