Design, Synthesis, and Activity Evaluation of Novel Acyclic Nucleosides as Potential Anticancer Agents In Vitro and In Vivo

In the present work, 103 novel acyclic nucleosides were designed, synthesized, and evaluated for their anticancer activities in vitro and in vivo. The structure-activity relationship (SAR) studies revealed that most target compounds inhibited the growth of colon cancer cells in vitro, of which 3-(6-chloro-9H-purin-9-yl)dodecan-1-ol (9b) exhibited the most potent effect against the HCT-116 and SW480 cells with IC50 values of 0.89 and 1.15 mu M, respectively. Furthermore, all of the (R)-configured acyclic nucleoside derivatives displayed more potent anticancer activity compared to their (S)-counterparts. Mechanistic studies revealed that compound 9b triggered apoptosis in the cancer cell lines via depolarization of the mitochondrial membrane and effectively inhibited colony formation. Importantly, compound 9b inhibited the growth of the SW480 xenograft in a mouse model with low systemic toxicity. These results indicated that acyclic nucleoside compounds are viable as potent and effective anticancer agents, and compound 9b may serve as a promising lead compound that merits further attention in future anticancer drug discovery.

Automated summary

The study designed, synthesized, and evaluated 103 novel acyclic nucleosides for their anticancer activities, with compound 9b showing promising inhibitory effects on colon cancer cells. All (R)-configured derivatives displayed stronger anticancer activity, with compound 9b inducing apoptosis and inhibiting colony formation. Importantly, compound 9b exhibited low systemic toxicity and inhibited tumor growth in a mouse model, suggesting it as a potential lead compound for future anticancer drug discovery.