Exploring the Chemical Space of G‑Quadruplex Binders: Discovery of a Novel Chemotype Targeting the Human Telomeric Sequence
Recent findings have unambiguously demonstrated that DNA G-rich sequences can adopt a G-quadruplex folding in living cells, thus further validating them as crucial targets for anticancer therapy. Herein, to identify new potent G4 binders as antitumor drug candidates, we have targeted a 24-nt G4-form...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-12, Vol.56 (23), p.9646-9654 |
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| container_issue | 23 |
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| container_title | Journal of medicinal chemistry |
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| creator | Di Leva, Francesco Saverio Zizza, Pasquale Cingolani, Chiara D’Angelo, Carmen Pagano, Bruno Amato, Jussara Salvati, Erica Sissi, Claudia Pinato, Odra Marinelli, Luciana Cavalli, Andrea Cosconati, Sandro Novellino, Ettore Randazzo, Antonio Biroccio, Annamaria |
| description | Recent findings have unambiguously demonstrated that DNA G-rich sequences can adopt a G-quadruplex folding in living cells, thus further validating them as crucial targets for anticancer therapy. Herein, to identify new potent G4 binders as antitumor drug candidates, we have targeted a 24-nt G4-forming telomeric sequence employing a receptor-based virtual screening approach. Among the best candidates, in vitro binding experiments allowed identification of three novel G4 ligands. Among them, the best compound features an unprecedented binding selectivity for the human telomeric DNA G-quadruplex with no detectable binding for other G4-forming sequences present at different genomic sites. This behavior correlates with the detected ability to generate DNA damage response in tumor cells at the telomeric level and efficient antiproliferative effect on different tumor cell lines at low micromolar concentrations. |
| doi_str_mv | 10.1021/jm401185b |
| format | Article |
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This behavior correlates with the detected ability to generate DNA damage response in tumor cells at the telomeric level and efficient antiproliferative effect on different tumor cell lines at low micromolar concentrations.</description><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Fluorescence Resonance Energy Transfer</subject><subject>G-Quadruplexes - drug effects</subject><subject>Humans</subject><subject>Ligands</subject><subject>Molecular Docking Simulation</subject><subject>Telomere - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1O20AQx1dVUQm0B14A7aUSHExnvxxvb234qoRAVdKztVnPBke21-zaiByQeAVekSfBkJBTTzOH3_xm5k_IAYMTBpz9WNYSGMvU_BMZMcUhkRnIz2QEwHnCUy52yV6MSwAQjIsvZJdLrlKRZiPyePbQVj6UzYJ2t0gnt1iX1lR02hqL1Dt68fL0_Lc3RejbCh_o77IpMMSf9LSM1t9jWL1Bhl4PffU-7rtVi3RmwgK7D-1lX5uGzrDyNYbS0ine9dhY_Ep2nKkiftvUffLv_Gw2uUyubi7-TH5dJUZkrEssK-bKMNCcK5mOx1ZJ5TJgIpXacSYLgfNCm0I657QGJx0zwJSzqVZGCxD75GjtbYMfNscur4fzsapMg76POZMaxkoPmQzo8Rq1wccY0OVtKGsTVjmD_C3tfJv2wB5utP28xmJLfsQ7AN_XgLExX_o-NMOX_xG9ApI7hy0</recordid><startdate>20131212</startdate><enddate>20131212</enddate><creator>Di Leva, Francesco Saverio</creator><creator>Zizza, Pasquale</creator><creator>Cingolani, Chiara</creator><creator>D’Angelo, Carmen</creator><creator>Pagano, Bruno</creator><creator>Amato, Jussara</creator><creator>Salvati, Erica</creator><creator>Sissi, Claudia</creator><creator>Pinato, Odra</creator><creator>Marinelli, Luciana</creator><creator>Cavalli, Andrea</creator><creator>Cosconati, Sandro</creator><creator>Novellino, Ettore</creator><creator>Randazzo, Antonio</creator><creator>Biroccio, Annamaria</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20131212</creationdate><title>Exploring the Chemical Space of G‑Quadruplex Binders: Discovery of a Novel Chemotype Targeting the Human Telomeric Sequence</title><author>Di Leva, Francesco Saverio ; 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| subjects | Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Fluorescence Resonance Energy Transfer G-Quadruplexes - drug effects Humans Ligands Molecular Docking Simulation Telomere - drug effects |
| title | Exploring the Chemical Space of G‑Quadruplex Binders: Discovery of a Novel Chemotype Targeting the Human Telomeric Sequence |
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