Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors

Bioorg Med Chem Lett. 2014 Jan 1;24(1):61-4. doi: 10.1016/j.bmcl.2013.11.072. Epub 2013 Dec 4.

Abstract

A series of SAHA-like molecules were prepared introducing different lactam-carboxyamides in position 7 of the suberoylanilide skeleton. The activity against different HDAC isoforms was tested and the data compared with the corresponding linear products, without substituent in position 7. In general, this modification provided an effective reinforcement of in vitro activity. While the lactam size or the CO/NH group orientation did not strongly influence the inhibition, the contemporary modification of the suberoylamide fragment gave vary active variants in the lactam series, with compound 28 (ST8078AA1) that showed IC50 values between 2 and 10nM against all Class I HDAC isoforms, demonstrating it to be a large spectrum pan-inhibitor. This strong affinity with HDAC was also confirmed by the value of IC50=0.5μM against H460 cells, ranking 28 as one of the most potent HDAC inhibitors described so far.

Keywords: Anticancer; HDAC; Heterocycles; Hydroxamic acid; Pan-inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Lactams / chemistry*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Lactams
  • Histone Deacetylases