Synthesis, topoisomerase I inhibitory activity and in vitro cytotoxicity of camptothecin derivatives bearing five-membered heterocycle containing 10-substituents

Authors: Zhao R.; Guan L.; Oreski B.¹; Lown J.²

Source: Anti-Cancer Drug Design, Volume 13, Number 2, 1998 , pp. 145-157(13)

Publisher: Cognizant Communication Corporation

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Abstract:

A series of new camptothecin derivatives bearing certain five-membered heterocycles was synthesized and evaluated for in vitro cytotoxic activity. The cytotoxicity results show that camptothecin derivatives bearing pyrrole and thiophene rings were more potent than camptothecin, whereas those bearing furan were less active than camptothecin. Agarose gel electrophoresis shows different inhibitory activities of the camtothecin analogs towards topoisomerase I DNA cleavage. The pyrrole-containing compounds inhibit topoisomerase I DNA cleavage more strongly than camptothecin, but the thiophene ad furan compounds do not show any 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 analogs.

Key words: camptothecin/DNA cleavage/pyrrole compounds/topoisomerase I

Document Type: Research article

Affiliations: 1: SynPhar Laboratories Inc., 4290 91a Street, Edmonton, Alberta, Canada 56E 5V2 2: Corresponding author

Publication date: 1998-01-01