Cancer threatens people's health and survival. Now, the development of new anticancer drugs has evolved from finding conventional cytotoxic agents to searching for target and immunity-based ones. The 3'-overhang of the human telomeric G-rich DNA sequence can form a G-quadruplex secondary structure. Ligands that bind to and stabilize the G-quadruplex can initiate telomere dysfunction by replacing telomere complex proteins or interfering with telomere replication. Targeting telomere G-quadruplex and interfering telomere extension have become an attractive spot of anti-cancer therapy. Herein, 14 benzoselenoxanthene derivatives (Se 1-7) synthesized in our previous work were found to be a small molecule ligand capable of binding to telomeric G-quadruplex, and their biological activities were first examined. The results by CCK-8 showed that the compounds exhibited different cytotoxicity to highly telomerase-expressed cancer cell lines, of which the Se 7 had strongest cytotoxicity to tumor cells. Further western bolt assay demonstrated that the Se 1 and Se 7 were able to induce DNA damage and lead to an increase in phosphorylation of P53 protein. Flow cytometry confirmed that the Se 1 and Se 7 can induce tumor cell apoptosis. The proliferation of tumor cells was inhibited by arresting the cell cycle of tumor cells in the G2-M phase. Taken together, almost all of data demonstrated that the Se 7 can target the telomere G-quadruplex, thereby inhibit telomerase activity; at the same time, it results in telomere dysfunction by inducing DNA damage, which in turn leads to p53-mediated cell cycle arrest and apoptosis. The research work has strengthened the view that small molecule G-quadruplex ligands may function as anti-tumor drugs targeting telomere, which provides a new choice for the development of small molecule telomeric G-quadruplex ligands as anti-tumor drugs.
benzoselenium derivative;G-quadruplex;DNA damage;anti-tumor