Polypyridyl Complexes of Ruthenium(II): Stabilization of G-quadruplex DNA and Inhibition of Telomerase Activity

Authors

  • Dr. Du Liu,

    1. Department of Chemistry, Jinan University, Guangzhou 510632 (P. R. China), Fax: (+86) 20-8522-1263
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    • These authors contributed equally to this work.

  • Yanan Liu,

    1. Department of Chemistry, Jinan University, Guangzhou 510632 (P. R. China), Fax: (+86) 20-8522-1263
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    • These authors contributed equally to this work.

  • Chuan Wang,

    1. Department of Chemistry, Jinan University, Guangzhou 510632 (P. R. China), Fax: (+86) 20-8522-1263
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  • Prof. Shuo Shi,

    1. Department of Chemistry, Tongji University, Shanghai 200092 (P. R. China)
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  • Dongdong Sun,

    1. Department of Chemistry, Jinan University, Guangzhou 510632 (P. R. China), Fax: (+86) 20-8522-1263
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  • Dr. Feng Gao,

    Corresponding author
    1. School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275 (P. R. China)
    • School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275 (P. R. China)
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  • Prof. Qianling Zhang,

    Corresponding author
    1. Chemistry and Chemical Engineering, Shenzhen University, Shenzhen 518061 (P. R. China)
    • Chemistry and Chemical Engineering, Shenzhen University, Shenzhen 518061 (P. R. China)
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  • Prof. Jie Liu

    Corresponding author
    1. Department of Chemistry, Jinan University, Guangzhou 510632 (P. R. China), Fax: (+86) 20-8522-1263
    • Department of Chemistry, Jinan University, Guangzhou 510632 (P. R. China), Fax: (+86) 20-8522-1263
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Abstract

Two ruthenium(II) complexes [Ru(phen)2(tip)](ClO4)2 (1) and [Ru(bpy)2(tip)](ClO4)2 (2; phen=1,10-phenanthroline, bpy=2,2’-bipyridine, tip=2-thiophenimidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized by elemental analysis, 1H NMR spectroscopy, and electrospray ionization-mass spectrometry to explore the role of metal complexes as novel telomeric quadruplex stabilizers. The different quadruplex binding properties of these compounds were evaluated by absorption and emission analyses, circular dichroism spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, NMR spectroscopy, and molecular modeling. The results show that both complexes can well induce and stabilize different G-quadruplex structures using a 1:1 [quadruplex]/[complex] binding mode ratio. Complex 1 exhibits higher interaction ability at 1.43×106M−1 binding affinity and superior G-quadruplex selectivity over duplex DNA through multiple interaction (mainly intercalating) with the G-quadruplex at the 3’-terminal face. Furthermore, polymerase chain reaction (PCR)-stop assay, electrophoretic mobility shift assay, telomerase repeat amplification protocol, and MTT assay demonstrate that complex 1 not only can stabilize dimer forms of the G-quadruplex at low concentrations but also exhibit better inhibitory activity for telomerase and cancer cells. The results suggest that complex 1 may be a potential telomerase inhibitor for cancer chemotherapy.

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