Amide analogues of TSA: synthesis, binding mode analysis and HDAC inhibition.
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.
Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
K
K
Van Ommeslaeghe
G
G
Elaut
V
V
Brecx
P
P
Papeleu
K
K
Iterbeke
P
P
Geerlings
D
D
Tourwé
V
V
Rogiers
D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002645:Chickens; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A