Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for Alzheimer's disease
| Autor: | C. James Chou, Ying Qu, Yingying Ran, Qiuqiong Zhang, Chenggong Yu, Feng He, Chao Wei, Jiahui Lv, Xiaoyang Li, Ana Xu, Defeng Wang, Xiangna Zhang, Jingde Wu |
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| Rok vydání: | 2020 |
| Předmět: |
Pharmacology
Blood–brain barrier 01 natural sciences Biochemistry Neuroprotection PC12 Cells Receptors N-Methyl-D-Aspartate Histone Deacetylases Structure-Activity Relationship Alzheimer Disease Cell Line Tumor Drug Discovery medicine Animals Humans Receptor Cytotoxicity Molecular Biology biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Memantine Hydrogen Peroxide HDAC6 0104 chemical sciences Rats Histone Deacetylase Inhibitors Isoenzymes 010404 medicinal & biomolecular chemistry medicine.anatomical_structure Histone Neuroprotective Agents Drug Design biology.protein NMDA receptor medicine.drug |
| Zdroj: | Bioorganic chemistry. 103 |
| ISSN: | 1090-2120 |
| Popis: | Histone deacetylases (HDACs) have been indicated important roles in neurodegenerative disorders including Alzheimer’s disease (AD). Herein, a series of novel compounds that contain a memantine moiety were designed to target HDACs and N-methyl- d -aspartate receptor (NMDAR) which are related to the treatment of AD. Biological characterization established that compound 9d exhibited a balanced inhibitory activity on NMDAR and HDACs. This compound is relatively selective to HDAC6 with IC50 of 0.18 μM and also maintains comparable activity on NMDAR (Ki = 0.59 μM) as memantine. Functionally, treatment with 9d increased the level of AcTubulin in MV4-11 cells and rescued PC-12 cells from H2O2-induced cytotoxicity with EC50 of 0.94 μM. Studies in mice also demonstrated that compound 9d efficiently penetrates the blood brain barrier to reach the brain tissue. Collectively, the results strongly encourage further development of 9d as a potential therapeutic agent for AD. |
| Databáze: | OpenAIRE |
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