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

The immunosuppressant fungal metabolite FR235222 (1), a potent natural inhibitor of mammalian Histone Deacetylase (HDAC), has been synthesized and its structure in solution elucidated by NMR techniques. Key steps in the synthesis were the preparation of unusual amino acids Ahoda and (2R,4S)-MePro obtained from a glutamic acid synthon. The availability of a synthetic sample allowed the development of a 3D model for cyclic peptide inhibitor interaction with HDAC active site. Such model provided critical insight on the binding process, shedding light, for the first time, on the different forces governing molecular mechanisms involving small-molecule and cyclic tetrapeptide HDAC inhibitors.