Simple inhibitors of histone deacetylase activity that combine features  of short-chain fatty acid and hydroxamic acid inhibitors.
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.
Tischler
Jessica L
JL
Department of Chemistry and Biochemistry, University of Michigan-Flint, Flint, MI 48502, USA. jtisch@umflint.edu
Abuaita
Basel
B
Cuthpert
Sierra C
SC
Fage
Christopher
C
Murphy
Kristi
K
Saxe
Andrew
A
Furr
Edward B
EB
Hedrick
Jamie
J
Meyers
Jennifer
J
Snare
David
D
Zand
Ali R
AR
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
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