Adriamycin analogues. 3. Synthesis of N-alkylated anthracyclines with enhanced efficacy and reduced cardiotoxicity.
Reaction of daunorubicin (1) and adriamycin (2) with aldehydes and ketones in the presence of NaCNBH3 afforded N-alkyl- and N,N-dialkylanthracyclines along with their 13-dihydro derivatives. Product ratios depended upon the nature of the carbonyl reagent and the starting drug. The majority of these analogues retained in vivo antitumor activity comparable to 1 and 2. However, unlike the parent compounds, which inhibit DNA and RNA synthesis at comparable concentrations, several of these analogues inhibit RNA synthesis at markedly lower concentrations than required to inhibit DNA synthesis. In addition, in some cases the ability to bind to DNA in vitro was reduced while antitumor activity was retained. N,N-Dibenzyldaunorubicin was especially notable for increased efficacy (T/C 259, qd 1--9) against P388 leukemia in mice, despite reduction of DNA binding in vitro. It showed almost complete loss of mutagenicity vs S. typhimurium (Ames test) and it was tenfold less cardiotoxic by electrocardiographic measurements (Zbinden test) in the rat.
D000478:Alkylation; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006331:Heart Diseases / Q000139:chemically induced*; D051379:Mice; D009153:Mutagens; D051381:Rats
D000903:Antibiotics, Antineoplastic; D009153:Mutagens; D004317:Doxorubicin; D004247:DNA