Synthesis and antiproliferative activity of some ellipticine-like 11H-pyrido[a]carbazole derivatives.

Some modified 11H-pyrido[a]carbazoles (11H-PyC) and their corresponding tetrahydro derivatives (11H-THPyC) were prepared. A common multistep pathway characterized by conventional reactions, including a Fischer-indole-type synthesis, yielded the tetracyclic compounds. To improve cytotoxicity, 11H-PyC and 11H-THPyC derivatives were endowed with a diethylaminoethyl side chain. The antiproliferative activity was assessed in three human tumor cell lines, and a number of derivatives showed a cytotoxic effect in agreement with their capacity to form a molecular intercalative complex with DNA and to interfere with the relaxation activity of DNA topoisomerase II. In contrast, three derivatives that exhibited significant antiproliferative efficacy, showed no inhibition of topoisomerase II, thus suggesting an unexpected and novel mode of action for these ellipticine-like compounds independent of topoisomerase II activity.