title: Chiral ruthenium(II) anthraquinone complexes as dual inhibitors of topoisomerases I and II.
abstract: DNA topoisomerases (I and II) have been one of the excellent targets in anticancer drug development. Here two chiral ruthenium(II) anthraquinone complexes, Δ- and Λ-[Ru(bpy)(2)(ipad)](2+), where bpy is 2,2'-bipyridine and ipad is 2-(anthracene-9,10-dione-2-yl)imidazo[4,5-f][1,10]phenanthroline, were synthesized and characterized. As expected, both of the Ru(II) complexes intercalate into DNA base pairs and possess an obviously greater affinity with DNA. Topoisomerase inhibition and DNA strand passage assay confirmed that the two complexes are efficient dual inhibitors of topoisomerases I and II by interference with the DNA religation. In MTT cytotoxicity studies, two Ru(II) complexes exhibited antitumor activity against HeLa, MCF-7, HepG2 and BEL-7402 tumor cell lines. Flow cytometry analysis shows an increase in the percentage of cells with apoptotic morphological features in the sub-G1 phase for Ru(II) complexes. Nuclear chromatin cleavage has also been observed from AO/EB staining assay and alkaline single-cell gel electrophoresis (comet assay). The results demonstrated that Δ- and Λ-[Ru(bpy)(2)(ipad)](2+) act as dual inhibitors of topoisomerases I and II, and cause DNA damage that can lead to cell cycle arrest and/or cell death by apoptosis.
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China.
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Kou
authors.forename: Chen
authors.initials: C
authors.lastname: Qian
authors.forename: Jin-Quan
authors.initials: JQ
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
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: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000201:enzymology; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D012428:Ruthenium; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II