Shooting for Selective Druglike G-Quadruplex Binders: Evidence for Telomeric DNA Damage and Tumor Cell Death

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• 作者：Sandro Cosconati ; Angela Rizzo ; Roberta Trotta ; Bruno Pagano ; Sara Iachettini ; Stefano De Tito ; Ilaria Lauri ; Iolanda Fotticchia ; Mariateresa Giustiniano ; Luciana Marinelli ; Concetta Giancola ; Ettore Novellino ; Annamaria Biroccio ; Antonio Randazzo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9785-9792
• 全文大小：385K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

Targeting of DNA secondary structures, such as G-quadruplexes, is now considered an appealing opportunity for drug intervention in anticancer therapy. So far, efforts made in the discovery of chemotypes able to target G-quadruplexes mainly succeeded in the identification of a number of polyaromatic compounds featuring end-stacking binding properties. Against this general trend, we were persuaded that the G-quadruplex grooves can recognize molecular entities with better drug-like and selectivity properties. From this idea, a set of small molecules was identified and the structural features responsible for G-quadruplex recognition were delineated. These compounds were demonstrated to have enhanced affinity and selectivity for the G-quadruplex over the duplex structure. Their ability to induce selective DNA damage at telomeric level and to induction of apoptosis and senescence on tumor cells is herein experimentally proven.