title: Synthesis and antiproliferative activity of basic thioanalogues of merbarone.
abstract: Three series of 5-substituted 1,3-diphenyl-6-(omega-dialkyl- and omega-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 microM), 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 microM. In contrast, 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 microM). 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(2)H(5)>COCH(3)>>C(6)H(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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genova, Italy. ranise@unige.it
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Andrea
authors.initials: A
authors.lastname: Spallarossa
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Francesco
authors.initials: F
authors.lastname: Bondavalli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pani
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Marongiu
authors.forename: Valeria
authors.initials: V
authors.lastname: Mascia
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007624:KB Cells; D007928:Lethal Dose 50; D013858:Thiobarbiturates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D013858:Thiobarbiturates; D059005:Topoisomerase II Inhibitors; C045459:merbarone