The anthracycline antitumor antibiotic adriamycin (doxorubicin) continues to be one of the most widely used drugs in cancer medicine. However, its toxicity and lack of effectiveness against some of the more common carcinomatous tumors continue to emphasize a need for analogs with improved therapeutic efficacy. While others approached this work from the generally-accepted mechanistic aspect of drug-DNA binding, work in these laboratories included the study of analogs having greatly altered capacity for DNA binding. This unconventional approach has resulted in the development of some of the most active and mechanistically-novel adriamycin analogs so far developed for clinical evaluation. One analog, N- trifluoroacetyladriamycin-14-valerate (AD 32), for which no interaction with DNA has yet been demonstrated, has already shown activity in humans, with low toxicity in general and no cardiotoxicity in specific; N-trifluoroacetyladriamycin-14-0- hemiadipate (AD 143), a second-generation AD 32 analog with improved aqueous solubility, is about to enter the clinic. We have now identified a new family of promising 14-acyl-N-alkyladriamycin analogs which show therapeutic superiority to adriamycin and, surprisingly, to the corresponding N-alkyl analogs lacking the 14- acyl substituent. In addition, these products, as typified by N- benzyladria-mycin-14-valerate (AD 198), show a range of mechanistic properties quite different from those of adriamycin or the N=acyl AD 32/AD 143-type compounds. The present proposal is concerned with preclinical developmental studies with these new N-alkyl- anthracycline analogs in order to better define their antitumor activity, toxicity, and pharmacology. In addition, the preparation and evaluation of similar 4-O-desmethyl-N-alkylanthracycline analogs will be conducted, based upon the finding of unusually high levels of 4-0-desmethylated metabolites in animals treated with AD 198. Further pharmacologic studies with AD 32 and AD 143, aimed at improving the potential clinical efficacy of these agents, are included. In addition, the resources provided by this program will be used for the early evaluation of other new and mechanistically novel adriamycin analogs emerging from our parallel drug synthesis effort: the results of these studies will thus provide a basis for the selection of future target compounds for eventual detailed investigation.
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