Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors

J Med Chem. 2004 Jan 15;47(2):467-74. doi: 10.1021/jm0303655.

Abstract

Among various classes of histone deacetylase (HDAC) inhibitors, short-chain fatty acids exhibit the least potency, with IC(50) 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 Zn(2+)-chelating motifs (hydroxamic acid and o-phenylenediamine) through aromatic omega-amino acid linkers. This strategy has led to a novel class of Zn(2+)-chelating, motif-tethered, short-chain fatty acids that exhibited varying degrees of HDAC inhibitory potency. One hydroxamate-tethered 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 p21(WAF/CIP1) expression, which are hallmark features associated with intracellular HDAC inhibition.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylation
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Chelating Agents / chemical synthesis*
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Fatty Acids / chemical synthesis*
  • Fatty Acids / chemistry
  • Fatty Acids / pharmacology
  • Histone Deacetylase Inhibitors*
  • Histones / metabolism
  • Humans
  • Male
  • Valproic Acid / analogs & derivatives
  • Valproic Acid / chemical synthesis
  • Valproic Acid / chemistry
  • Valproic Acid / pharmacology
  • Zinc / chemistry*

Substances

  • Antineoplastic Agents
  • Benzamides
  • CDKN1A protein, human
  • Chelating Agents
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Fatty Acids
  • Histone Deacetylase Inhibitors
  • Histones
  • N-hydroxy-4-(4-phenylbutyrylamino)benzamide
  • Valproic Acid
  • Zinc