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

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Discovery, Synthesis, and Activity Evaluation of Novel Five-Membered Sulfur-Containing Heterocyclic Nucleosides as Potential Anticancer Agents In Vitro and In Vivo
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-17 , DOI: 10.1021/acs.jmedchem.4c00443
Er-Jun Hao ₁ , Yan Zhao ₁ , Min Yu ₂ , Xian-Jia Li ₁ , Ke-Xin Wang ₁ , Fu-Ying Su ₁ , Yu-Ru Liang ₃ , Yang Wang ₂ , Hai-Ming Guo ₁

Affiliation

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.

中文翻译：

新型五元含硫杂环核苷作为体外和体内潜在抗癌剂的发现、合成和活性评价

设计、合成了一系列新型五元含硫杂环核苷衍生物，并评估了它们的体外和体内抗癌活性。构效关系研究表明，其中一些化合物在多种癌细胞系中表现出明显的抗肿瘤活性。其中，化合物22o对HeLa细胞表现出显着的抗增殖活性，并且比顺铂更有效（IC ₅₀ = 2.80 vs 7.99 μM）。此外，机制研究表明22o通过PI3K-Akt-mTOR信号通路抑制细胞转移、诱导细胞凋亡、降低线粒体膜电位并激活自噬。此外，药物亲和力响应靶稳定性和细胞热位移测定表明22o靶向RPS6并抑制其磷酸化。重要的是， 22o可抑制 HeLa 异种移植小鼠模型的生长，且全身毒性较低。这些结果表明22o可能作为有效的抗癌剂，在未来的抗癌药物发现中值得进一步关注。

更新日期：2024-07-17

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