title: V-shaped dinuclear Pt(II) complexes: selective interaction with human telomeric G-quadruplex and significant inhibition towards telomerase.
abstract: A quaternized trigeminal ligand, 4-[4,6-di(4-pyridyl)-1,3,5-(2-triazinyl)]-1-methylpyridine-1-ium hexafluorophosphate (dptmp·PF6), and two derivative V-shaped dinuclear Pt(II) complexes, {[Pt(dien)]₂(dptmp)}(PF₆)₅ (1) and {[Pt(dpa)]₂(dptmp)}(PF₆)₅ (2), were synthesized, characterized and applied to a series of biochemical studies. FRET and SPR analyses showed these compounds, especially Pt(II) complexes, bound more strongly to human telomeric (hTel) G-quadruplex than to promoters (such as c-myc and bcl2) or to the duplex DNA. PCR-stop assays revealed that the Pt(II) complexes could bind to and stabilize G-quadruplex far more effectively than corresponding ligand. CD analyses further indicated the three compounds likely stabilized the formation of mixed-type parallel/antiparallel G-quadruplex structures. Their efficacy as telomerase inhibitors and potential anticancer drugs was explored via TRAP. The IC₅₀ value was determined to be 0.113 ± 0.019 μM for 1, indicating that it is one of the strongest known telomerase inhibitors. These results confirm that both V-shaped dinuclear Pt(II) complexes act as selective G-quadruplex binders and significant telomerase inhibitors.
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Cui-Xia
authors.initials: CX
authors.lastname: Xu
authors.forename: Yu-Xuan
authors.initials: YX
authors.lastname: Zheng
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Zheng
authors.forename: Qian
authors.initials: Q
authors.lastname: Hu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Liang-Nian
authors.initials: LN
authors.lastname: Ji
authors.forename: Zong-Wan
authors.initials: ZW
authors.lastname: Mao
mesh_terms: D054856:G-Quadruplexes; D006801:Humans; D009690:Nucleic Acid Conformation; D017671:Platinum Compounds / Q000378:metabolism*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere
chemical_list: D017671:Platinum Compounds; D019098:Telomerase