title: Topoisomerase I-mediated antiproliferative activity of enantiomerically pure fluorinated homocamptothecins.
abstract: Homocamptothecin (hCPT) is an E-ring modified camptothecin (CPT) analogue bearing a methylene spacer between the alcohol and carboxyl functions of the CPT lactone. Combining pronounced inhibitory activity of topoisomerase I (Topo I) with enhanced plasma stability, hCPT constitutes an attractive template for the elaboration of new anticancer agents. Fluorinated hCPT analogues, prepared in enantiomerically pure form, were assayed by their stimulation of Topo I-mediated DNA cleavage. Translation into cytotoxicity against tumor cells was evaluated on HT29 human colon adenocarcinoma and on the multidrug resistant lung and bladder tumor cell lines, A549 and T24r. Good correlation is observed between the ability of the drugs to stimulate Topo I-mediated DNA cleavage and the respective 50% inhibitory concentrations (IC(50) values) of the HT29, A549, and T24r cell growth. Fluorine substitution in the A-ring of hCPT was found to have a pronounced influence on biological activity, providing several compounds which are up to 100-fold more potent than CPT in terms of IC(50). Among these, 10,11-difluoro-hCPT has been selected for further development.
authors.affiliation: Institut Henri Beaufour, Les Ulis, France. olivier.lavergne@beaufour-ipsen.com
authors.forename: O
authors.initials: O
authors.lastname: Lavergne
authors.forename: D
authors.initials: D
authors.lastname: Demarquay
authors.forename: C
authors.initials: C
authors.lastname: Bailly
authors.forename: C
authors.initials: C
authors.lastname: Lanco
authors.forename: A
authors.initials: A
authors.lastname: Rolland
authors.forename: M
authors.initials: M
authors.lastname: Huchet
authors.forename: H
authors.initials: H
authors.lastname: Coulomb
authors.forename: N
authors.initials: N
authors.lastname: Muller
authors.forename: N
authors.initials: N
authors.lastname: Baroggi
authors.forename: J
authors.initials: J
authors.lastname: Camara
authors.forename: C
authors.initials: C
authors.lastname: Le Breton
authors.forename: E
authors.initials: E
authors.lastname: Manginot
authors.forename: J B
authors.initials: JB
authors.lastname: Cazaux
authors.forename: D C
authors.initials: DC
authors.lastname: Bigg
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C120029:homocamptothecin; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin