Discovery of aliphatic-chain hydroxamates containing indole derivatives with potent class I histone deacetylase inhibitory activities
| Autor: | Wei Jan Huang, Chia Chun Yu, Shi Wei Chao, Kai Cheng Hsu, Tony Eight Lin, Jih-Hwa Guh, Chen Yu Wang, Chun Yung Chen, Chang Yi Liu, Liang Chieh Chen |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Indoles Antineoplastic Agents Histone Deacetylase 1 Hydroxamic Acids Inhibitory postsynaptic potential Isozyme Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Drug Discovery Tumor Cells Cultured Humans Structure–activity relationship Potency Cell Proliferation Pharmacology Indole test Dose-Response Relationship Drug Molecular Structure Rhodamines Chemistry Organic Chemistry General Medicine HDAC1 Histone Deacetylase Inhibitors 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Histone deacetylase Drug Screening Assays Antitumor Linker |
| Zdroj: | European Journal of Medicinal Chemistry. 143:792-805 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.11.092 |
| Popis: | Histone deacetylase (HDAC) is a validated drug target for various diseases. This study combined indole recognition cap with SAHA, an FDA-approved HDAC inhibitor used to treat cutaneous T-cell lymphoma (CTCL). The structure activity relationship of the resulting compounds that inhibited HDAC was disclosed as well. Some compounds exhibited much stronger inhibitory activities than SAHA. We identified two meta-series compounds 6j and 6k with a two-carbon linker had IC50 values of 3.9 and 4.5 nM for HDAC1, respectively. In contrast, the same oriented compounds with longer carbon chain linkers showed weaker inhibition. The result suggests that the linker chain length greatly contributed to enzyme inhibitory potency. In addition, comparison of enzyme-inhibiting activity between the compounds and SAHA showed that compounds 6j and 6k displayed higher inhibiting activity for class I (HDAC1, -2, -3 and -8). The molecular docking and structure analysis revealed structural differences with the inhibitor cap and metal-binding regions between the HDAC isozymes that affect interactions with the inhibitors and play a key role for selectivity. Further biological evaluation showed multiple cellular effects associated with compounds 6j- and 6k-induced HDAC inhibitory activity. |
| Databáze: | OpenAIRE |
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