Design, Synthesis, and Activity Evaluation of Novel Acyclic Nucleosides as Potential Anticancer Agents In Vitro and In Vivo
Design, Synthesis, and Activity Evaluation of Novel Acyclic Nucleosides as Potential Anticancer Agents In Vitro and In Vivo
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新型无环核苷类抗癌药物的设计、合成及活性评价
DOI：
10.1021/acs.jmedchem.0c01717
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发表时间：
2021-02-04
影响因子：
7.3
通讯作者：
Guo, Hai-Ming
中科院分区：
文献类型：
--
作者：
Hao, Er-Jun;Li, Gong-Xin;Guo, Hai-Ming
本工作设计、合成了103个新的无环核苷，并对其体内外抗癌活性进行了评价。构效关系(SAR)研究表明，大多数目标化合物对体外培养的结肠癌细胞均有抑制作用，其中3-(6-氯-9H-嘌呤-9-基)十二烷-1-醇(9b)对HCT-116和SW480细胞的抑制作用最强，IC50值分别为0.89和1.15µM。此外，所有(R)构型的开环核苷衍生物都比它们的(S)-衍生物显示出更强的抗癌活性。机制研究表明，化合物9b通过线粒体膜去极化诱导癌细胞凋亡，并有效地抑制集落形成。重要的是，化合物9b在小鼠模型中抑制了SW480异种移植瘤的生长，全身毒性很低。这些结果表明，无环核苷类化合物作为一种有效的抗癌药物是可行的，化合物9b可能是一种很有前途的先导化合物，在未来的抗癌药物开发中值得进一步关注。
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.