SYNTHESIS, ANTI-TUMOR ACTIVITY, AND CARDIAC TOXICITY OF NEW 4-DEMETHOXYANTHRACYCLINES

  • 1 January 1983
    • journal article
    • research article
    • Vol. 67  (7-8) , 665-673
Abstract
The new anthracycline glycosides 4-demethoxy-4''-deoxydaunorubicin and 4-demethoxy-4''-O-methyldaunorubicin, synthesized by coupling 4-demethoxydaunomycinone with 1-chloro-derivatives of protected 4-O-methyl and 4-deoxydaunosamine derivatives, were converted into the corresponding doxorubicin analogs. The new compounds were compared for antitumor effect with the parent drugs and with the previously described 4-demethoxydaunorubicin, 4-demethoxy-4''-epidaunorubicin and their doxorubicin analogs. All of the new analogs were more cytotoxic against HeLa [human cervical carcinoma] cells in vitro and were more toxic and more potent in mice than the parent drugs. Comparison at optimal antitumor doses showed that the new analogs were as active as the parent drugs against ascitic [murine] P388 leukemia and disseminated Gross leukemia cells. They were also active when administered orally. The new doxorubicin analogs were slightly more active than doxorubicin against ascitic L1210 leukemia and were markedly more active against disseminated L1210 leukemia. In a parallel activity-cardiotoxicity test in C3H mice repeatedly treated i.v., 4-demethoxydoxorubicin, 4-demethoxy-4''-epidoxorubicin, 4-demethoxy-4''-O-methyldoxorubicin and 4-demethoxy-4''-deoxydoxorubicin showed antitumor activity against mammary carcinoma without inducing the typical myocardial lesions observed after doxorubicin treatment. 4-Demethoxy-4''-O-methyldoxorubicin, because of its high antitumor effectiveness, lack of cardiac toxicity in mice and activity by the oral route, deserves further study.