title: Simple inhibitors of histone deacetylase activity that combine features  of short-chain fatty acid and hydroxamic acid inhibitors.
abstract: Butyric acid and trichostatin A (TSA) are anti-cancer compounds that cause the upregulation of genes involved in differentiation and cell cycle regulation by inhibiting histone deacetylase (HDAC) activity. In this study we have synthesized and evaluated compounds that combine the bioavailability of short-chain fatty acids, like butyric acid, with the bidentate binding ability of TSA. A series of analogs were made to examine the effects of chain length, simple aromatic cap groups, and substituted hydroxamates on the compounds' ability to inhibit rat-liver HDAC using a fluorometric assay. In keeping with previous structure-activity relationships, the most effective inhibitors consisted of longer chains and hydroxamic acid groups. It was found that 5-phenylvaleric hydroxamic acid and 4-benzoylbutyric hydroxamic acid were the most potent inhibitors with IC50's of 5 microM and 133 microM respectively.
authors.affiliation: Department of Chemistry and Biochemistry, University of Michigan-Flint, Flint, MI 48502, USA. jtisch@umflint.edu
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Tischler
authors.forename: Basel
authors.initials: B
authors.lastname: Abuaita
authors.forename: Sierra C
authors.initials: SC
authors.lastname: Cuthpert
authors.forename: Christopher
authors.initials: C
authors.lastname: Fage
authors.forename: Kristi
authors.initials: K
authors.lastname: Murphy
authors.forename: Andrew
authors.initials: A
authors.lastname: Saxe
authors.forename: Edward B
authors.initials: EB
authors.lastname: Furr
authors.forename: Jamie
authors.initials: J
authors.lastname: Hedrick
authors.forename: Jennifer
authors.initials: J
authors.lastname: Meyers
authors.forename: David
authors.initials: D
authors.lastname: Snare
authors.forename: Ali R
authors.initials: AR
authors.lastname: Zand
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005227:Fatty Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051381:Rats
chemical_list: C533374:4-benzoylbutyric hydroxamic acid; C533375:5-phenylvaleric hydroxamic acid; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D006655:Histone Deacetylases