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.
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Mun Juinn Chow, Cynthia Licona, Daniel Yuan Qiang Wong, Giorgia Pastorin, Christian Gaiddon, et al.. Discovery and Investigation of Anticancer Ruthenium–Arene Schiff-Base Complexes via Water-Promoted Combinatorial Three-Component Assembly. Journal of Medicinal Chemistry, American Chemical Society, 2014, 57 (14), pp.6043-6059. ⟨10.1021/jm500455p⟩. ⟨inserm-02360394⟩

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