Discovery of Novel Schizocommunin Derivatives as Telomeric G‑Quadruplex Ligands That Trigger Telomere Dysfunction and the Deoxyribonucleic Acid (DNA) Damage Response

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.