期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 5, 页码 1140-1156出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm1013665
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资金
- MIUR
- Sapienza Universita di Roma
- Italian Association for Cancer Research (AIRC)
- Minister della Salute
- Cancer Research UK
- Italian Foundation for Cancer Research (FIRC)
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.
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