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, 4e–h, 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：

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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4g和4h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4e和4f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。