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.