Screening of Scaffolds for the Design of G-Quadruplex Ligands

António Paulo,Carla Cruz,Maria Cristina Oliveira,Jean-Louis Mergny,David Peitinho,Maria Paula Cabral Campello,Joana Figueiredo

doi:10.3390/app12042170

Abstract

In the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small (MW < 400 Da) heterocycle compounds, containing different aromatic scaffolds, such as phenyl, quinoline, naphthalene, phenanthroline and acridine moieties, in order to explore their stabilization effect towards different DNA G4s, such as those found in c-MYC, KRAS21 and VEGF promoters, 21G human telomeric motif and pre-MIR150. The fluorescence resonance energy transfer (FRET) melting assay indicates that the acridine moiety is the most active scaffold, followed by phenanthroline. The different scaffolds are promising in terms of drug-like properties and, in general, the IC50 values of the respective heterocycle compounds are lower in a cancer cell line, when compared with a normal cell line. The acridine derivative C5NH2 has the most favorable cytotoxic profile in terms of cell selectivity.

Highlights

Chemical reactions were followed by thin-layer chromatography (TLC) using Merck-Nagel (0.2 mm) plates which are visualized by UV detection
Chemistrysmall molecules have been reported in the literature as ligands/drugs for the targeting of G4 structures, including new chemotypes [22]
Among the several classes of Several small molecules have been reported in the literature as ligands/drugs for the ligands, heterocycles have proven to be a promising scaffold for the classes design of of targetingsynthetic of G4 structures, including new chemotypes

Summary

Introduction

The formation of G4 requires monovalent (Na+ and K+ ) or divalent/multivalent (e.g., Sr2+ ) cations, or small molecules, known as G4 ligands, which are chemical compounds that bind and stabilize the structure of G4. G4s provide recognition sites for ligands, since different G4 structures adopt specific conformations. These ligands generally have an aromatic surface, allowing π–π stacking interactions with a terminal G-quartet, one or more positive charge(s) or basic groups to selectively bind to the loops or grooves of the G4, and a geometry/shape preventing intercalation into double-stranded DNA. Many G4 ligands have characteristic cores that can be chemically modified, allowing the synthesis of various analogues whose therapeutic activity in cancer is being investigated.

Methods

Discussion

Conclusion