Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity

Ling Hsien Tu, Ning Hsuan Tseng, Ya Ru Tsai, Tien Wei Lin, Yi Wei Lo, Jien Lin Charng, Hua Ting Hsu, Yu Sheng Chen, Rong Jie Chen, Ying Ta Wu, Yi Tsu Chan, Chang Shi Chen, Jim Min Fang, Yun Ru Chen

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Abstract

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 Å 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.

Original languageEnglish
Pages (from-to)393-404
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume158
DOIs
Publication statusPublished - 2018 Oct 5

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Keywords

  • Alzheimer's disease
  • Amyloid-β
  • Caffeic acid
  • Cytotoxicity
  • Divalent caffeic amide
  • Inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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, Y. R. (2018). Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity. European Journal of Medicinal Chemistry, 158, 393-404. https://doi.org/10.1016/j.ejmech.2018.08.084