G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

Guanine‐rich sequences of DNA are known to readily fold into tetra‐stranded helical structures known as G‐quadruplexes (G4). Due to their biological relevance, G4s are potential anticancer drug targets and therefore there is significant interest in molecules with high affinity for these structures. Most G4 binders are polyaromatic planar compounds which π–π stack on the G4′s guanine tetrad. However, many of these compounds are not very selective since they can also intercalate into duplex DNA. Herein we report a new class of binder based on an octahedral cobalt(III) complex that binds to G4 via a different mode involving hydrogen bonding, electrostatic interactions and π–π stacking. We show that this new compound binds selectivity to G4 over duplex DNA (particularly to the G‐rich sequence of the c‐myc promoter). This new octahedral complex also has the ability to template the formation of G4 DNA from the unfolded sequence. Finally, we show that upon binding to G4, the complex prevents helicase Pif1‐p from unfolding the c‐myc G4 structure.

Section: Introductionmentioning

confidence: 99%

An Octahedral Cobalt(III) Complex with Axial NH₃ Ligands that Templates and Selectively Stabilises G‐quadruplex DNA

Ruehl

Lim

Kench

et al. 2019

“…Initially, most G‐quadruplex binding molecules were based on organic heteroaromatic compounds . Subsequently, it was shown that metal complexes can also be excellent G4 DNA binders thanks to their unique electronic and structural features, as has been discussed in detail elsewhere . An example of this, are metal salphen and salen complexes, which have been extensively studied over the past 10 years (see Figure ) .…”

Section: Introductionmentioning

confidence: 99%

Binding Studies of Metal–Salphen and Metal–Bipyridine Complexes towards G‐Quadruplex DNA

Łęczkowska

González‐García

Pérez‐Arnaiz

et al. 2018

The proposed in vivo formation of G-quadruplex DNA (G4 DNA) in promoter regions of oncogenes and in telomeres has prompted the development of small molecules with high affinity and selectivity for these structures. Herein we report the synthesis of a new di-substituted bipyridine ligand and the corresponding complexes with Ni and VO . Both these new complexes have been characterized spectroscopically and by X-ray crystallography. Detailed DNA binding studies of these two complexes, together with three previously reported metal salphen complexes, are presented. Using FRET melting assays, the binding affinity and selectivity of the five metal complexes against six different G4 DNA structures as well as a duplex DNA have been determined. In addition, we present detailed ITC and UV/Vis studies to characterize the interaction of the complexes with human telomeric G4 DNA. Finally, we show via a polymerase stop assay that these complexes are able to stabilize a G4 DNA structure (from the c-Myc oncogene promoter) and halt the activity of Taq polymerase.

“…The interaction with the G‐quadruplex grooves and loops is also taken into account for improving the selectivity for G‐quadruplex versus duplex DNA. Among the compounds able to target G‐quadruplexes, a number of metal complexes bearing aromatic ligands have been reported, including those of porphyrin, salphens, and salophens . In this context, we have designed a new extended planar ligand, based on a pyrazine core, namely dipyrazino[2,3‐ a :2′,3′‐ h ]phenazine (dph; Figure a).…”

Section: Introductionmentioning

confidence: 99%

New Ruthenium‐Based Probes for Selective G‐Quadruplex Targeting

Piraux

Bar

Abraham

et al. 2017

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.