Er-Jun Hao, Yan Zhao, Min Yu, Xian-Jia Li, Ke-Xin Wang, Fu-Ying Su, Yu-Ru Liang, Yang Wang, Hai-Ming Guo
{"title":"作为体外和体内潜在抗癌剂的新型五元含硫杂环核苷的发现、合成和活性评估。","authors":"Er-Jun Hao, Yan Zhao, Min Yu, Xian-Jia Li, Ke-Xin Wang, Fu-Ying Su, Yu-Ru Liang, Yang Wang, Hai-Ming Guo","doi":"10.1021/acs.jmedchem.4c00443","DOIUrl":null,"url":null,"abstract":"<p><p>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 <b>22o</b> exhibited remarkable antiproliferative activity against HeLa cells and was more potent than cisplatin (IC<sub>50</sub> = 2.80 vs 7.99 μM). Furthermore, mechanism studies indicated that <b>22o</b> 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 <b>22o</b> targeted RPS6 and inhibited its phosphorylation. Importantly, <b>22o</b> inhibited the growth of the HeLa xenograft mouse model with a low systemic toxicity. These results indicated that <b>22o</b> may serve as potent anticancer agents that merit further attention in future anticancer drug discovery.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery, Synthesis, and Activity Evaluation of Novel Five-Membered Sulfur-Containing Heterocyclic Nucleosides as Potential Anticancer Agents In Vitro and In Vivo.\",\"authors\":\"Er-Jun Hao, Yan Zhao, Min Yu, Xian-Jia Li, Ke-Xin Wang, Fu-Ying Su, Yu-Ru Liang, Yang Wang, Hai-Ming Guo\",\"doi\":\"10.1021/acs.jmedchem.4c00443\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <b>22o</b> exhibited remarkable antiproliferative activity against HeLa cells and was more potent than cisplatin (IC<sub>50</sub> = 2.80 vs 7.99 μM). Furthermore, mechanism studies indicated that <b>22o</b> 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 <b>22o</b> targeted RPS6 and inhibited its phosphorylation. Importantly, <b>22o</b> inhibited the growth of the HeLa xenograft mouse model with a low systemic toxicity. These results indicated that <b>22o</b> may serve as potent anticancer agents that merit further attention in future anticancer drug discovery.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-08-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.4c00443\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/17 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c00443","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/17 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
研究人员设计、合成了一系列新型五元含硫杂环核苷衍生物,并对它们的体外和体内抗癌活性进行了评估。结构-活性关系研究表明,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 细胞具有显著的抗增殖活性,且比顺铂更有效(IC50 = 2.80 vs 7.99 μM)。此外,机理研究表明,22o 可通过 PI3K-Akt-mTOR 信号通路抑制细胞转移、诱导细胞凋亡、降低线粒体膜电位和激活自噬。此外,药物亲和力反应靶点稳定性和细胞热转移试验显示,22o靶向RPS6并抑制其磷酸化。重要的是,22o 能抑制 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 可作为强效抗癌剂,值得在未来的抗癌药物研发中进一步关注。
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.