title: Ruthenium-Arene-β-Carboline Complexes as Potent Inhibitors of Cyclin-Dependent Kinase 1: Synthesis, Characterization and Anticancer Mechanism Studies.
abstract: A series of Ru(II)-arene complexes (1-6) of the general formula [(η(6)-arene)Ru(L)Cl]PF6 (arene=benzene or p-cymene; L=bidentate β-carboline derivative, an indole alkaloid with potential cyclin-dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X-ray crystallography. Hydrolytic studies show that β-carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3- to 12-fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross-resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1-6 may directly target CDK1, because they can block cells in the G2M phase, down-regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial-related pathways and intracellular reactive oxygen species (ROS) elevation.
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275 (P. R. China), Fax: (+86) 20-8411-2245.
authors.forename: Liang
authors.initials: L
authors.lastname: He
authors.forename: Si-Yan
authors.initials: SY
authors.lastname: Liao
authors.forename: Cai-Ping
authors.initials: CP
authors.lastname: Tan
authors.forename: Rui-Rong
authors.initials: RR
authors.lastname: Ye
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Xu
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.forename: Liang-Nian
authors.initials: LN
authors.lastname: Ji
authors.forename: Zong-Wan
authors.initials: ZW
authors.lastname: Mao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D012428:Ruthenium; D016203:CDC2 Protein Kinase; D002945:Cisplatin
keywords: alkaloids; antitumor agents; apoptosis; inhibitors; ruthenium