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

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.