Exploring the Chemical Space of G-Quadruplex Binders: Discovery of a Novel Chemotype Targeting the Human Telomeric Sequence

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• 作者：Francesco Saverio Di Leva ; Pasquale Zizza ; Chiara Cingolani ; Carmen D鈥橝ngelo ; Bruno Pagano ; Jussara Amato ; Erica Salvati ; Claudia Sissi ; Odra Pinato ; Luciana Marinelli ; Andrea Cavalli ; Sandro Cosconati ; Ettore Novellino ; Antonio Randazzo ; Annamaria Biroccio
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9646-9654
• 全文大小：448K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

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.