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Synthesis of Yakuchinone B-Inspired Inhibitors against Islet Amyloid Polypeptide Aggregation
Journal of Natural Products ( IF 3.3 ) Pub Date : 2021-02-18 , DOI: 10.1021/acs.jnatprod.0c01162
Jui-Yi Hsu, Ashish Rao Sathyan, Kai-Cheng Hsu, Liang-Chieh Chen, Cheng-Chung Yen, Hui-Ju Tseng, Kun-Chang Wu, Hui-Kang Liu, Wei-Jan Huang

Type 2 diabetes mellitus (T2DM) is associated with pancreatic β-cell dysfunction and insulin resistance. Islet amyloid polypeptide (IAPP) aggregation is found to induce islet β-cell death in T2DM patients. Recently, we demonstrated that yakuchinone B derivative 1 exhibited inhibitory activity against IAPP aggregation. Thus, in this study, a series of synthesized yakuchinone B-inspired compounds were tested for their anti-IAPP aggregation activity. Four of these compounds, 4eh, showed greater activity than the lead compound 1, in the sub-μM range (IC50 = 0.7–0.8 μM). The molecular docking analysis revealed crucial hydrogen bonds between the compounds and residues S19 and N22 and important hydrophobic interactions with residue I26. Notably, compounds 4g and 4h significantly protected β-cells against IAPP-induced toxicity with EC50 values of 0.1 and 0.2 μM, respectively. In contrast, the protective activities of compounds 4e and 4f were weak. Overall, these results suggest that the compounds exhibiting IAPP aggregation-inhibiting activity have the potential to treat T2DM.

中文翻译:

胰岛淀粉样多肽聚集抑制药的合成

2 型糖尿病 (T2DM) 与胰腺 β 细胞功能障碍和胰岛素抵抗有关。发现胰岛淀粉样多肽 (IAPP) 聚集可诱导 T2DM 患者的胰岛 β 细胞死亡。最近,我们证明了 yakuchinone B 衍生物1表现出对 IAPP 聚集的抑制活性。因此,在本研究中,测试了一系列合成的药草酮 B 类化合物的抗 IAPP 聚集活性。这些化合物中,四4E - ħ,显示出更大的活性比铅化合物1,在子μM范围(IC 50= 0.7–0.8 μM)。分子对接分析揭示了化合物与残基 S19 和 N22 之间的关键氢键以及与残基 I26 的重要疏水相互作用。值得注意的是,化合物4g4h显着保护 β 细胞免受 IAPP 诱导的毒性,EC 50值分别为 0.1 和 0.2 μM。相比之下,化合物4e4f的保护活性较弱。总的来说,这些结果表明具有 IAPP 聚集抑制活性的化合物具有治疗 T2DM 的潜力。
更新日期:2021-04-23
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