Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer’s disease
| Autor: | Chih Jou Su, Wei Jan Huang, Liang Chieh Chen, Chen Yu Wang, Ying Chen Yang, Hui Ju Tseng, Young Ji Shiao, Shiow Lin Pan, Mei Hsiang Lin, Jung Chun Chu, Kai Cheng Hsu, Tony Eight Lin, Yi Ying Chen, Chun Yung Chen |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Gene isoform
Neurite Cell Survival Aché Pharmacology 01 natural sciences Histone Deacetylases Mice Protein Aggregates Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Alzheimer Disease Drug Discovery Tumor Cells Cultured medicine Animals Humans 030304 developmental biology chemistry.chemical_classification 0303 health sciences Amyloid beta-Peptides Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Neurotoxicity General Medicine HDAC6 medicine.disease Peptide Fragments language.human_language 0104 chemical sciences Histone Deacetylase Inhibitors Enzyme chemistry Acridine Acetylcholinesterase language Acridines Cholinesterase Inhibitors Histone deacetylase |
| Zdroj: | European Journal of Medicinal Chemistry. 192:112193 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2020.112193 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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