Discovery of Novel
Schizocommunin Derivatives as Telomeric
G‑Quadruplex Ligands That Trigger Telomere Dysfunction and
the Deoxyribonucleic Acid (DNA) Damage Response
Posted on 2018-04-04 - 00:00
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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Che, Tong; Chen, Shuo-Bin; Tu, Jia-Li; Wang, Bo; Wang, Yu-Qing; Zhang, Yan; et al. (2018). Discovery of Novel
Schizocommunin Derivatives as Telomeric
G‑Quadruplex Ligands That Trigger Telomere Dysfunction and
the Deoxyribonucleic Acid (DNA) Damage Response. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.7b01615
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AUTHORS (13)
TC
Tong Che
SC
Shuo-Bin Chen
JT
Jia-Li Tu
BW
Bo Wang
YW
Yu-Qing Wang
YZ
Yan Zhang
JW
Jing Wang
ZW
Zeng-Qing Wang
ZZ
Ze-Peng Zhang
TO
Tian-Miao Ou
YZ
Yong Zhao
JT
Jia-Heng Tan
ZH
Zhi-Shu Huang
KEYWORDS
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