Antitumor Agents 6. Synthesis, Structure-Activity Relationships, and Biological Evaluation of Spiroimidazolidine-4,3'-thieno2,3-gquinoline-tetraones and Spirothieno2,3-gquinoline-3,5'-1,2,4triazinane-tetraones with Potent Antiproliferativ

摘要

Two series of quinolinquinone derivatives, 2'H-spiroimidazolidine-4,3'-thieno2,3-gquinoline-2,4',5,9'-tetraone s (2a-n) and 2H-spirothieno2,3-gquinoline-3.5'-1,2,4triazinane-3',4,6',9-tetra ones (3a-e), were designed and synthesized using the previously described ethyl 3-amino-4,9-dioxo-2,3,4,9-tetrahydrothieno2,3-gquinoline-3-carboxylat e (1) as a starting material. All compounds were evaluated for their anti proliferative activity against a panel of representative liquid and solid human tumor cell lines and exhibit IC50 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 11 in a concentration-dependent mode. 2g was the most active Topo II inhibitor with activity levels comparable to those of VP-16.