Design, synthesis and primary activity assay of tripeptidomimetics as histone deacetylase inhibitors with linear linker and branched cap group

Eur J Med Chem. 2011 Nov;46(11):5387-97. doi: 10.1016/j.ejmech.2011.08.045. Epub 2011 Sep 8.

Abstract

A novel series of tripeptidomimetics with spiro ring containing sulfur atoms as cap group and linear carbochain as linker was designed and synthesized as HDACs inhibitors. Several compounds possessed more potent HDAC8 inhibitory activity than clinically used drug SAHA, although their HDAC1 inhibitory activities and anti-proliferative activities against human breast cancer cell lines (MCF-7, MDA-MB-231) and prostate cancer cell line (PC-3) were not satisfactory. Among them, compounds 11l and 11k showed excellent potency against HDAC8 (IC(50) values were 0.021 ± 0.004 μM and 0.035 ± 0.007 μM, respectively, whereas SAHA was 0.70 ± 0.12 μM), and good selectivity over HDAC1. Up to now, few hydroxamic acid derivatives with linear linker were reported to possess HDAC8 selectivity over HDAC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase 1 / chemistry
  • Histone Deacetylase Inhibitors / chemical synthesis*
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydrolysis
  • Inhibitory Concentration 50
  • Peptidomimetics / chemical synthesis*
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*

Substances

  • Amino Acids
  • Histone Deacetylase Inhibitors
  • Peptidomimetics
  • Histone Deacetylase 1
  • Histone Deacetylases