SYNTHESIS, TOPOISOMERASE-I INHIBITORY ACTIVITY AND IN-VITRO CYTOTOXICITY OF CAMPTOTHECIN DERIVATIVES BEARING 5-MEMBERED HETEROCYCLE CONTAINING 10-SUBSTITUENTS

A series of new camptothecin derivatives bearing certain five-membered heterocycles was synthesized and evaluated for in vitro cytotoxic act ivity. The cytotoxicity results show that camptothecin derivatives bea ring pyrrole and thiophene rings were more potent than camptothecin, w hereas those bearing furan were less active than camptothecin. Agarose gel electrophoresis shows different inhibitory activities of the camp tothecin analogs towards topoisomerase I DNA. cleavage. The pyrrole-co ntaining compounds inhibit topoisomerase I DNA cleavage more strongly than camptothecin, but the thiophene and furan compounds do not show a ny inhibitory activities for DNA cleavage functions of topoisomerase I . Polyacrylamide gel sequencing electrophoresis shows that the pyrrole compounds induce single-strand breaks after incubating with a labeled DNA fragment. The results suggest that the pyrrole compounds fit the compound-enzyme-DNA complex better than camptothecin and the other ana logs.