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

研究成果: Article同行評審

95 引文 斯高帕斯(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.

頁(從 - 到)467-474
期刊Journal of Medicinal Chemistry
出版狀態Published - 2004 一月 15

All Science Journal Classification (ASJC) codes

  • 分子醫學
  • 藥物發現


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