Platinum(II) Complexes with Dipyridophenazine Ligands as Human Telomerase Inhibitors and Luminescent Probes for G-Quadruplex DNA

Abstract

A series of platinum(II) complexes containing dipyridophenazine (dppz) and C-deprotonated 2-phenylpyridine (N-CH) ligands were prepared and assayed for G-quadruplex DNA binding activities. [PtII(dppz-COOH)(N-C)]CF3SO3 (1; dppz-COOH = 11-carboxydipyrido[3,2-a:2',3'-c]phenazine) binds G-quadruplex DNA through an external end-stacking mode with a binding affinity of approximately 10(7) dm3 mol-1. G-quadruplex DNA binding is accompanied by up to a 293-fold increase in the intensity of photoluminescence at lambdamax = 512 nm. Using a biotinylated-primer extension telomerase assay, 1 was shown to be an effective inhibitor of human telomerase in vitro, with a telIC50 value of 760 nM.

Promoting the formation and stabilization of human telomeric G-quadruplex DNA, inhibition of telomerase and cytotoxicity by phenanthroline derivatives

“…1 H and 13 C NMR spectra were recorded on a Bruker DRX300 spectrometer at room temperature. ESI-MS spectra were obtained using Waters Q-TOF MicroTM instrument.…”

“…5b,9c, 13 Investigations into the thermodynamics properties of the interactions are currently underway in our laboratory.…”

DNA Reactivity Profile of trans‐Platinum Planar Amine Derivatives

“…This idea follows from recent studies in which platinum complexes have been used to target G-quadruplexes through reversible interactions, [17,18] through the formation of stable covalent adducts, [19,20] or as luminescent probes. [21] To better describe the uniqueness of these novel derivatives, all data were compared with the "parent" compounds, cisplatin and transplatin. For comparison of the effects of the leaving group (Cl À versus formate or acetate) we also used trans-[PtCl 2 (NH 3 )(thiazole)] (SA1) as a control, as its DNA binding profile is well understood.…”

Cationic Platinum(II) Complexes Bearing Aryl-BIAN Ligands: Synthesis and Structural and Optoelectronic Characterization

“…10 The weak emission of [Pt(ppy)(dppz-COOH)]OTf was found to red-shift and dramatically increase in intensity when intercalated within G-quadruplex DNA (dppz-COOH = 11-carboxydipyrido[3,2-a:2′,3′-c]phenazine; ppyH = 2-phenylpyridine). 11 The nature of the emission of related cationic Pt complexes had been historically ascribed to a metal-to-ligand charge transfer ( 3 MLCT) to the cyclometalating ligand 12 or the diimine ligand, despite the structured profile of the emission spectra 13 These assignments clash with the more recent structre-property study by Bernhard (vide supra).…”