title: Synthesis, topoisomerase I inhibitory activity and in vitro cytotoxicity of camptothecin derivatives bearing five-membered heterocycle containing 10-substituents.
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 camptothecin analogs towards topoisomerase I DNA cleavage. The pyrrole-containing compounds inhibit topoisomerase I DNA cleavage more strongly than camptothecin, but the thiophene and 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.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Zhao
authors.forename: L L
authors.initials: LL
authors.lastname: Guan
authors.forename: B
authors.initials: B
authors.lastname: Oreski
authors.forename: J W
authors.initials: JW
authors.lastname: Lown
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001483:Base Sequence; D002166:Camptothecin / Q000031:analogs & derivatives*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004278:DNA, Superhelical / Q000187:drug effects / Q000378:metabolism; D004586:Electrophoresis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells; D008223:Lymphoma / Q000188:drug therapy; D051379:Mice; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin