Synthesis of n-hydroxycinnamides capped with a naturally occurring moiety as inhibitors of histone deacetylase

Wei Jan Huang, Ching Chow Chen, Shi We Chao, Shoei Sheng Lee, Feng-Lin Hsu, Yeh Lin Lu, Ming Fang Hung, Chung I. Chang

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 9d, 9e, 9g 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; IC 50=24.5 nm), a potent inhibitor clinically used for the treatment of cutaneous T-cell lymphoma (CTCL). While compounds 9d and 9e showed SAHA-like activity towards HDAC1 and HDAC6, compound 9g was more selective for HDAC1. Compound 9d exhibited the best cellular effect, which was comparable to that of SAHA, of enhancing acetylation of either a-tubulin or histone H3. Molecular docking analysis showed that the osthole moiety of compound 9d 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.

Original languageEnglish
Pages (from-to)598-607
Number of pages10
JournalChemMedChem
Volume5
Issue number4
DOIs
Publication statusPublished - Apr 6 2010

Fingerprint

Histone Deacetylase Inhibitors
Molecular Docking Simulation
Enzyme inhibition
Cutaneous T-Cell Lymphoma
Acetylation
T-cells
Tubulin
Chelation
HeLa Cells
Histones
Inhibitory Concentration 50
Zinc
osthol
Enzymes
Neoplasms
Therapeutics

Keywords

  • Epigenetics
  • Histone deacetylase
  • Inhibitors
  • Molecular modeling
  • Ostholes

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Synthesis of n-hydroxycinnamides capped with a naturally occurring moiety as inhibitors of histone deacetylase. / Huang, Wei Jan; Chen, Ching Chow; Chao, Shi We; Lee, Shoei Sheng; Hsu, Feng-Lin; Lu, Yeh Lin; Hung, Ming Fang; Chang, Chung I.

In: ChemMedChem, Vol. 5, No. 4, 06.04.2010, p. 598-607.

Research output: Contribution to journalArticle

Huang, Wei Jan ; Chen, Ching Chow ; Chao, Shi We ; Lee, Shoei Sheng ; Hsu, Feng-Lin ; Lu, Yeh Lin ; Hung, Ming Fang ; Chang, Chung I. / Synthesis of n-hydroxycinnamides capped with a naturally occurring moiety as inhibitors of histone deacetylase. In: ChemMedChem. 2010 ; Vol. 5, No. 4. pp. 598-607.
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