Eightly-four novel thioheterocyclic nucleoside derivatives were designed,synthesized,and evaluated for antitumor activity in vitro and in vivo.Most of the compounds inhibited the growth of HCT116 and HeLa cancer cells...Eightly-four novel thioheterocyclic nucleoside derivatives were designed,synthesized,and evaluated for antitumor activity in vitro and in vivo.Most of the compounds inhibited the growth of HCT116 and HeLa cancer cells in vitro,among them 33a and 36b exhibited potent activity against HCT116 cells(IC_(50)=0.27 and 0.49μmol/L,respectively).Both compounds 33a and 36b inhibited cell metastasis,arrested the cell cycle in the G2/M phase,and induced apoptosis in vitro.Mechanistic studies revealed that 33a and 36b 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 33a and 36b showed antitumor activity by suppressing the c-MYC pathway.c-MYC silencing assays indicated that c-MYC proteins participated in 33a-mediated anticancer activities in HCT116 cells.More importantly,compound 33a presented favorable pharmacokinetic properties in mice(T_(1/2)=6.8 h)and showed significant antitumor efficacy in vivo without obvious toxicity,showing promising potential for further clinical development.展开更多
基金support from the National Natural Science Foundation of China(Nos.22071046,U22A20378,22301148,and 22277012)the Natural Science Foundation of Henan Province(No.232300421126,China)Program for Innovative Research Team in Science and Technology in University of Henan Province(No.22IRTSTHN003,China).
文摘Eightly-four novel thioheterocyclic nucleoside derivatives were designed,synthesized,and evaluated for antitumor activity in vitro and in vivo.Most of the compounds inhibited the growth of HCT116 and HeLa cancer cells in vitro,among them 33a and 36b exhibited potent activity against HCT116 cells(IC_(50)=0.27 and 0.49μmol/L,respectively).Both compounds 33a and 36b inhibited cell metastasis,arrested the cell cycle in the G2/M phase,and induced apoptosis in vitro.Mechanistic studies revealed that 33a and 36b 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 33a and 36b showed antitumor activity by suppressing the c-MYC pathway.c-MYC silencing assays indicated that c-MYC proteins participated in 33a-mediated anticancer activities in HCT116 cells.More importantly,compound 33a presented favorable pharmacokinetic properties in mice(T_(1/2)=6.8 h)and showed significant antitumor efficacy in vivo without obvious toxicity,showing promising potential for further clinical development.
