SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF ISOINDOLO[1,2-B]QUINAZOLINONE AND ISOINDOLO[2,1-A]BENZIMIDAZOLE DERIVATIVES RELATED TO THE ANTITUMOR AGENT BATRACYLIN

The synthesis and pharmacological activity of isoindolo[1,2-b]quinazol in-12(10H)-ones and isoindolo[2,1-a]benzimidazoles related to batracyl in are described. The acute toxicity of batracyclin has been associate d with the formation of its N-acetyl metabolite which is a potent indu cer of unscheduled DNA synthesis in rat hepatocytes. The desamino deri vative and the 8-aza analog of batracylin retained the ability to inhi bit topoisomerase II but did not induce unscheduled DNA synthesis. Whi le less active than batracylin, these analogs were cytotoxic to CCRF C EM leukemia cells. The isoindolo[2,1-a]benzimidazole derivatives were inactive as topoisomerase II inhibitors and, in general, failed to exh ibit comparable antitumor activity or to induce unscheduled DNA synthe sis.