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American Chemical Society, Journal of Medicinal Chemistry, 5(54), p. 1140-1156, 2011

DOI: 10.1021/jm1013665

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N -Cyclic Bay-Substituted Perylene G-Quadruplex Ligands Have Selective Antiproliferative Effects on Cancer Cells and Induce Telomere Damage

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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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 hive differing N-cyclic substituents on the bay area and differing side chains on the perylene major axis. ESI-MS and FEET 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 gamma-H2AX and 53BP1. This effect mainly occurred in replicating cells and was consistent with Pod dissociation. Compound S 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.