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

Abstract

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.

Recent Developments in Small-Molecule Ligands of Medicinal Relevance for Harnessing the Anticancer Potential of G-Quadruplexes

“…Natural sources have also provided significant scaffolds as a basis for the development of G-quadruplex ligands. Schizocommunin, an alkaloid from a fungal source, has been derivatized to provide efficient telomeric G-quadruplex stabilizing ligands [109]. Gquadruplex occurrence in the telomeres upon exposure of cancer cells to a schizocommunin analogue has been demonstrated via use of a BG4 antibody in the nucleus.…”

Quadruplex Ligands in Cancer Therapy

“…The natural compound quercetin even interacts with telomeric G4 in acidic conditions [97]. Novel derivatives of Schizocommunin, an alkaloid from a fungal source, have been also designed for telomeric G4 targeting [104]. Anticancer drugs, such as epirubicin [64] and adriamycin [40] bind as monomers to telomeric G4 with a high affinity.…”

Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential

“…One such derivative named compound 16 was able to activate DDR at telomeric regions, induced telomere shortening and telomere uncapping, resulting in cell cycle arrest and apoptosis. Compound 16 was also found to inhibit tumor growth in a mouse xenograft model of cervical squamous cancer [ 216 ]. A disubstituted bisbenzimidazole naphthalenediimide (NDI) ligand BBZ-ARO, was reported to possess high telomeric G4 affinity, which could inhibit telomerase enzyme activity and caused G2/M arrest subsequently inducing apoptosis in cells with a good therapeutic index [ 217 ].…”