Inhibition of human DNA topoisomerase IB by nonmutagenic ruthenium(II)-based compounds with antitumoral activity

摘要: Herein we synthesized two new ruthenium(II) compounds [Ru(pySH)(bipy)(dppb)]PF6 (1) and [Ru(HSpym)(bipy)(dppb)]PF6 (2) that are analogs to an antitumor agent recently described, [Ru(SpymMe2)(bipy)(dppb)]PF6 (3), where [(Spy) = 2-mercaptopyridine anion; (Spym) 2-mercaptopyrimidine anion (SpymMe2) 4,6-dimethyl-2-mercaptopyrimidine anion]. In vitro cell culture experiments revealed significant anti-proliferative activity for 1-3 against HepG2 MDA-MB-231 tumor cells, higher than the standard anti-cancer drugs doxorubicin cisplatin. No mutagenicity is detected when evaluated by cytokinesis-blocked micronucleus cytome Ames test in presence absence of S9 metabolic activation from rat liver. Interaction studies show can bind DNA through electrostatic interactions albumin hydrophobic interactions. The three able inhibit supercoiled relaxation mediated human topoisomerase IB (Top1). Compound 3 most efficient Top1 inhibitor inhibitory effect enhanced upon pre-incubation with enzyme. Analysis different steps catalytic cycle indicates inhibits cleavage reaction impeding binding enzyme slows down religation reaction. Molecular docking shows preferentially binds closer residues active site free lies on groove downstream Top1-DNA complex. Thus, be considered further a possible use as anticancer agent.