Microbial transformations of natural antitumor agents, 25. Conversions of 3-ketoaphidicolin.
Microbial transformation experiments were conducted using 3-ketoaphidicolin (2) as a starting material. Metabolites were isolated by solvent extraction and chromatography, and structures were elaborated by cmr and pmr spectroscopy, ms, and ir analyses. Several microorganisms provided metabolites in excellent yields, including 3-epiaphidicolin (4), 6 beta-hydroxy-3-ketoaphidicolin (5), and 19-nor-16,17-dihydroxyaphidicolan-3-one (6). The last compound is formed via oxidation of the primary alcohol functional group at position 18 to the corresponding beta-keto acid derivative which spontaneously decarboxylates. This reaction is analogous to the metabolic demethylation of sterol intermediates. Each metabolite was tested for antitumor activity in the P-388 leukemic test system, and in the 6C631 colon tumor model system. None of the compounds were active in vivo, and all were less active than aphidicolin in the in vitro P-388 test system.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D016590:Aphidicolin; D001711:Biotransformation; D002597:Chaetomium / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism* / Q000494:pharmacology; D005285:Fermentation; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D013302:Streptomyces / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D004224:Diterpenes; D016590:Aphidicolin