N-cyclic bay-substituted perylene g-quadruplex ligands have selective antiproliferative effects on cancer cells and induce telomere damage

Valentina Casagrande, Erica Salvati, Antonello Alvino, Armandodoriano Bianco, Alina Ciammaichella, Carmen D'Angelo, Luca Ginnari-Satriani, Anna Maria Serrilli, Sara Iachettini, Carlo Leonetti, Stephen Neidle, Giancarlo Ortaggi, Manuela Porru, Angela Rizzo, Marco Franceschin, Annamaria Biroccio

Research output: Contribution to journalArticlepeer-review

Abstract

A series of bay-substituted perylene derivatives is reported as a new class of G-quadruplex ligands. The synthesized compounds have differing N-cyclic substituents on the bay area and differing side chains on the perylene major axis. ESI-MS and FRET measurements highlighted the strongest quadruplex binders in this series and those showing the highest quadruplex/duplex selectivity. Several biological assays were performed on these compounds, which showed that compound 5 (PPL3C) triggered a DNA damage response in transformed cells with the formation of telomeric foci containing phosphorylated γ-H2AX and 53BP1. This effect mainly occurred in replicating cells and was consistent with Pot1 dissociation. Compound 5 does not induce telomere damage in normal cells, which are unaffected by treatment with the compound, suggesting that this agent preferentially kills cancer cells. These results reinforce the notion that G-quadruplex binding compounds can act as broad inhibitors of telomere-related processes and have potential as selective antineoplastic drugs.

Original languageEnglish
Pages (from-to)1140-1156
Number of pages17
JournalJournal of Medicinal Chemistry
Volume54
Issue number5
DOIs
Publication statusPublished - Mar 10 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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