Synthesis and antiproliferative activity of basic thioanalogues of merbarone

Three series of 5-substituted 1,3-diphenyl-6-(ω-dialkyl- and ω-cyclo-aminoalkyl)thio-2-thiobarbiturates were synthesized as polysubstituted thioanalogues of merbarone, a topoisomerase II inhibitor acting on the catalytic site. To better understand pharmacophore requirements, a forth series of conformationally constrained analogs was also prepd. Some of these compds. were active in the low micromolar concn. range (IC50: 3.3-4.3 μM), and other compds. showed IC50 values between 10 and 15.5 μM. In contrast, some other were inactive. Cytotoxicity data provided from N.C.I. on selected compds. provided evidence that these compds. were endowed with potent antiproliferative activity against leukemia and prostate cell lines (GI50 up to 0.01 μM). In general, bicyclic derivs. were up to 10-fold more potent than monocyclic counterparts against solid tumor-derived cell lines. Structure-activity relationships (SAR) studies indicated that, in general, a certain tolerability in length of the alkyl side chains and in shape of distal amines is allowed in the four series, but in the monocyclic derivs. antiproliferative activity was strongly affected by the nature of the 5-substituents (COOC2H5>COCH3»C6H5). Some compds. were also evaluated against KB cell subclones expressing altered levels of topoisomerases or the multidrug resistance phenotype (MDR). In both cases the above compds. showed a decrease in potency. In enzyme assays two compds. turned out to be inhibitors of topoisomerase II as merbarone.