School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta‑cho, Midori‑ku, Yokohama 226‑8501, Japan.
School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta‑cho, Midori‑ku, Yokohama 226‑8501, Japan; Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta‑cho, Midori‑ku, Yokohama 226‑8503, Japan.
Bioorg Med Chem. 2021 Sep 15;46:116357. doi: 10.1016/j.bmc.2021.116357. Epub 2021 Aug 8.
Amyloid β (Aβ) aggregation inhibitor activity cliff involving a curcumin structure was predicted using the SAR Matrix method on the basis of 697 known Aβ inhibitors from ChEMBL (data set 2487). Among the compounds predicted, compound B was found to possess approximately 100 times higher inhibitory activity toward Aβ aggregation than curcumin. TEM images indicate that compound B induced the shortening of Aβ fibrils and increased the generation of Aβ oligomers in a concentration dependent manner. Furthermore, compound K, in which the methyl ester of compound B was replaced by the tert-butyl ester, possessed low cytotoxicity on N2A cells and attenuated Aβ-induced cytotoxicity, indicating that compound K would have an ability for preventing neurotoxicity caused by Aβ aggregation.
基于 ChEMBL（数据集 2487）中 697 种已知的 Aβ 抑制剂，使用 SAR Matrix 方法预测了涉及姜黄素结构的淀粉样蛋白β（Aβ）聚集抑制剂活性悬崖。在所预测的化合物中，发现化合物 B 对 Aβ 聚集的抑制活性大约比姜黄素高 100 倍。TEM 图像表明，化合物 B 以浓度依赖的方式诱导 Aβ 纤维缩短并增加 Aβ 寡聚物的生成。此外，化合物 K，其中化合物 B 的甲酯被叔丁酯取代，对 N2A 细胞具有低细胞毒性，并减弱了 Aβ 诱导的细胞毒性，表明化合物 K 具有预防由 Aβ 聚集引起的神经毒性的能力。
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