https://scholars.lib.ntu.edu.tw/handle/123456789/411903
標題: | Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity | 作者: | Tu, L.-H. Tseng, N.-H. Tsai, Y.-R. Lin, T.-W. Lo, Y.-W. Charng, J.-L. Hsu, H.-T. Chen, Y.-S. Chen, R.-J. Wu, Y.-T. Chan, Y.-T. Chen, C.-S. Fang, J.-M. Chen, Yun-Ru |
公開日期: | 2018 | 卷: | 158 | 起(迄)頁: | 393-404 | 來源出版物: | European Journal of Medicinal Chemistry | 摘要: | One of the pathologic hallmarks in Alzheimer's disease (AD) is extracellular senile plaques composed of amyloid-β (Aβ) fibrils. Blocking Aβ self-assembly or disassembling Aβ aggregates by small molecules would be potential therapeutic strategies to treat AD. In this study, we synthesized a series of rationally designed divalent compounds and examined their effects on Aβ fibrillization. A divalent amide (2) derived from two molecules of caffeic acid with a propylenediamine linker of ?5.0 ? in length, which is close to the distance of adjacent β sheets in Aβ fibrils, showed good potency to inhibit Aβ(1–42) fibrillization. Furthermore, compound 2 effectively dissociated the Aβ(1–42) preformed fibrils. The cytotoxicity induced by Aβ(1–42) aggregates in human neuroblastoma was reduced in the presence of 2, and feeding 2 to Aβ transgenic C. elegans rescued the paralysis phenotype. In addition, the binding and stoichiometry of 2 to Aβ(1–40) were demonstrated by using electrospray ionization?traveling wave ion mobility?mass spectrometry, while molecular dynamic simulation was conducted to gain structural insights into the Aβ(1–40)?2 complex. ? 2018 Elsevier Masson SAS |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85053414613&doi=10.1016%2fj.ejmech.2018.08.084&partnerID=40&md5=65895164977057b0d67699b6fc2cb903 https://scholars.lib.ntu.edu.tw/handle/123456789/411903 |
DOI: | 10.1016/j.ejmech.2018.08.084 | SDG/關鍵字: | amide; amyloid beta protein[1-40]; amyloid beta protein[1-42]; caffeic acid; caffeic acid derivative; curcumin; lonidamine; amide; amyloid beta protein; amyloid beta-protein (1-42); caffeic acid; caffeic acid derivative; peptide fragment; Article; beta sheet; Caenorhabditis elegans; controlled study; drug binding; drug design; drug potency; drug synthesis; electrospray; human; human cell; ion mobility spectrometry-mass spectrometry; neuroprotection; neurotoxicity; nonhuman; paralysis; phenotype; SH-SY5Y cell line; stoichiometry; Alzheimer disease; animal; chemistry; drug effect; metabolism; molecular model; protein multimerization; ultrastructure; Alzheimer Disease; Amides; Amyloid beta-Peptides; Animals; Caenorhabditis elegans; Caffeic Acids; Humans; Models, Molecular; Peptide Fragments; Protein Multimerization |
顯示於: | 化學系 |
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