Toward the Development of Specific G‑Quadruplex Binders: Synthesis, Biophysical, and Biological Studies of New Hydrazone Derivatives

G-Quadruplex-binding compounds are currently perceived as possible anticancer therapeutics. Here, starting from a promising lead, a small series of novel hydrazone-based compounds were synthesized and evaluated as G-quadruplex binders. The in vitro G-quadruplex-binding properties of the synthesized...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 59; no. 12; pp. 5706 - 5720
Main Authors Amato, Jussara, Morigi, Rita, Pagano, Bruno, Pagano, Alessia, Ohnmacht, Stephan, De Magis, Alessio, Tiang, Yee-Peng, Capranico, Giovanni, Locatelli, Alessandra, Graziadio, Alessandra, Leoni, Alberto, Rambaldi, Mirella, Novellino, Ettore, Neidle, Stephen, Randazzo, Antonio
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 23.06.2016
Amer Chemical Soc
Subjects
Cell Proliferation - drug effects
Chemistry, Medicinal
DNA - drug effects
Dose-Response Relationship, Drug
G-Quadruplexes - drug effects
Humans
Hydrazones - chemical synthesis
Hydrazones - chemistry
Hydrazones - pharmacology
Life Sciences & Biomedicine
Molecular Docking Simulation
Molecular Structure
Pharmacology & Pharmacy
Science & Technology
Structure-Activity Relationship
Tumor Cells, Cultured
TARGETS
POTENTIAL ANTITUMOR AGENTS
TELOMERASE
CANCER
DNA
DAMAGE
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Summary:G-Quadruplex-binding compounds are currently perceived as possible anticancer therapeutics. Here, starting from a promising lead, a small series of novel hydrazone-based compounds were synthesized and evaluated as G-quadruplex binders. The in vitro G-quadruplex-binding properties of the synthesized compounds were investigated employing both human telomeric and oncogene promoter G-quadruplexes with different folding topologies as targets. The present investigation led to the identification of potent G-quadruplex stabilizers with high selectivity over duplex DNA and preference for one G-quadruplex topology over others. Among them, selected derivatives have been shown to trap G-quadruplex structures in the nucleus of cancer cells. Interestingly, this behavior correlates with efficient cytotoxic activity in human osteosarcoma and colon carcinoma cells.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00129