期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 8, 页码 3436-3453出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01615
关键词
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资金
- Natural Science Foundation of China [81330077, 21172272, 21672268, 21472252]
- Natural Science Foundation of Guangdong Province [2017A030308003, 2015A030306004]
- Guangdong Provincial Key Laboratory of Construction Foundation [2011A060901014]
Telomeric G-quadruplex targeting and telomere maintenance interference are emerging as attractive strategies for anticancer therapies. Here, a novel molecular scaffold is explored for telomeric G-quadruplex targeting. A series of novel schizocommunin derivatives was designed and synthesized as potential telomeric G-quadruplex ligands. The interaction of telomeric G-quadruplex DNA with the derivatives was explored by biophysical assay. The cytotoxicity of the derivatives toward cancer cell lines was evaluated by the methyl thiazolyl tetrazolium (MTT) assay. Among the derivatives, compound 16 showed great stabilization ability toward telomeric G-quadruplex DNA and good cytotoxicity toward cancer cell lines. Further cellular experiments indicated that 16 could induce the formation of telomeric G-quadruplex in cells, triggering a DNA damage response at the telomere and causing telomere dysfunction. These effects ultimately provoked p53-mediated cell cycle arrest and apoptosis, and suppressed tumor growth in a mouse xenograft model. Our work provides a novel scaffold for the development of telomeric G-quadruplex ligands.
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