Platinum(II) phenanthroimidazoles for targeting telomeric G-quadruplexes |
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Authors: | Castor Katherine J Mancini Johanna Fakhoury Johans Weill Nathanael Kieltyka Roxanne Englebienne Pablo Avakyan Nicole Mittermaier Anthony Autexier Chantal Moitessier Nicolas Sleiman Hanadi F |
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Affiliation: | Department of Chemistry, McGill University, Montreal, QC, Canada. |
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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. |
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Keywords: | antitumor agents G‐quadruplexes human telomeres phenanthroimidazole platinum |
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