Shooting for selective druglike G-quadruplex binders: Evidence for telomeric DNA damage and tumor cell death

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)9785-9792
Number of pages8
JournalJournal of Medicinal Chemistry
Volume55
Issue number22
DOIs
Publication statusPublished - Nov 26 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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