Development of curcumin-based amyloid β aggregation inhibitors for Alzheimer's disease using the SAR matrix approach
- Bioorg Med Chem. 2021 Sep 15:46:116357. doi: 10.1016/j.bmc.2021.116357.
- 1. School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta‑cho, Midori‑ku, Yokohama 226‑8501, Japan.
- 2. 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.
- 3. Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, South Korea.
- 4. Institute for Theoretical Medicine, Inc., 26‑1, Muraoka‑Higashi 2‑chome, Fujisawa, Kanagawa 251‑0012, Japan.
- 5. Department of Life Science Informatics, B‑IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Friedrich-Hirzebruch-Allee 6, 53115 Bonn, Germany.
- 6. 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. Electronic address: [email protected].
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.