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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Veröffentlicht in:Biochimica et biophysica acta. General subjects Jg. 1861; H. 5; S. 1271 - 1280
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Netherlands Elsevier B.V 01.05.2017
Schlagworte:
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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Zusammenfassung: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.
Bibliographie: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