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

Research output: Contribution to journalArticle

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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Dissociative Disorders
Cytotoxicity
Amyloid
Amides
Alzheimer Disease
Molecules
Amyloid Plaques
Molecular Dynamics Simulation
Neuroblastoma
Stoichiometry
Paralysis
Self assembly
Spectrometry
Molecular dynamics
Spectrum Analysis
Ions
Phenotype
Computer simulation
Therapeutics
caffeic acid

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Tu, Ling Hsien ; Tseng, Ning Hsuan ; Tsai, Ya Ru ; Lin, Tien Wei ; Lo, Yi Wei ; Charng, Jien Lin ; Hsu, Hua Ting ; Chen, Yu Sheng ; Chen, Rong Jie ; Wu, Ying Ta ; Chan, Yi Tsu ; Chen, Chang-Shi ; Fang, Jim Min ; Chen, Yun Ru. / Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 158. pp. 393-404.
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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 {\AA} 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.",
author = "Tu, {Ling Hsien} and Tseng, {Ning Hsuan} and Tsai, {Ya Ru} and Lin, {Tien Wei} and Lo, {Yi Wei} and Charng, {Jien Lin} and Hsu, {Hua Ting} and Chen, {Yu Sheng} and Chen, {Rong Jie} and Wu, {Ying Ta} and Chan, {Yi Tsu} and Chang-Shi Chen and Fang, {Jim Min} and Chen, {Yun Ru}",
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Tu, LH, Tseng, NH, Tsai, YR, Lin, TW, Lo, YW, Charng, JL, Hsu, HT, Chen, YS, Chen, RJ, Wu, YT, Chan, YT, Chen, C-S, Fang, JM & Chen, YR 2018, 'Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity', European Journal of Medicinal Chemistry, vol. 158, pp. 393-404. https://doi.org/10.1016/j.ejmech.2018.08.084

Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity. / Tu, Ling Hsien; Tseng, Ning Hsuan; Tsai, Ya Ru; Lin, Tien Wei; Lo, Yi Wei; Charng, Jien Lin; Hsu, Hua Ting; Chen, Yu Sheng; Chen, Rong Jie; Wu, Ying Ta; Chan, Yi Tsu; Chen, Chang-Shi; Fang, Jim Min; Chen, Yun Ru.

In: European Journal of Medicinal Chemistry, Vol. 158, 05.10.2018, p. 393-404.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and ameliorate cytotoxicity

AU - Tu, Ling Hsien

AU - Tseng, Ning Hsuan

AU - Tsai, Ya Ru

AU - Lin, Tien Wei

AU - Lo, Yi Wei

AU - Charng, Jien Lin

AU - Hsu, Hua Ting

AU - Chen, Yu Sheng

AU - Chen, Rong Jie

AU - Wu, Ying Ta

AU - Chan, Yi Tsu

AU - Chen, Chang-Shi

AU - Fang, Jim Min

AU - Chen, Yun Ru

PY - 2018/10/5

Y1 - 2018/10/5

N2 - 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.

AB - 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.

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