title: Synthesis and pharmacological evaluation of novel non-lactone analogues of camptothecin.
abstract: Ten novel camptothecin (CPT) derivatives devoid of the lactone function in the E-ring were synthesized and evaluated as anticancer agents. Several of these CPT analogues bearing a five-membered E-ring are potent inhibitors of the DNA relaxation and cleavage reactions catalyzed by topoisomerase I and exhibit promising cytotoxic activities with IC(50) values in the nM range. This is the first successful design of lactone-free CPT, providing thus a new avenue to the development of topoisomerase I targeted antitumor agents.
authors.affiliation: Institut de Recherches Servier, 125 Chemin de Ronde, 78290, Croissy sur Seine, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hautefaye
authors.forename: Bernard
authors.initials: B
authors.lastname: Cimetière
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: John
authors.initials: J
authors.lastname: Hickman
authors.forename: William
authors.initials: W
authors.lastname: Laine
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lavielle
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D015195:Drug Design; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000737:chemistry; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D007783:Lactones; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin