Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
School of Pharmacy, Fudan University, Shanghai 201203, China.
J Med Chem. 2021 Feb 25;64(4):2077-2109. doi: 10.1021/acs.jmedchem.0c01717. Epub 2021 Feb 4.
In the present work, 103 novel acyclic nucleosides were designed, synthesized, and evaluated for their anticancer activities and . The structure-activity relationship (SAR) studies revealed that most target compounds inhibited the growth of colon cancer cells , of which 3-(6-chloro-9-purin-9-yl)dodecan-1-ol () exhibited the most potent effect against the HCT-116 and SW480 cells with IC values of 0.89 and 1.15 μM, respectively. Furthermore, all of the ()-configured acyclic nucleoside derivatives displayed more potent anticancer activity compared to their ()-counterparts. Mechanistic studies revealed that compound triggered apoptosis in the cancer cell lines depolarization of the mitochondrial membrane and effectively inhibited colony formation. Importantly, compound 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 may serve as a promising lead compound that merits further attention in future anticancer drug discovery.
在本工作中，设计、合成并评价了 103 种新型无环核苷，研究其抗癌活性。构效关系（SAR）研究表明，大多数目标化合物抑制结肠癌细胞的生长，其中 3-(6-氯-9-嘌呤-9-基)十二烷-1-醇（）对 HCT-116 和 SW480 细胞的抑制作用最强，IC 值分别为 0.89 和 1.15 μM。此外，所有（）构型的无环核苷衍生物的抗癌活性均强于其（）对映体。机制研究表明，化合物在癌细胞系中诱导细胞凋亡，线粒体膜去极化，并有效抑制集落形成。重要的是，化合物在 SW480 异种移植小鼠模型中能抑制肿瘤生长，且全身毒性低。这些结果表明，无环核苷类化合物具有作为有效抗癌药物的潜力，化合物可能是一种有前途的先导化合物，值得在未来的抗癌药物发现中进一步关注。
