title: A platinum(II) phenylphenanthroimidazole with an extended side-chain exhibits slow dissociation from a c-Kit G-quadruplex motif.
abstract: A series of three platinum(II) phenanthroimidazoles each containing a protonable side-chain appended from the phenyl moiety through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) were evaluated for their capacities to bind to human telomere, c-Myc, and c-Kit derived G-quadruplexes. The side-chain has been optimized to enable a multivalent binding mode to G-quadruplex motifs, which would potentially result in selective targeting. Molecular modeling, high-throughput fluorescence intercalator displacement (HT-FID) assays, and surface plasmon resonance (SPR) studies demonstrate that complex 2 exhibits significantly slower dissociation rates compared to platinum phenanthroimidazoles without side-chains and other reported G-quadruplex binders. Complex 2 showed little cytotoxicity in HeLa and A172 cancer cell lines, consistent with the fact that it does not follow a telomere-targeting pathway. Preliminary mRNA analysis shows that 2 specifically interacts with the ckit promoter region. Overall, this study validates 2 as a useful molecular probe for c-Kit related cancer pathways.
authors.affiliation: McGill University Department of Chemistry, 801 Sherbrooke West, Montreal, Quebec, H3A 0B8 (Canada).
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Castor
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Liu
authors.forename: Johans
authors.initials: J
authors.lastname: Fakhoury
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hancock
authors.forename: Anthony
authors.initials: A
authors.lastname: Mittermaier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moitessier
authors.forename: Hanadi F
authors.initials: HF
authors.lastname: Sleiman
mesh_terms: D057930:Click Chemistry; D015195:Drug Design; D054856:G-Quadruplexes; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D010984:Platinum / Q000737:chemistry*
chemical_list: D010984:Platinum
keywords: G-quadruplexes; cancer therapeutic; click chemistry; drug design; platinum(II)