Shooting for Selective Druglike G-Quadruplex Binders: Evidence for Telomeric DNA Damage and Tumor Cell Death

Abstract

Targeting of DNA secondary structures, such as G-quadruplexes, is now considered an appealing opportunity for drug intervention in anticancer therapy. So far, efforts made in the discovery of chemotypes able to target G-quadruplexes mainly succeeded in the identification of a number of polyaromatic compounds featuring end-stacking binding properties. Against this general trend, we were persuaded that the G-quadruplex grooves can recognize molecular entities with better drug-like and selectivity properties. From this idea, a set of small molecules was identified and the structural features responsible for G-quadruplex recognition were delineated. These compounds were demonstrated to have enhanced affinity and selectivity for the G-quadruplex over the duplex structure. Their ability to induce selective DNA damage at telomeric level and to induction of apoptosis and senescence on tumor cells is herein experimentally proven.

Bis-indole derivatives with antitumor activity turn out to be specific ligands of human telomeric G-quadruplex

“…Several different classes of ligands that target G4 DNA have been developed (Granzhan et al, 2010; Monchaud et al, 2010; Ohnmacht and Neidle, 2014). A number of these have been identified by our research group and most of them were discovered in order to target the grooves of the G4 structures (Cosconati et al, 2009, 2010, 2012; Pagano et al, 2010; Petraccone et al, 2011; Di Leva et al, 2013). On the other hand, several other research groups have developed molecules characterized by an extended planar aromatic scaffold, which is generally able to stack on the external G-tetrads of the G4.…”

Mechanistic insight into ligand binding to G-quadruplex DNA

“…Molecular docking calculations on duplex DNA were performed using the structure of the B-DNA dodecamer [d(CGCGAATTCGCG)] 2 (PDB code: 1bna) (57), which has been reported to be recognized by 1 (42). …”

“…Furthermore, isothermal titration calorimetry (ITC) experiments showed that 1 binds to [d(TGGGGT)] 4 more tightly than distamycin A (41), that is the reference compound among the G-quadruplex groove binders. These biophysical experiments have been complemented by in vitro assays showing that 1 is able to induce DNA damage and cell-cycle arrest in specific cancer cell lines (42). …”

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

“…The small molecule pyridostatin, a very good stabilizer of the telomeric G-quadruplex with high selectivity over duplex DNA in vitro, also uncaps POT1 from human telomeres and triggers a DNA damage response [69]. A plethora of synthetic small molecules, synthetically more accessible than telomestatin, have high G-quadruplex affinity including the telomeric G-quadruplex (some are presented in [70][71][72][73][74][75][76]). A study using pyridostatin with a biotin affinity tag (FIGURE 4A & 4B) showed that telomeric DNA can be isolated from cells with a G-quadruplex interacting small molecule [16], and treating cultured cells with pyridostatin or some of its analogs leads to telomere shortening and senescence [16,77].…”