G-quadruplex interacting small molecules and drugs: from bench toward bedside

Abstract

G-quadruplexes are non-Watson-Crick four-stranded nucleic acid structures. Recent evidence points toward their existence in vivo and their implication in various biological processes. Over the past two decades, small molecules have been developed to specifically and selectively target these structures in order to dissect mechanisms they have been linked to. This has led to the development of potential therapeutic agents, particularly for anti-carcinogenic activity. Here, we first present how major biological roles of G-quadruplexes have been uncovered by the use of specifically designed small molecule probes. We use this to highlight how fundamental research has contributed to identifying biological functions of G-quadruplexes and their potential as therapeutic targets. We then discuss the development of G-quadruplex interacting small molecules as potential drug candidates.

Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer

“…In this context, G4s exhibit a variety of well-defined structural elements such as molecularity, strand and loop orientation (generally defined as topology), loop composition/length and groove features [8–12]. Such a diversity of G4 structural elements provides, at least in principle, a repertoire of specific druggable sites amenable to be efficiently recognized and stabilized by small molecules (i.e., G4-ligands or G4 stabilizing agents) for therapeutic purposes [13, 14]. …”

General method for nucleophilic aromatic substitution of aryl fluorides and chlorides with dimethylamine using hydroxide-assisted decomposition of N,N-dimethylforamide

“…Aromatic compounds substituted with a dimethylamino group compose an important class of molecules that possess a range of biological activities including central nervous system stimulant, [1] antimicrobial, [2] anti-cancer, [3,4] anti-HIV, [5] AT2 receptor antagonist, [6–8] progesterone receptor modulator, [9,10] and rho kinase antagonists. [11] Additionally, numerous aromatic natural products are substituted with a dimethylamino group with some notable examples being Tigecycline, [2] Minocycline, [12] Orthoformimycin, [13] and Dendrodione.…”

A Nitroxide‐Tagged Platinum(II) Complex Enables the Identification of a DNA G‐Quadruplex Binding Mode

“…[7] In designing and developing compounds targeting GQs, detailed information on the mode of interaction between GQs and small molecules is highly valuable. These interactions have been investigated by a variety of experimental (e.g., X-ray crystallography, [8] NMR spectroscopy, [9] optical spectroscopy, [10] atomic force microscopy [11] and optical tweezers [12] ) and computational (e.g., molecular dynamics simulations [13] ) approaches.…”