Discovery of the first dual G-triplex/G-quadruplex stabilizing compound: a new opportunity in the targeting of G-rich DNA structures?

Guanine-rich DNA motifs can form non-canonical structures known as G-quadruplexes, whose role in tumorigenic processes makes them attractive drug-target candidates for cancer therapy. Recent studies revealed that the folding and unfolding pathways of G-quadruplexes proceed through a quite stable int...

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Vydané v:	Biochimica et biophysica acta. General subjects Ročník 1861; číslo 5; s. 1271 - 1280
Hlavní autori:	Amato, Jussara, Pagano, Alessia, Cosconati, Sandro, Amendola, Giorgio, Fotticchia, Iolanda, Iaccarino, Nunzia, Marinello, Jessica, De Magis, Alessio, Capranico, Giovanni, Novellino, Ettore, Pagano, Bruno, Randazzo, Antonio
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Netherlands Elsevier B.V 01.05.2017
Predmet:	Anticancer agents antineoplastic agents Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Binding Sites bioassays Calorimetry, Differential Scanning Cell Line, Tumor cell proliferation Cell Proliferation - drug effects Circular Dichroism cytotoxicity DNA DNA, Neoplasm - chemistry DNA, Neoplasm - drug effects DNA, Neoplasm - metabolism Dose-Response Relationship, Drug Drug Design Drug discovery G-quadruplex G-Quadruplexes - drug effects G-triplex gel electrophoresis Guanosine - chemistry Guanosine - metabolism Humans Inhibitory Concentration 50 Ligand Ligands Magnetic Resonance Spectroscopy melting Molecular Docking Simulation molecular models Native Polyacrylamide Gel Electrophoresis nuclear magnetic resonance spectroscopy nucleotide motifs osteosarcoma Osteosarcoma - drug therapy Osteosarcoma - genetics Osteosarcoma - pathology screening Structure-Activity Relationship therapeutics Time Factors G-triplex Anticancer agents Drug discovery Ligand G-quadruplex
ISSN:	0304-4165, 1872-8006
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Shrnutí:	Guanine-rich DNA motifs can form non-canonical structures known as G-quadruplexes, whose role in tumorigenic processes makes them attractive drug-target candidates for cancer therapy. Recent studies revealed that the folding and unfolding pathways of G-quadruplexes proceed through a quite stable intermediate named G-triplex. Virtual screening was employed to identify a small set of putative G-triplex ligands. The G-triplex stabilizing properties of these compounds were analyzed by CD melting assay. DSC, non-denaturing gel electrophoresis, NMR and molecular modeling studies were performed to investigate the interaction between the selected compound 1 and G-rich DNA structures. Cytotoxic activity of 1 was evaluated by MTT cell proliferation assay. The experiments led to the identification of a promising hit that was shown to bind preferentially to G-triplex and parallel-stranded G-quadruplexes over duplex and antiparallel G-quadruplexes. Molecular modeling results suggested a partial end-stacking of 1 to the external G-triad/G-tetrads as a binding mode. Biological assays showed that 1 is endowed with cytotoxic effect on human osteosarcoma cells. A tandem application of virtual screening along with the experimental investigation was employed to discover a G-triplex-targeting ligand. Experiments revealed that the selected compound actually acts as a dual G-triplex/G-quadruplex stabilizer, thus stimulating further studies aimed at its optimization. The discovery of molecules able to bind and stabilize G-triplex structures is highly appealing, but their transient state makes challenging their recognition. These findings suggest that the identification of ligands with dual G-triplex/G-quadruplex stabilizing properties may represent a new route for the design of anticancer agents targeting the G-rich DNA structures. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. [Display omitted] •Identification of the first G-triplex DNA-targeting compound•Results show that the selected compound is a dual G-triplex/G-quadruplex stabilizer.•Compound 1 is endowed with cytotoxic activity on human osteosarcoma cells.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0304-4165 1872-8006
DOI:	10.1016/j.bbagen.2016.11.008