Design, synthesis, and antitumor activity of novel thioheterocyclic nucleoside derivatives by suppressing the c-MYC pathway.

Eightly-four novel thioheterocyclic nucleoside derivatives were designed, synthesized, and evaluated for antitumor activity and . Most of the compounds inhibited the growth of HCT116 and HeLa cancer cells , among them and exhibited potent activity against HCT116 cells (IC = 0.27 and 0.49 μmol/L, respectively). Both compounds and inhibited cell metastasis, arrested the cell cycle in the G/M phase, and induced apoptosis . Mechanistic studies revealed that and increased ROS levels, led to DNA damage, ER stress, and mitochondrial dysfunction, and inhibited autophagy in HCT116 cells. Biological information analysis, RNA-sequencing, Gene Set Enrichment Analysis (GSEA), drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and SPR experiments identified that compounds and showed antitumor activity by suppressing the c-MYC pathway. silencing assays indicated that c-MYC proteins participated in -mediated anticancer activities in HCT116 cells. More importantly, compound presented favorable pharmacokinetic properties in mice ( = 6.8 h) and showed significant antitumor efficacy without obvious toxicity, showing promising potential for further clinical development.