Production of new anthracycline antibiotics by microbial 4-O-methylation using a specific daunorubicin-negative mutant.
Microbial 4-O-methylation using a specific daunorubicin-blocked, nonproducing mutant provided the new anthracycline antibiotics 4-O-methylbetaclamycin T, 4-O-methylyellamycin A and 4-O-methyl-13-hydroxyoxaunomycin, from which 4-O-methyloxaunomycin and 4-O-methyl-6-deoxyoxaunomycin were then prepared by further photochemical N-demethylation. Antitumor activities in vitro and in vivo against L1210 cells were compared with those of their 4-O-demethyl derivatives. It was found that all the 4-O-methyl derivatives had a markedly reduced cytotoxicity in vitro as compared with the 4-O-demethyl compounds. However, some of them were endowed with a significantly improved antitumor activity in vivo.
Johdo
O
O
Central Research Laboratories, Mercian Corporation, Fujisawa, Japan.
Tone
H
H
Okamoto
R
R
Yoshimoto
A
A
Takeuchi
T
T
D000818:Animals; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D001711:Biotransformation; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004354:Drug Screening Assays, Antitumor; D007939:Leukemia L1210 / Q000188:drug therapy; D008745:Methylation; D051379:Mice; D013302:Streptomyces / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C079463:4-O-methyloxaunomycin; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; C079460:4-O-methylbetaclamycin T; C079459:4-O-methyl-13-hydroxyoxaunomycin; C079461:4-O-methylyellamycin A; C079462:4-O-methyl-6-deoxyoxaunomycin; D003630:Daunorubicin