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Platinum(II) Phenanthroimidazoles for Targeting Telomeric G‐Quadruplexes
Author(s) -
Castor Katherine J.,
Mancini Johanna,
Fakhoury Johans,
Weill Nathanael,
Kieltyka Roxanne,
Englebienne Pablo,
Avakyan Nicole,
Mittermaier Anthony,
Autexier Chantal,
Moitessier Nicolas,
Sleiman Hanadi F.
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100453
Subject(s) - telomerase , telomere , g quadruplex , circular dichroism , dna , chemistry , intramolecular force , cytotoxic t cell , fluorescence , microbiology and biotechnology , cancer cell , stereochemistry , biology , cancer , cancer research , biochemistry , gene , genetics , in vitro , physics , quantum mechanics
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 μ M ). 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.