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  3. Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer's disease

Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer's disease

  • Eur J Med Chem. 2020 Apr 15;192:112193. doi: 10.1016/j.ejmech.2020.112193.
Hui-Ju Tseng 1,  Mei-Hsiang Lin 2,  Young-Ji Shiao 3,  Ying-Chen Yang 4,  Jung-Chun Chu 5,  Chun-Yung Chen 5,  Yi-Ying Chen 6,  Tony Eight Lin 6,  Chih-Jou Su 6,  Shiow-Lin Pan 7,  Liang-Chieh Chen 8,  Chen-Yu Wang 9,  Kai-Cheng Hsu 10,  Wei-Jan Huang 11
Affiliations

Affiliations

  • 1 Ph.D. Program in Biotechnology Research and Development, Taipei Medical University, Taipei, Taiwan.
  • 2 School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 3 National Research Institute of Chinese Medicine, Taipei, Taiwan.
  • 4 Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan.
  • 5 Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
  • 6 Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
  • 7 Ph.D. Program in Biotechnology Research and Development, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
  • 8 Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; School of Life and Health Sciences and Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, PR China.
  • 9 TaiMed Biologics Inc., Taipei, Taiwan.
  • 10 Ph.D. Program in Biotechnology Research and Development, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan. Electronic address: [email protected].
  • 11 Ph.D. Program in Biotechnology Research and Development, Taipei Medical University, Taipei, Taiwan; School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan. Electronic address: [email protected].
PMID: 32151835 DOI: 10.1016/j.ejmech.2020.112193
Abstract

Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC Inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine-derived moiety and resulted in compounds that exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity when compared to the pan-HDAC inhibitor SAHA in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aβ-aggregation as well as significantly disrupted Aβ-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aβ-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a, which have the potential to treat AD.

Keywords

Acetylcholine esterase; Acridine; Histone deacetylase; Multitarget.

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