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Discovery of Novel Schizocommunin Derivatives as Telomeric G‑Quadruplex Ligands That Trigger Telomere Dysfunction and the Deoxyribonucleic Acid (DNA) Damage Response
journal contribution
posted on 2018-04-04, 00:00 authored by Tong Che, Shuo-Bin Chen, Jia-Li Tu, Bo Wang, Yu-Qing Wang, Yan Zhang, Jing Wang, Zeng-Qing Wang, Ze-Peng Zhang, Tian-Miao Ou, Yong Zhao, Jia-Heng Tan, Zhi-Shu HuangTelomeric
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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cancer cell linesmouse xenograft modelnovel schizocommunin derivativesG-quadruplex DNAMTTNovel Schizocommunin Derivativestelomere maintenance interferencemethyl thiazolyl tetrazoliump 53-mediated cell cycle arrestTrigger Telomere DysfunctionG-quadruplex ligandsDNA damage responseDamage Response Telomeric G-quadruplex
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