Synthesis of a selective HDAC6 inhibitor active in neuroblasts

Bioorg Med Chem Lett. 2016 Oct 15;26(20):4955-4959. doi: 10.1016/j.bmcl.2016.09.011. Epub 2016 Sep 7.

Abstract

In recent years, the role of HDAC6 in neurodegeneration has been partially elucidated, which led some authors to propose HDAC6 inhibitors as a therapeutic strategy to treat neurodegenerative diseases. In an effort to develop a selective HDAC6 inhibitor which can cross the blood brain barrier (BBB), a modified hydroxamate derivative (compound 3) was designed and synthetized. This compound was predicted to have potential for BBB penetration based on in silico and in vitro evaluation of passive permeability. When tested for its HDAC inhibitory activity, the IC50 value of compound 3 towards HDAC6 was in the nM range in both enzymatic and cell-based assays. Compound 3 showed a cell-based selectivity profile close to that of tubastatin A in SH-SY5Y human neuroblastoma cells, and a good BBB permeability profile.

Keywords: HDAC6; Histone deacetylases; Isoform selectivity; Neuroblastoma cells; PAMPA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood-Brain Barrier
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid / methods
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / chemical synthesis*
  • Histone Deacetylase Inhibitors / pharmacokinetics
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / drug effects*
  • Humans
  • Neurons / drug effects*

Substances

  • Histone Deacetylase Inhibitors
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases