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 synthesized. A common multistep pathway characterized by conventional reactions, involving Fischer-indole type syntheses, yielded the tetracyclic compounds. With the aim to improve solubility under physiological conditions and cytotoxic activity, 11H-PyC and 11H-THPyC derivatives were provided with a diethylaminoethyl side-chain. The antiproliferative activity was assayed on human tumor cell lines and derivatives 8a, 22, 25 and 27 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. Otherwise, for 9, 14 and 15, notwithstanding a significant antiproliferative effect, no inhibition on the enzyme activity was evidenced, thus suggesting for these ellipticine-like structures an unexpected and novel mode of action independent from DNA binding and/or topoisomerase II activity.