Synthesis of N‐Hydroxycinnamides Capped with a Naturally Occurring Moiety as Inhibitors of Histone Deacetylase |
| |
Authors: | Wei‐Jan Huang Prof Ching‐Chow Chen Prof Shi‐Wei Chao Shoei‐Sheng Lee Prof Fen‐Lin Hsu Prof Yeh‐Lin Lu Ming‐Fang Hung Chung‐I Chang Prof |
| |
Affiliation: | 1. Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu‐Xing Street, Taipei 110 (Taiwan);2. Department of Pharmacology, National Taiwan University, College of Medicine, 1 Ren‐Ai Road, Taipei 100 (Taiwan);3. School of Pharmacy, National Taiwan University College of Medicine, 1 Ren‐Ai Road, Taipei 100 (Taiwan);4. Institute of Biological Chemistry, Academia Sinica, 128 Academia Road, Sec. 2, Nankang, Taipei 11529 (Taiwan), Fax: (+886)?2‐2788‐9759 |
| |
Abstract: | 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 (IC50=24.5, 20.0, 19.6 nM ) against nuclear HDACs in HeLa cells comparable to that of suberoylanilide hydroxamic acid (SAHA; IC50=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 α‐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. |
| |
Keywords: | epigenetics histone deacetylase inhibitors molecular modeling ostholes |
|
|