title: Structural Determinants of p53-Independence in Anticancer Ruthenium-Arene Schiff-Base Complexes.
abstract: p53 is a key tumor suppressor gene involved in key cellular processes and implicated in cancer therapy. However, it is inactivated in more than 50% of all cancers due to mutation or overexpression of its negative regulators. This leads to drug resistance and poor chemotherapeutic outcome as most clinical drugs act via a p53-dependent mechanism of action. An attractive strategy to circumvent this resistance would be to identify new anticancer drugs that act via p53-independent mode of action. In the present study, we identified 9 Ru (II)-Arene Schiff-base (RAS) complexes able to induce p53-independent cytotoxicity and discuss structural features that are required for their p53-independent activity. Increasing hydrophobicity led to an increase in cellular accumulation in cells with a corresponding increase in efficacy. We further showed that all nine complexes demonstrated p53-independent activity. This was despite significant differences in their physicochemical properties, suggesting that the iminoquinoline ligand, a common structural feature for all the complexes, is required for the p53-independent activity.
authors.affiliation: Department of Chemistry, National University of Singapore , 3 Science Drive 3, 117543 Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore , 28 Medical Drive, 117456 Singapore.
authors.forename: Mun Juinn
authors.initials: MJ
authors.lastname: Chow
authors.affiliation: Department of Chemistry, National University of Singapore , 3 Science Drive 3, 117543 Singapore.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Babak
authors.affiliation: Department of Chemistry, National University of Singapore , 3 Science Drive 3, 117543 Singapore.
authors.forename: Daniel Yuan Qiang
authors.initials: DY
authors.lastname: Wong
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore , 28 Medical Drive, 117456 Singapore.|Department of Pharmacy, National University of Singapore , 18 Science Drive 4, 117543 Singapore.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pastorin
authors.affiliation: U1113 INSERM, 3 Avenue Molière, Strasbourg 67200, France.|Oncology Section, FMTS, Université de Strasbourg , F-67081 Strasbourg, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Gaiddon
authors.affiliation: Department of Chemistry, National University of Singapore , 3 Science Drive 3, 117543 Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore , 28 Medical Drive, 117456 Singapore.
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D045325:HCT116 Cells; D006801:Humans; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry*; D012545:Schiff Bases / Q000737:chemistry*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D012545:Schiff Bases; D016159:Tumor Suppressor Protein p53; D012428:Ruthenium
keywords: anticancer; p53-independent activity; ruthenium-arene Schiff-base complexes; structure−activity relationship studies