Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China.
Technical Innovation Center for Exploitation of Marine Biological Resources, Ministry of Natural Resources, Xiamen 361005, China.
Mar Drugs. 2020 Oct 23;18(11):526. doi: 10.3390/md18110526.
In recent years, a large number of pharmacologically active compounds containing a butenolide functional group have been isolated from secondary metabolites of marine microorganisms. Butyrolactone I was found to be produced by isolated from several marine-derived samples. The hypoglycemic activity of butyrolactone I has aroused our great interest. In this study, we synthesized six racemic butenolide derivatives (namely BL-1-BL-6) by modifying the C-4 side chain of butyrolactone I. Among them, BL-3 and BL-5 improved the insulin resistance of HepG2 cells and did not affect the proliferation of RIN-m5f cell line, which indicated the efficacy and safety of BL-3 and BL-5. Furthermore, BL-3, BL-4, BL-5, and BL-6 displayed a significant protein tyrosine phosphatase 1B (PTP1B) inhibitory effect, while the enantiomers of BL-3 displayed different 50% percentage inhibition concentration (IC) values against PTP1B. The results of molecular docking simulation of the BLs and PTP1B explained the differences of biological consequences observed between the enantiomers of BL-3, which supported BLs as PTP1B inhibitors, and also indicated that the chirality of C-4 might influence the inhibitory effect of the BLs. Our findings provide a novel strategy for the development of butyrolactone derivatives as potential PTP1B inhibitors for the treatment of type 2 diabetes mellitus.
近年来，从海洋微生物的次生代谢产物中分离得到了大量含有丁烯内酯官能团的具有药理活性的化合物。我们发现内酯 I 是由几种海洋来源的样品中分离得到的。内酯 I 的降血糖活性引起了我们的极大兴趣。在这项研究中，我们通过修饰内酯 I 的 C-4 侧链合成了六个外消旋丁烯内酯衍生物（即 BL-1-BL-6）。其中，BL-3 和 BL-5 改善了 HepG2 细胞的胰岛素抵抗，且不影响 RIN-m5f 细胞系的增殖，表明 BL-3 和 BL-5 的疗效和安全性。此外，BL-3、BL-4、BL-5 和 BL-6 对蛋白酪氨酸磷酸酶 1B（PTP1B）表现出显著的抑制作用，而 BL-3 的对映异构体对 PTP1B 的 50%抑制浓度（IC）值不同。BL 与 PTP1B 的分子对接模拟结果解释了 BL-3 对映异构体之间观察到的生物学结果的差异，这支持了 BL 作为 PTP1B 抑制剂的作用，也表明 C-4 的手性可能影响 BL 的抑制作用。我们的研究结果为开发丁烯内酯衍生物作为治疗 2 型糖尿病的潜在 PTP1B 抑制剂提供了一种新策略。
