title: Antitumor agents 6. Synthesis, structure-activity relationships, and biological evaluation of spiro[imidazolidine-4,3'-thieno[2,3-g]quinoline]-tetraones and spiro[thieno[2,3-g]quinoline-3,5'-[1,2,4]triazinane]-tetraones with potent antiproliferative activity.
abstract: Two series of quinolinquinone derivatives, 2'H-spiro[imidazolidine-4,3'-thieno[2,3-g]quinoline]-2,4',5,9'-tetraones (2a-n) and 2H-spiro[thieno[2,3-g]quinoline-3,5'-[1,2,4]triazinane]-3',4,6',9-tetraones (3a-e), were designed and synthesized using the previously described ethyl 3-amino-4,9-dioxo-2,3,4,9-tetrahydrothieno[2,3-g]quinoline-3-carboxylate (1) as a starting material. All compounds were evaluated for their antiproliferative activity against a panel of representative liquid and solid human tumor cell lines and exhibit IC(50) values in the micromolar/submicromolar range. Series 2 displayed higher cytotoxicity than did series 3. The nature of the substituents on both imidazoline and triazinane N1 nitrogen markedly affected the activity profile of these series. Spectrophotometric and fluorescence measurements as well as unwinding assays performed on the most cytotoxic compounds, 2c, 2g, and 2k, showed that they are nonintercalative DNA agents and inhibit the catalytic activity of Topo II in a concentration-dependent mode. 2g was the most active Topo II inhibitor with activity levels comparable to those of VP-16.
authors.affiliation: Dipartimento di Chimica Organica e Biochimica, Universita di Napoli Federico II, Via Cynthia 6, Monte Sant'Angelo, I-80126 Napoli, Italy. bologne@unina.it
authors.forename: Adele
authors.initials: A
authors.lastname: Bolognese
authors.forename: Gaetano
authors.initials: G
authors.lastname: Correale
authors.forename: Michele
authors.initials: M
authors.lastname: Manfra
authors.forename: Anna
authors.initials: A
authors.lastname: Esposito
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D004247:DNA