A cyclodextrin-capped histone deacetylase inhibitor

Jahangir Amin; Antonino Puglisi; James Clarke; John Milton; Minghua Wang; Ronald M Paranal; James E Bradner; John Spencer

doi:10.1016/j.bmcl.2013.03.084

A cyclodextrin-capped histone deacetylase inhibitor

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3346-8. doi: 10.1016/j.bmcl.2013.03.084. Epub 2013 Apr 2.

Authors

Jahangir Amin¹, Antonino Puglisi, James Clarke, John Milton, Minghua Wang, Ronald M Paranal, James E Bradner, John Spencer

Affiliation

¹ Dept. of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, East Sussex, UK. j.amin@sussex.ac.uk

PMID: 23591111
DOI: 10.1016/j.bmcl.2013.03.084

Abstract

We have synthesized a β-cyclodextrin (βCD)-capped histone deacetylase (HDAC) inhibitor 3 containing an alkyl linker and a zinc-binding hydroxamic acid motif. Biological evaluation (HDAC inhibition studies) of 3 enabled us to establish the effect of replacing an aryl cap (in SAHA (vorinostat,)) 1 by a large saccharidic scaffold "cap". HDAC inhibition was observed for 3, to a lesser extent than SAHA, and rationalized by molecular docking into the active site of HDAC8. However, compound 3 displayed no cellular activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cell Line, Tumor
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / metabolism
Histone Deacetylases / chemistry*
Histone Deacetylases / metabolism
Humans
Hydroxamic Acids / chemistry
Molecular Docking Simulation
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Protein Structure, Tertiary
Repressor Proteins / chemistry*
Repressor Proteins / metabolism
Vorinostat
Zinc / chemistry
beta-Cyclodextrins / chemistry*
beta-Cyclodextrins / metabolism

Substances

Histone Deacetylase Inhibitors
Hydroxamic Acids
Protein Isoforms
Repressor Proteins
beta-Cyclodextrins
Vorinostat
HDAC8 protein, human
Histone Deacetylases
Zinc
betadex