Synthesis and evaluation of aliphatic-chain hydroxamates capped with osthole derivatives as histone deacetylase inhibitors

Our previous studies have demonstrated that osthole, a Chinese herbal compound, could be incorporated into the hydroxycinnamide scaffold of LBH-589, a potent HDAC inhibitor, as an effective hydrophobic cap; the resulting compounds showed significant potency against several HDAC isoforms. Here, we presented a series of osthole derivatives fused with the aliphatic-hydroxamate core of suberoylanilide hydroxamic acid (SAHA), a clinically-approved HDAC inhibitor. Several compounds showed potent activity against nuclear HDACs. Further assays against individual HDAC isoforms revealed that some compounds showed not only SAHA-like activity towards HDAC1, -4 and -6, they inhibited HDAC8 by log difference than SAHA and thus exhibited a broader HDAC inhibition spectrum. Among them, compound 6g showed potent antiproliferative effect on several human cancer cell lines.

A new series of osthole-based aliphatic hydroxamates have been synthesized and tested for inhibition of HDAC. Compound 6g showed potent antiproliferative effect on several human cancer cell lines.Figure optionsDownload as PowerPoint slideHighlights
► Osthole derivatives fused with the core scaffold of SAHA were developed.
► Compounds identified with a broader HDAC inhibition spectrum comparing to SAHA.
► One compound showed potent antiproliferative effect on several cancer cell lines.