N-(cyanomethyl)- and N-(2-methoxy-1-cyanoethyl)anthracyclines and related carboxyl derivatives.
Treatment of doxorubicin with formaldehyde and NaCN afforded the N-(cyanomethyl) derivative as a stable alpha-cyanoamine with but moderate antitumor activity in mice, although it was prototypal to the intensely potent alpha-cyanomorpholine derivative. 2-Methoxyacetaldehyde and NaCN afforded the N-(2-methoxy-1-cyanoethyl) derivative as an open-chain analogue of the cyanomorpholine. This analogue underwent rapid hydrolysis to doxorubicin and appeared to act as a prodrug, giving increased antitumor efficacy although with decreased potency. N-(Carboxymethyl)daunorubicin was a highly water-soluble but inactive analogue, synthesized by N-alkylation with ethyl iodoacetate and saponification. The similar N-alkylation of N-(cyanomethyl) daunorubicin demonstrated the combining of N-alkyl chains having different functional substituents.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D009279:Naphthacenes / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D009279:Naphthacenes