| Abstract
| - New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones (PIQDs, 1−7), were designed on the basis of a molecular model obtained by aligningthe common quinolinquinone substructure of 5H-pyrido[3,2-a]phenoxazin-5-one (PPH) and someknown anticancer agents. A Diels−Alder reaction between quinolin-5,8-dione (QD) and a2-azadiene, formed by demolition of 2-aryl-1,3-thiazolidine ethyl esters (T compounds), wasused to produce 1−7 and the isomeric 1-aryl-3-ethoxycarbonylpyrido[3,2-g]isoquinolin-5,10-diones (8−14). Two other compounds, the 3-amino-3-ethoxycarbonyldihydrothieno[2,3-g]quinolin-4,9-dione (15) and the 3-amino-3-ethoxycarbonyldihydrothieno[3,2-g]quinolin-4,9-dione(16), arising from a 1,4 Michael reaction of QD with a thiolate species formed by opening of Tcompounds, were recovered from the reaction mixture. The antiproliferative activity of 1−16was evaluated against representative human liquid and solid neoplastic cell lines. The IC50 ofthese compounds had median values in the range 2.00−0.01 μM, with 2−4 and 15 exhibitingsignificantly higher in vitro cytotoxic activity. Compound 2, also evaluated against KB subclones(KBMDR, KB7D, and KBV20C), was shown to be scarcely subject to the MDR1/P-glycoprotein drugefflux pump responsible for drug resistance. The noncovalent DNA-binding properties of PIQDswere examined using UV−vis and 1H NMR spectroscopy experiments. Accordingly, thesecompounds were confirmed to have an ability to intercalate into double-stranded DNA bytopoisomerase I superhelix unwinding assay. Interesting structure−activity relationships werefound. Three important features seem to contribute to the cytotoxic activity of these anticancerligands: (i) the DNA intercalating capability of the three-cyclic quinonic system, typical ofthis class of compounds, (ii) the position of the pendant phenyl ring that, according to thesuperimposition model, must occupy the same area of the corresponding benzo-fused ring A ofPPH, and (iii) the effect of electron-withdrawing substituents on the phenyl ring, which cancontribute improving the π−π stacking interactions between ligand and DNA base pairs.Besides, a mechanism of action suspected to involve topoisomerases could be hypothesized tointerpret the antiproliferative activity of the thienoquinolindione 15, which can be regardedas a cyclic cysteine derivative.
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