title: Homocamptothecins: synthesis and antitumor activity of novel E-ring-modified camptothecin analogues.
abstract: Homocamptothecin (hCPT), a camptothecin (CPT) analogue with a seven membered beta-hydroxylactone which combines enhanced plasma stability and potent topoisomerase I (Topo I)-mediated activity, is an attractive template for the elaboration of new anticancer agents. Like CPT, hCPT carries an asymmetric tertiary alcohol and displays stereoselective inhibition of Topo I. The preparation and biological screening of racemic hCPT analogues are described. The 10 hCPTs tested were better Topo I inhibitors than CPT. Fluorinated hCPTs 23c, d,f,g were found to have potent cytotoxic activity on A427 and PC-3 tumor cell lines. Their cytotoxicity remained high on the K562adr and MCF7mdr cell lines, which overexpress a functionally active P-glycoprotein. Fluorinated hCPTs were more efficacious in vivo than CPT on HT-29 xenografts. In this model, a tumor growth delay of 25 days was reached with hCPT 23g at a daily dose of 0.32 mg/kg, compared to 4 days with CPT at 0.625 mg/kg. Thus difluorinated hCPT 23g warrants further investigation as a novel Topo I inhibitor with high cytotoxicity toward tumor cells and promising in vivo efficacy.
authors.affiliation: Institut Henri Beaufour, 5, avenue du Canada, F-91966 Les Ulis, France.
authors.forename: O
authors.initials: O
authors.lastname: Lavergne
authors.forename: L
authors.initials: L
authors.lastname: Lesueur-Ginot
authors.forename: F
authors.initials: F
authors.lastname: Pla Rodas
authors.forename: P G
authors.initials: PG
authors.lastname: Kasprzyk
authors.forename: J
authors.initials: J
authors.lastname: Pommier
authors.forename: D
authors.initials: D
authors.lastname: Demarquay
authors.forename: G
authors.initials: G
authors.lastname: Prévost
authors.forename: G
authors.initials: G
authors.lastname: Ulibarri
authors.forename: A
authors.initials: A
authors.lastname: Rolland
authors.forename: A M
authors.initials: AM
authors.lastname: Schiano-Liberatore
authors.forename: J
authors.initials: J
authors.lastname: Harnett
authors.forename: D
authors.initials: D
authors.lastname: Pons
authors.forename: J
authors.initials: J
authors.lastname: Camara
authors.forename: D C
authors.initials: DC
authors.lastname: Bigg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C116718:5-ethyl-9,10-difluoro-1,4,5,13-tetrahydro-5-hydroxy-3H,15H-oxepino(3',4'-6,7)indolizino(1,2-b)quinoline-3,15-dione; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001584:Benzoxepins; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin