title: Dual topoisomerase I and II poisoning by chiral Ru(II) complexes containing 2-thiophenylimidazo[4,5-f][1,10]phenanthroline derivatives.
abstract: A series of chiral Ru(II) complexes bearing thiophene ligands were synthesized and characterized. Both Ru(II) complexes Δ/Λ-[Ru(bpy)2(pscl)](2+) (Δ/Λ-1) and Δ/Λ-[Ru(bpy)2(psbr)](2+) (Δ/Λ-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, Δ enantiomers were more active than Λ 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). Δ-1 and Δ-2 inhibited the growth of HeLa cells through the induction of apoptotic cell death, as evidenced by the Alexa Fluor® 488 annexin V staining assays and flow cytometry analysis. The results demonstrated that Δ/Λ-1 and Δ/Λ-2 acted as dual topoisomerase I and II poisons and caused DNA damage that could lead to cell cycle arrest by apoptosis.
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Optoelectronic Materials and Technologies, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
authors.forename: Yu-Chuan
authors.initials: YC
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Qian
authors.forename: Zai-Li
authors.initials: ZL
authors.lastname: Peng
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Hou
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Chao
authors.forename: Liang-Nian
authors.initials: LN
authors.lastname: Ji
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry* / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D010618:Phenanthrolines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors; D012428:Ruthenium; D004247:DNA
keywords: Apoptosis; DNA-binding; Ru(II) complexes; Topoisomerase inhibition