Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides

J Med Chem. 2005 May 5;48(9):3344-53. doi: 10.1021/jm049002a.


Chemical manipulations performed on aroyl-pyrrolyl-hydroxyamides (APHAs) led to (aryloxopropenyl)pyrrolyl hydroxamates 2a-w, and their inhibition against maize HDACs and their class I or class II HDAC selectivity were determined. In particular, from these studies some benzene meta-substituted compounds emerged as highly class II (IIa)-selective HDAC inhibitors, the most selective being the 3-chloro- and 3-fluoro-substituted compounds 2c (SI = 71.4) and2f (SI = 176.4). The replacement of benzene with a 1-naphthyl ring afforded 2s, highly active against the class II homologue HD1-A (IC(50) = 10 nM) but less class II-selective than 2c,f. When tested against human HDAC1 and HDAC4, 2f showed no inhibitory activity against HDAC1 but was able to inhibit HDAC4. Moreover, in human U937 acute myeloid leukaemia cells 2f did not produce any effect on apoptosis, granulocytic differentiation, and the cell cycle, whereas 2s (that retain class I HDAC inhibitory activity) was 2-fold less potent than SAHA used as reference.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase 1
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases
  • Humans
  • Propane / analogs & derivatives*
  • Propane / chemical synthesis*
  • Propane / pharmacology
  • Pyrroles / chemical synthesis*
  • Pyrroles / pharmacology
  • Repressor Proteins / antagonists & inhibitors
  • Structure-Activity Relationship
  • U937 Cells
  • Zea mays


  • Amides
  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Pyrroles
  • Repressor Proteins
  • HDAC1 protein, human
  • HDAC4 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases
  • Propane