Dual topoisomerase I and II poisoning by chiral Ru(II) complexes containing 2-thiophenylimidazo[4,5-f][1,10]phenanthroline derivatives

A series of chiral Ru(II) complexes bearing thiophene ligands were synthesized and characterized. Both Ru(II) complexes Delta/Lambda-[Ru(bpy)(2)(pscl)](2+) (Delta/Lambda-1) and Delta/Lambda-[Ru(bpy)(2)(psbr)](2+) (Delta/Lambda-2) (bpy = 2,2'-bipyridine, pscl = 2(5-chlorothiophen-2-yl)imidazo[4,5-f][1,10]phenanthroline, psbr = 2-(5-bromothiophen-2-yl)imidazo[4,5-f][1,10]phenanthroline) showed antitumor activities against A549, HepG2 and BEL-7402 tumor cell lines, especially HeLa tumor cell line. Moreover, Delta enantiomers were more active than Lambda enantiomers, accounting for the different cellular uptake. In addition, with the extension of time, these enantiomers could finally accumulate in the nucleus, suggesting that nucleic acids were the cellular target of these enantiomers. The DNA-binding behaviors of complexes were studied using spectroscopic and viscosity measurements. Results suggested that four complexes could bind to DNA in an intercalative mode but no obvious DNA-binding selectivity between the enantiomers was observed. Topoisomerase inhibition and DNA religation assay confirmed that four complexes acted as efficient dual topoisomerase I and II poisons, DNA strand breaks had also been observed from alkaline single cell gel electrophoresis (comet assay). Delta-1 and Delta-2 inhibited the growth of HeLa cells through the induction of apoptotic cell death, as evidenced by the Alexa Fluor (R) 488 annexin V staining assays and flow cytometry analysis. The results demonstrated that Delta/Lambda-1 and Delta/Lambda-2 acted as dual topoisomerase I and II poisons and caused DNA damage that could lead to cell cycle arrest by apoptosis. (C) 2013 Elsevier Inc. All rights reserved.