title: Synthesis and evaluation of aliphatic-chain hydroxamates capped with osthole derivatives as histone deacetylase inhibitors.
abstract: 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.
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, 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: Chia-Chun
authors.initials: CC
authors.lastname: Yu
authors.forename: Chen-Yui
authors.initials: CY
authors.lastname: Yang
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
authors.forename: Yun-Chieh
authors.initials: YC
authors.lastname: Lin
authors.forename: Chiao-I
authors.initials: CI
authors.lastname: Kuo
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Chung-I
authors.initials: CI
authors.lastname: Chang
mesh_terms: D015153:Blotting, Western; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D021241:Spectrometry, Mass, Electrospray Ionization; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D006655:Histone Deacetylases