Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China.
Changde Vocational Technical College, Changde, Hunan, China.
Med Chem. 2022;18(8):895-902. doi: 10.2174/1573406418666220210111458.
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 relatively high. Thus, we focus on structural modification of biguanides to obtain better antitumor candidates. A previous study in our laboratory has found that a biguanide compound containing the n-heptyl group has potent anticancer activity. However, the effect of different substituents on the benzene ringside of the biguanides on the anti-proliferative activity is unknown.
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.
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 underlying mechanisms.
The optimal biguanide derivatives 10a-10c, 11d exhibited IC50 values of 2.21-9.59 μΜ 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 the AMPK signal pathway and downregulates mTOR/4EBP1/p70S6K.
All biguanide derivatives containing n-heptyl groups 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.
近年来，双胍类药物的抗癌作用受到了相当的关注。然而，双胍类药物杀死癌细胞的有效浓度相对较高。因此，我们专注于双胍类药物的结构修饰，以获得更好的抗肿瘤候选药物。我们实验室的先前研究发现，含有正庚基的双胍类化合物具有很强的抗癌活性。然而，不同取代基对双胍类药物苯环侧的影响尚不清楚。
基于中间体衍生化方法，进一步合成了一系列苯环被卤素取代的含正庚基双胍衍生物，以寻找具有改善抗增殖活性的新化合物。
通过既定的化学程序合成了 10 种含正庚基的双胍衍生物。通过 MTT 测定、集落形成测定和划痕测定来探索这些衍生物的活性。通过 Western blot 检测蛋白水平，以探讨潜在的机制。
最佳的双胍衍生物 10a-10c、11d 对五种人癌细胞系的 IC50 值为 2.21-9.59 μΜ，明显优于对照药物丙氧嘧啶。集落形成和划痕愈合测定的结果也证实了衍生物 10a-10c、11d 对人癌细胞系增殖和迁移的抑制作用。Western blot 结果表明，一种代表性的衍生物 10c 上调 AMPK 信号通路并下调 mTOR/4EBP1/p70S6K。
所有含正庚基的双胍衍生物都比丙氧嘧啶更活跃，这表明含正庚基的双胍衍生物的修饰为开发新型高效抗肿瘤药物提供了一种新方法。
