Zn2+-Chelating Motif-Tethered Short-Chain Fatty Acids as a Novel Class of Histone Deacetylase Inhibitors

Qiang Lu, Ya Ting Yang, Chang Shi Chen, Melanie Davis, John C. Byrd, Mark R. Etherton, Asad Umar, Ching Shih Chen

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99 Citations (Scopus)


Among various classes of histone deacetylase (HDAC) inhibitors, short-chain fatty acids exhibit the least potency, with IC50 in the millimolar range. We rationalized that this weak potency was, in part, attributable to their inability to access the zinc cation in the HDAC active-site pocket, which is pivotal to the deacetylation catalysis. We thus explored the structural optimization of valproate, butyrate, phenylacetate, and phenylbutyrate by coupling them with Zn2+-chelating motifs (hydroxamic acid and o-phenylenediamine) through aromatic ω-amino acid linkers. This strategy has led to a novel class of Zn2+-chelating, motif-tethered, short-chain fatty acids that exhibited varying degrees of HDAC inhibitory potency. One hydroxamatetethered phenylbutyrate compound, N-hydroxy-4-(4-phenylbutyrylamino)benzamide (HTPB), displayed nanomolar potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at the submicromolar level showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21WAF/CIP1 expression, which are hallmark features associated with intracellular HDAC inhibition.

Original languageEnglish
Pages (from-to)467-474
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number2
Publication statusPublished - 2004 Jan 15

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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