G‐Quadruplexes: Targets in Anticancer Drug Design

Abstract

G-quadruplexes are special secondary structures adopted in some guanine-rich DNA sequences. As guanine-rich sequences are present in important regions of the eukaryotic genome, such as telomeres and the regulatory regions of many genes, such structures may play important roles in the regulation of biological events in the body. G-quadruplexes have become valid targets for new anticancer drugs in the past few decades. Many leading compounds that target these structures have been reported, and a few of them have entered preclinical or clinical trials. Nonetheless, the selectivity of this kind of antitumor compound has yet to be improved in order to suppress the side effects caused by nonselective binding. As drug design targets, the topology and structural characteristics of quadruplexes, their possible biological roles, and the modes and sites of small-ligand binding to these structures should be understood clearly. Herein we provide a summary of published research that has set out to address the above problem to provide useful information on the design of small ligands that target G-quadruplexes. This review also covers research methodologies that have been developed to study the binding of ligands to G-quadruplexes.

A pyrene-imidazolium derivative that selectively Recognizes G-Quadruplex DNA

“…In addition, the intercalative methods for detection of the quadruplex can be cytotoxic with relatively low selectivity and can induce the destabilization of the quadruplex within telomeres, which is critical for telomerase activity inhibition [6]. Since there are various types of quadruplex structures, rapid and simple screening methods with high selectivity, sensitivity and nontoxicity are required for understanding the biological roles of quadruplex DNA as well as for designing therapeutics [24,25].…”

Targeting G-Quadruplex DNA with Small Molecules

“…G-quadruplexes that exist as a dynamic mixture of conformations in the unbound state, like the human telomeric sequence, [91] should generally exhibit lower ligand affinities as compared to G-quadruplexes that adopt a single conformation. [58,90] While a large number of G-quadruplex ligands have been reported in the literature, [41,42,46,89,[92][93][94] the cationic porphyrin TMPyP4 (Fig. 5) is the most extensively studied to date.…”

The Supramolecular Attitude of Metal–Salophen and Metal–Salen Complexes

“…Human telomeric DNA consists of hundreds of 5 -TTAGGG repeat sequence TTAGGG, that end in an overhanging single-stranded of around 200 nucleobases [39]. This can fold into guanine-rich quadruplex (G-quadruplex) structures under physiological conditions.…”