title: Total synthesis and full histone deacetylase inhibitory profiling of Azumamides A-E as well as β²- epi-Azumamide E and β³-epi-Azumamide E.
abstract: Cyclic tetrapeptide and depsipeptide natural products have proven useful as biological probes and drug candidates due to their potent activities as histone deacetylase (HDAC) inhibitors. Here, we present the syntheses of a class of cyclic tetrapeptide HDAC inhibitors, the azumamides, by a concise route in which the key step in preparation of the noncanonical disubstituted β-amino acid building block was an Ellman-type Mannich reaction. By tweaking the reaction conditions during this transformation, we gained access to the natural products as well as two epimeric homologues. Thus, the first total syntheses of azumamides B-D corroborated the originally assigned structures, and the synthetic efforts enabled the first full profiling of HDAC inhibitory properties of the entire selection of azumamides A-E. This revealed unexpected differences in the relative potencies within the class and showed that azumamides C and E are both potent inhibitors of HDAC10 and HDAC11.
authors.affiliation: Department of Chemistry, Technical University of Denmark, Kemitorvet 207, Kongens Lyngby DK-2800, Denmark.
authors.forename: Jesper S
authors.initials: JS
authors.lastname: Villadsen
authors.forename: Helle M
authors.initials: HM
authors.lastname: Stephansen
authors.forename: Alex R
authors.initials: AR
authors.lastname: Maolanon
authors.forename: Pernille
authors.initials: P
authors.lastname: Harris
authors.forename: Christian A
authors.initials: CA
authors.lastname: Olsen
mesh_terms: D018360:Crystallography, X-Ray; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic