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]quinazolin-12(10H)-ones and isoindolo[2,1-a]benzimidazoles related to batracylin are described. The acute toxicity of batracyclin has been associated with the formation of its N-acetyl metabolite which is a potent inducer of unscheduled DNA synthesis in rat hepatocytes. The desamino derivative and the 8-aza analog of batracylin retained the ability to inhibit topoisomerase II but did not induce unscheduled DNA synthesis. While less active than batracylin, these analogs were cytotoxic to CCRF CEM leukemia cells. The isoindolo[2,1-a]benzimidazole derivatives were inactive as topoisomerase II inhibitors and, in general, failed to exhibit comparable antitumor activity or to induce unscheduled DNA synthesis.