Synthesis and antitumor activity of 2-deamino- and N2-(gamma-hydroxypropyl)actinomycin D.
2-Deamino- and N2-(gamma-hydroxypropyl)actinomycin D were synthesized by modification of the parent actinomycin D molecule at the 2 position of the phenoxazinone moiety. The common intermediate was 2-deamino-2-chloroactinomycin D. Catalytic hydrogenation of this material afforded the 2-deamino derivative while treatment with gamma-hydroxypropylamine yielded the N2-(gamma-hydroxypropyl) derivative. These 2-substituted actinomycin D derivatives were less potent in microbiological assays than the parent compound. Evaluation of activity in vivo against three murine tumor systems indicated that optimal dose levels of 2-deaminoactinomydin D were 50 times greater than toxic dose levels of actinomycin D. N2-(gamma-hydroxyporpyl)actinomycin D exhibited antitumor activity similar to the parent compound.
D000433:1-Propanol / Q000138:chemical synthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001412:Bacillus subtilis / Q000187:drug effects; D003609:Dactinomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D003641:Deamination; D007939:Leukemia L1210 / Q000188:drug therapy; D007942:Leukemia, Experimental / Q000188:drug therapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008826:Microbial Sensitivity Tests; D009374:Neoplasms, Experimental / Q000188:drug therapy; D012505:Sarcina / Q000187:drug effects; D013053:Spectrophotometry; D013211:Staphylococcus aureus / Q000187:drug effects
D000970:Antineoplastic Agents; D003609:Dactinomycin; D000433:1-Propanol