New Ruthenium‐Based Probes for Selective G‐Quadruplex Targeting

Abstract

Telomeric regions containing G-quadruplex (G4) structures play a pivotal role in the development of cancers. The development of specific binders for G4s is thus of great interest in order to gain a deeper understanding of the role of these structures, and to ultimately develop new anticancer drug candidates. For several years, Ru complexes have been studied as efficient probes for DNA. Interest in these complexes stems mainly from the tunability of their structures and properties, and the possibility of using light excitation as a tool to probe their environment or to selectively trigger their reaction with a biological target. Herein, we report on the synthesis and thorough study of new Ru complexes based on a novel dipyrazino[2,3-a:2',3'-h]phenazine ligand (dph), obtained through a Chichibabin-like reaction. Luminescence experiments, surface plasmon resonance (SPR), and computational studies have demonstrated that these complexes behave as selective probes for G-quadruplex structures.

Towards the Development of Photo‐Reactive Ruthenium(II) Complexes Targeting Telomeric G‐Quadruplex DNA

“…By virtue of their optical properties, including a large Stokes shift, good photostability, high quantum yield, and long‐lived luminescence, they have been developed to probe different DNA sequences, such as mismatches, abasic sites, or G4s . More recently, two ruthenium(II) complexes, [Ru(phen) 2 (dph)] 2+ and [{Ru(phen) 2 } 2 (dph)] 4+ , based on the dph ligand (dph=dipyrazino[2,3‐ a :2′,3′‐ h ]phenazine), have been reported to show good selectivity towards G4s . However, none of the reported compounds is able to photo‐induce oxidative damage under light irradiation.…”

“…As mentioned in the Introduction, G‐quadruplex DNA is a guanine‐rich sequence present in the genome. Recently, we have reported on a new family of Ru complexes exhibiting good affinity and selectivity towards G‐quadruplex DNA . However, these complexes proved not to be sufficiently oxidizing in their excited state to trigger direct oxidative damage (type I photoreactivity).…”

Binding Modes and Selectivity of Ruthenium Complexes to Human Telomeric DNA G‐Quadruplexes

“…The results are presented below for each type of G4 structure, that is, with solutions containing either Na + or K + ions. Given the difficulty to obtain enantiopure samples for each Ru complex under study, all the complexes experimentally studied here are in the form of a mixtures of optical isomers (i.e., Δ and Λ for mononuclear complexes), as for other studies on the binding of Ru complexes to G4s . However, differences in terms of binding modes could occur for Δ or Λ isomers, as observed for the binding of Ru complexes to double‐stranded DNA or other types of G4s –…”

Cover Feature: Towards the Development of Photo‐Reactive Ruthenium(II) Complexes Targeting Telomeric G‐Quadruplex DNA (Chem. Eur. J. 72/2018)

“…Recently,w eh ave reported on an ew family of Ru complexes exhibiting good affinity and selectivity towards G-quadruplex DNA. [41] However, these complexes provedn ot to be sufficiently oxidizingi n their excited state to trigger direct oxidative damage (typeI photoreactivity). Ruthenium(II) complexes bearing at least two TAPl igands are well known in the literature to photoreact with ag uanine moietyu pon irradiation.T herefore, the photoreactivities of our complexes towards dGMP were investigated by Stern-Volmer steady-state luminescence quenching experiments.Asiswell established in the literature, the luminescence quenching of an Ru II -TAP complex upon addition of dGMP is due to electron transfer( ET) from dGMP to the complex in its excited state.…”

“…[32] More recently,t wo ruthenium(II) complexes, [Ru(phen) 2 (dph)] 2 + and [{Ru(phen) 2 } 2 (dph)] 4 + ,b ased on the dph ligand (dph = dipyrazino[2,3-a:2',3'-h]phenazine), have been reported to show good selectivity towards G4s. [41] However,none of the reported compounds is able to photo-induce oxidative damage under light irradiation. Highly p-deficient ligands, such as 1,4,5,8-tetraazaphenanthrene( TAP), are known to enhance the photo-oxidizing powero ft he resulting complexes.…”