Adriamycin analogues. Preparation and biological evaluation of some N-perfluoroacyl analogues of daunorubicin, adriamycin, and N-(trifluoroacetyl)adriamycin 14-valerate and their 9,10-anhydro derivatives.
The experimental and clinical antitumor activity, as well as the low toxicity, of N-(trifluoroacetyl)adriamycin 14-valerate (AD 32), a non-DNA binding anthracycline analogue, has led us to prepare and evaluate several N-perfluoroacyl analogues of daunorubicin, adriamycin, and N-(trifluoroacetyl)adriamycin 14-valerate. Target compounds were prepared by reaction of the appropriate perfluoroacyl anhydride with daunorubicin in chloroform-ether, with adriamycin in cold pyridine, and with adriamycin 14-valerate in ethyl acetate. In connection with this work, it was found that reaction of perfluoroacyl anhydrides with N-acylated or N-unsubstituted anthracyclines in pyridine at room temperature afforded with ease and in good yield the corresponding 9,10-anhydro-N-acylated derivatives. A number of products showed good to highly significant antitumor activity in vivo against the murine P388 leukemia system. However, the lack of in vivo antitumor activity of the pentafluoropropionyl and heptafluorobutyryl analogues of N-(trifluoroacetyl)adriamycin 14-valerate is noteworthy. The results continue to show that non-DNA binding anthracycline analogues can exhibit in vivo antitumor activity. Loss of the anthracycline 9-carbinol function by dehydration leads to reduction of biological activity as compared to the parent compound.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008968:Molecular Conformation
D000970:Antineoplastic Agents; C016163:valrubicin; D004317:Doxorubicin; D003630:Daunorubicin