Synthesis ofN-Hydroxycinnamides Capped with a Naturally Occurring Moiety as Inhibitors of Histone Deacetylase
| Autor: | Yeh Lin Lu, Shi We Chao, Ching-Chow Chen, Ming Fang Hung, Shoei-Sheng Lee, Chung-I Chang, Wei Jan Huang, Feng-Lin Hsu |
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| Rok vydání: | 2010 |
| Předmět: |
Stereochemistry
Hydroxamic Acids Lymphoma T-Cell Biochemistry Histone Deacetylases HeLa Histone H3 Coumarins Catalytic Domain Drug Discovery medicine Humans Moiety Computer Simulation General Pharmacology Toxicology and Pharmaceutics Vorinostat Pharmacology Binding Sites biology Chemistry Organic Chemistry HDAC6 biology.organism_classification HDAC1 Histone Deacetylase Inhibitors Acetylation Molecular Medicine Histone deacetylase HeLa Cells medicine.drug |
| Zdroj: | ChemMedChem. 5:598-607 |
| ISSN: | 1860-7187 1860-7179 |
| Popis: | Histone deacetylase (HDAC) inhibitors are regarded as promising therapeutics for the treatment of cancer. All reported HDAC inhibitors contain three pharmacophoric features: a zinc-chelating group, a hydrophobic linker, and a hydrophobic cap for surface recognition. In this study we investigated the effectiveness of osthole, a hydrophobic Chinese herbal compound, as the surface recognition cap in hydroxamate-based compounds as inhibitors of HDAC. Nine novel osthole-based N-hydroxycinnamides were synthesized and screened for enzyme inhibition activity. Compounds 9 d, 9 e, 9 g exhibited inhibitory activities (IC(50)=24.5, 20.0, 19.6 nM) against nuclear HDACs in HeLa cells comparable to that of suberoylanilide hydroxamic acid (SAHA; IC(50)=24.5 nM), a potent inhibitor clinically used for the treatment of cutaneous T-cell lymphoma (CTCL). While compounds 9 d and 9 e showed SAHA-like activity towards HDAC1 and HDAC6, compound 9 g was more selective for HDAC1. Compound 9 d exhibited the best cellular effect, which was comparable to that of SAHA, of enhancing acetylation of either alpha-tubulin or histone H3. Molecular docking analysis showed that the osthole moiety of compound 9 d may interact with the same hydrophobic surface pocket exploited by SAHA and it may be modified to provide class-specific selectivity. These results suggest that osthole is an effective hydrophobic cap when incorporated into N-hydroxycinnamide-derived HDAC inhibitors. |
| Databáze: | OpenAIRE |
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