Total Synthesis, NMR Solution Structure, and Binding Model of the Potent Histone Deacetylase Inhibitor FR235222

An alternative route: The fungal metabolite FR235222, a potent inhibitor of mammalian histone deacetylase (HDAC), has been synthesized. Key steps are the preparation of unusual amino acids Ahoda and (2R,4S)-MePro. A 3D model for cyclopeptide inhibitor interaction with the HDAC active site (see picture) highlights the differences between the binding mode of small-molecule and cyclopeptide inhibitors.