Development of new mitomycin C and porfiromycin analogues.
New mitomycin C and porfiromycin analogues were prepared by treating mitomycin A and N-methylmitomycin A with a variety of amines, including aziridines, allylamines, propargylamines, chloroalkylamines, hydroxyalkylamines, glycine derivatives, aralkylamines, and heterocyclic amines. All analogues were evaluated against P-388 murine leukemia and selected ones were examined for their leukopenic properties. Certain analogues were found to be superior to mitomycin C in potency, efficacy, and therapeutic ratio in the P-388 assay. The most active substituents at the mitosane 7 position included aziridine, 2-methylaziridine, propargylamine, furfurylamine, methyl glycinate, and 3-aminopyridine. Mitomycin A and the 7-aziridino, 7-(2-methylaziridino), and 3-aminopyridine analogues were less leukopenic than mitomycin C. Certain other analogues, including propargylamino and methyl glycinate, were highly leukopenic. The three compounds tested against B-16 melanoma in mice were significantly more effective than mitomycin C in this assay. Previously established structure--activity relationships were found inadequate to account for all of the new data.
D000818:Animals; D000970:Antineoplastic Agents; D004305:Dose-Response Relationship, Drug; D007942:Leukemia, Experimental / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008937:Mitomycins / Q000138:chemical synthesis* / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011160:Porfiromycin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D008937:Mitomycins; D011160:Porfiromycin