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

Casagrande, V; Salvati, E; Alvino, A; Bianco, A; Ciammaichella, A; D'Angelo, C; Ginnari-Satriani, L; ... Biroccio, A; + view all (2011) N-cyclic bay-substituted perylene G-quadruplex ligands have selective antiproliferative effects on cancer cells and induce telomere damage. J Med Chem , 54 (5) pp. 1140-1156. 10.1021/jm1013665.

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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.

Type: Article
Title: N-cyclic bay-substituted perylene G-quadruplex ligands have selective antiproliferative effects on cancer cells and induce telomere damage.
Location: United States
DOI: 10.1021/jm1013665
Keywords: Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cell Survival, DNA Damage, Drug Screening Assays, Antitumor, Fluorescence Resonance Energy Transfer, G-Quadruplexes, Histones, Humans, Ligands, Perylene, Phosphorylation, Piperidines, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Telomere
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: http://discovery.ucl.ac.uk/id/eprint/1351757
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