Discovery, Synthesis, and Activity Evaluation of Novel Five-Membered Sulfur-Containing Heterocyclic Nucleosides as Potential Anticancer Agents In Vitro and In Vivo

A series
of novel five-membered sulfur-containing heterocyclic
nucleoside derivatives were designed, synthesized, and evaluated for
their anticancer activities in vitro and in vivo. The structure–activity
relationship studies revealed that some of them showed obvious antitumor
activities in several cancer cell lines. Among them, compound 22o exhibited remarkable antiproliferative activity against
HeLa cells and was more potent than cisplatin (IC50 = 2.80
vs 7.99 μM). Furthermore, mechanism studies indicated that 22o inhibited cell metastasis, induced cell apoptosis, decreased
mitochondrial membrane potential, and activated autophagy through
the PI3K-Akt-mTOR signaling pathway. Moreover, drug affinity responsive
target stability and the cellular thermal shift assay revealed that 22o targeted RPS6 and inhibited its phosphorylation. Importantly, 22o inhibited the growth of the HeLa xenograft mouse model
with a low systemic toxicity. These results indicated that 22o may serve as potent anticancer agents that merit further attention
in future anticancer drug discovery.