Amide analogues of TSA: synthesis, binding mode analysis and HDAC inhibition

K Van Ommeslaeghe; G Elaut; V Brecx; P Papeleu; K Iterbeke; P Geerlings; D Tourwé; V Rogiers

doi:10.1016/s0960-894x(03)00284-1

Amide analogues of TSA: synthesis, binding mode analysis and HDAC inhibition

Bioorg Med Chem Lett. 2003 Jun 2;13(11):1861-4. doi: 10.1016/s0960-894x(03)00284-1.

Authors

K Van Ommeslaeghe¹, G Elaut, V Brecx, P Papeleu, K Iterbeke, P Geerlings, D Tourwé, V Rogiers

Affiliation

¹ Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.

PMID: 12749885
DOI: 10.1016/s0960-894x(03)00284-1

Abstract

The synthesis of new amide type histone deacetylase inhibitors is described, having an (R)-methyl substituent and a diene or saturated structure of the chain linking the hydroxamic acid and dimethylaminobenzoyl groups. The saturated compound shows stronger HDAC inhibition than the unsaturated analogue. Molecular modeling suggests that the flexibility of the linker chain is important for an optimal orientation of the dimethylaminobenzoyl group in the enzyme.

Publication types

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

MeSH terms

Amides / chemistry*
Amides / metabolism
Amides / pharmacology*
Animals
Binding Sites
Chickens
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Histone Deacetylase Inhibitors*
Hydroxamic Acids / chemistry*
Hydroxamic Acids / pharmacology*
Inhibitory Concentration 50
Models, Molecular
Rats
Structure-Activity Relationship

Substances

Amides
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Hydroxamic Acids
trichostatin A