V-Shaped Dinuclear Pt(II) Complexes: Selective Interaction with Human Telomeric G-quadruplex and Significant Inhibition towards Telomerase

A quaternized trigeminal ligand, 4-[4,6-di(4-pyridyl)-1,3,5-(2-triazinyl)]-1-methylpyridine-1-ium hexafluorophosphate (dptmp·PF(6)), and two derivative V-shaped dinuclear Pt(II) complexes, {[Pt(dien)](2)(dptmp)}(PF(6))(5) (1) and {[Pt(dpa)](2)(dptmp)}(PF(6))(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 IC(50) 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.