Homocamptothecins:  Synthesis and Antitumor Activity of Novel E-Ring-Modified Camptothecin Analogues

• Published in: Journal of medicinal chemistry Vol. 41; no. 27; pp. 5410 - 5419
• Main Authors: Lavergne, Olivier, Lesueur-Ginot, Laurence, Pla Rodas, Francesc, Kasprzyk, Philip G, Pommier, Jacques, Demarquay, Danièle, Prévost, Grégoire, Ulibarri, Gérard, Rolland, Alain, Schiano-Liberatore, Anne-Marie, Harnett, Jeremiah, Pons, Dominique, Camara, José, Bigg, Dennis C. H
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 31-12-1998
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Benzoxepins - chemical synthesis; Benzoxepins - chemistry; Benzoxepins - pharmacology; Biological and medical sciences; Camptothecin - analogs & derivatives; Camptothecin - chemical synthesis; Camptothecin - chemistry; Camptothecin - pharmacology; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Female; General aspects; Humans; Inhibitory Concentration 50; Male; Medical sciences; Mice; Mice, Nude; Neoplasm Transplantation; Pharmacology. Drug treatments; Stereoisomerism; Structure-Activity Relationship; Topoisomerase I Inhibitors; Transplantation, Heterologous; Tumor Cells, Cultured; Antineoplastic agent; Pentacyclic compound; Intraperitoneal administration; Lactam; Cytotoxicity; Isomerases; Structure activity relation; Aromatic compound; Colon; Chemical synthesis; Tumor cell; Oxygen nitrogen heterocycle; Human; Enzyme; DNA topoisomerase; Enzyme inhibitor; Lactone; Malignant tumor; In vitro; In vivo; Chemotherapy; Experimental disease; Cell line; Treatment; Chemical homologation; Fluorine Organic compounds
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980400l

Homocamptothecin (hCPT), a camptothecin (CPT) analogue with a seven membered β-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 23 g at a daily dose of 0.32 mg/kg, compared to 4 days with CPT at 0.625 mg/kg. Thus difluorinated hCPT 23 g warrants further investigation as a novel Topo I inhibitor with high cytotoxicity toward tumor cells and promising in vivo efficacy.