title: Discovery and investigation of anticancer ruthenium-arene Schiff-base complexes via water-promoted combinatorial three-component assembly.
abstract: The structural diversity of metal scaffolds makes them a viable alternative to traditional organic scaffolds for drug design. Combinatorial chemistry and multicomponent reactions, coupled with high-throughput screening, are useful techniques in drug discovery, but they are rarely used in metal-based drug design. We report the optimization and validation of a new combinatorial, metal-based, three-component assembly reaction for the synthesis of a library of 442 Ru-arene Schiff-base (RAS) complexes. These RAS complexes were synthesized in a one-pot, on-a-plate format using commercially available starting materials under aqueous conditions. The library was screened for their anticancer activity, and several cytotoxic lead compounds were identified. In particular, [(η6-1,3,5-triisopropylbenzene)RuCl(4-methoxy-N-(2-quinolinylmethylene)aniline)]Cl (4) displayed low micromolar IC50 values in ovarian cancers (A2780, A2780cisR), breast cancer (MCF7), and colorectal cancer (HCT116, SW480). The absence of p53 activation or changes in IC50 value between p53+/+ and p53-/- cells suggests that 4 and possibly the other lead compounds may act independently of the p53 tumor suppressor gene frequently mutated in cancer.
authors.affiliation: Department of Chemistry, National University of Singapore , 3 Science Drive 3, 117543 Singapore.
authors.forename: Mun Juinn
authors.initials: MJ
authors.lastname: Chow
authors.forename: Cynthia
authors.initials: C
authors.lastname: Licona
authors.forename: Daniel
authors.initials: D
authors.lastname: Yuan Qiang Wong
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pastorin
authors.forename: Christian
authors.initials: C
authors.lastname: Gaiddon
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*; D012545:Schiff Bases / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014867:Water / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D012545:Schiff Bases; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014867:Water; D012428:Ruthenium; D002945:Cisplatin