title: Platinum(II) phenanthroimidazoles for targeting telomeric G-quadruplexes.
abstract: A rationally designed progression of phenanthroimidazole platinum(II) complexes were examined for their ability to target telomere-derived intramolecular G-quadruplex DNA. Through the use of circular dichroism, fluorescence displacement assays, and molecular modeling we show that these complexes template and stabilize G-quadruplexes from sequences based on the human telomeric repeat (TTAGGG)(n). The greatest stabilization was observed for the p-chlorophenyl derivative 6((G4)DC(50) =0.31 μM). We also show that the G-quadruplex binding complexes are able to inhibit telomerase activity through a modified telomerase repeat amplification protocol (TRAP-LIG assay). Preliminary cell studies show that complex 6 is preferentially cytotoxic toward cancer over normal cell lines, indicating its potential use in cancer therapy.
authors: Department of Chemistry, McGill University, Montreal, QC, Canada.
authors: Katherine J
authors: KJ
authors: Castor
authors: Johanna
authors: J
authors: Mancini
authors: Johans
authors: J
authors: Fakhoury
authors: Nathanael
authors: N
authors: Weill
authors: Roxanne
authors: R
authors: Kieltyka
authors: Pablo
authors: P
authors: Englebienne
authors: Nicole
authors: N
authors: Avakyan
authors: Anthony
authors: A
authors: Mittermaier
authors: Chantal
authors: C
authors: Autexier
authors: Nicolas
authors: N
authors: Moitessier
authors: Hanadi F
authors: HF
authors: Sleiman
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology*; D016615:Telomere / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010616:Phenanthrenes; D004247:DNA