Synthesis, Anticancer Activities, and Mechanism of N-Heptyl-Containing Biguanide Derivatives
Synthesis, Anticancer Activities, and Mechanism of N-Heptyl-Containing Biguanide Derivatives
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正庚基双胍衍生物的合成、抗癌活性及机制
DOI：
10.2174/1573406418666220210111458
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发表时间：
2022
影响因子：
2.3
通讯作者：
Xiaoping Yang
中科院分区：
文献类型：
--
作者：
Wei Wang;Di Xiao;Sichun Zhou;Simeng Xu;Xinyi Tang;Xinchong Zhou;Jinbing Liu;Cangcang Xu;Mei Peng;Xiaoping Yang
背景：近年来，双胍类药物的抗肿瘤作用受到了广泛关注。然而，双胍类药物杀死癌细胞的有效浓度相对较高。因此，我们致力于双胍类化合物的结构修饰，以获得更好的抗肿瘤候选物。本实验室前期研究发现，含正庚基的双胍类化合物具有较强的抗癌活性。然而，双胍的苯环侧上的不同取代基对抗增殖活性的影响是未知的。目的：通过中间体衍生化法合成一系列含正庚基的双胍类化合物，并对其苯环进行卤素取代修饰，以寻找抗增殖活性更高的新化合物。方法：通过化学方法合成了10个含正庚基的双胍衍生物。用MTT法、克隆形成实验和划痕实验检测了这些衍生物的抗肿瘤活性。通过Western blotting检测蛋白水平，探讨其作用机制。结果：最佳双胍衍生物10a-10 c、11 d对5种人癌细胞系表现出2.21-9.59μ M的IC 50值，显著优于对照药物氯胍。克隆形成和划痕愈合试验的结果也证实了衍生物10a-10 c、11 d对人癌细胞系的增殖和迁移的抑制作用。Western blot结果表明，10 c能上调AMPK信号通路，下调mTOR/4 EBP 1/p70 S6 K。结论：所有含正庚基双胍衍生物的抗肿瘤活性均高于氯胍，表明对含正庚基双胍衍生物进行修饰为开发新型高效抗肿瘤药物提供了一条新途径。
Background:.In recent years, the anticancer effects of biguanide drugs have received considerable attention. However, the effective concentration of biguanide drugs to kill cancer cells is relative high. Thus, we focus on structural modification of biguanides to obtain better antitumor candidates. Previous study in our laboratory has found that a biguanide compound containing n-heptyl group has the potent anticancer activity. However, the effect of different substituents on the benzene ring side of the biguanides on the anti-proliferative activity is unknown..Objective:.A series of n-heptyl-containing biguanide derivatives whose benzene rings were modified by halogen substitution based on the intermediate derivatization method were further synthesized to find new compounds with improved antiproliferative activities..Method:.Ten n-heptyl-containing biguanide derivatives were synthesized via established chemical procedures. The activities of these derivatives were explored by MTT assay, clonogenic assay, and scratch assay. The protein levels were detected via Western blotting to explore the mechanisms underlying..Results:.The optimal biguanide derivatives 10a-10c, 11d exhibited IC50 values of 2.21–9.59µΜ for five human cancer cell lines, significantly better than the control drug proguanil. The results of clonogenic and scratch wound healing assays also confirmed the inhibitory effects of derivatives 10a-10c, 11d on the proliferation and migration of human cancer cell lines. Western blot results demonstrated that one representative derivative, 10c upregulates AMPK signal pathway and downregulates mTOR/4EBP1/p70S6K..Conclusion:.All biguanide derivatives containing n-heptyl group are more active than proguanil, indicating that the modification of n-heptyl-containing biguanide derivatives provides a novel approach for the development of novel high efficient antitumor drugs.