title: Synthesis of N-hydroxycinnamides capped with a naturally occurring moiety as inhibitors of histone deacetylase.
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 (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.
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.forename: Ching-Chow
authors.initials: CC
authors.lastname: Chen
authors.forename: Shi-Wei
authors.initials: SW
authors.lastname: Chao
authors.forename: Shoei-Sheng
authors.initials: SS
authors.lastname: Lee
authors.forename: Fen-Lin
authors.initials: FL
authors.lastname: Hsu
authors.forename: Yeh-Lin
authors.initials: YL
authors.lastname: Lu
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Hung
authors.forename: Chung-I
authors.initials: CI
authors.lastname: Chang
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016399:Lymphoma, T-Cell / Q000188:drug therapy; D000077337:Vorinostat
chemical_list: D003374:Coumarins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C550628:N-hydroxy-3-(2-(3,4-dihydro-8-isopentyl-2-oxo-2H-chromen-7-yloxy)ethoxy)cinnamide; C550629:N-hydroxy-3-(3-(3,4-dihydro-8-isopentyl-2-oxo-2H-chromen-7-yloxy)propoxy)cinnamide; C550630:N-hydroxy-4-(2-(3,4-dihydro-8-isopentyl-2-oxo-2H-chromen-7-yloxy)ethoxy)cinnamide; D000077337:Vorinostat; D006655:Histone Deacetylases; C046627:osthol