Synthesis and antiproliferative activity of basic thioanalogues of merbarone

Abstract

Three series of 5-substituted 1,3-diphenyl-6-(ω-dialkyl- and ω-cyclo-aminoalkyl)thio-2-thiobarbiturates ( 11– 13) 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 analogues 14 was also prepared. Derivatives 11b, e, 14b, e, h, i, j were active in the low micromolar concentration range (IC 50: 3.3–4.3 μM), whereas compounds 11a, c, d, f,h, j and 13a, b, d, g, j and 14a, d, f showed IC 50 values between 10 and 15.5 μM. In constrast, compounds 12a– c, g– j, 13e, f, h and 14k were inactive. Cytotoxicity data provided from N.C.I. on selected compounds provided evidence that 11b, d, 13d, g and 14b, d, f, h, i, j were endowed with potent antiproliferative activity against leukemia and prostate cell lines (GI 50 up to 0.01 μM). In general, bicyclic derivatives 14 were up to 10-fold more potent than monocyclic counterparts against solid tumor-derived cell lines. 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 derivatives ( 11– 13) antiproliferative activity was strongly affected by the nature of the 5-substituents (COOC 2H 5>COCH 3≫C 6H 5). Compounds 11b and 14b were also evaluated against KB cell subclones expressing altered levels of topoisomerases or the multidrug resistance phenotype (MDR). In both cases the above compounds showed a decrease in potency. In enzyme assays, 11b and 14b turned out to be inhibitors of topoisonerase II as merbaron.