title: The first biologically active synthetic analogues of FK228, the depsipeptide histone deacetylase inhibitor.
abstract: The FK228 and spiruchostatin bicyclic depsipeptide natural products are among the most potent histone deacetylase (HDAC) inhibitors known. Although FK228 is in advanced clinical trials, the complexity of the natural products has precluded mechanistic studies and the discovery of structure-activity relationships. By total synthesis, we have prepared the first depsipeptide analogues. Our results prove that the dehydrobutyrine residue in FK228 is not essential, and other residues can be substituted without loss of HDAC inhibitory activity. Conformational restriction by the macrocyclic scaffold is important, as a linear peptide was inactive. The intramolecular disulfide formed with a cysteine side chain can be removed provided the zinc-binding thiol is protected to ensure good cellular availability. Like the natural products, the analogues are selective against class I isoforms, with nanomolar inhibition of class I HDAC1 and significantly less potency against class II HDAC6.
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Yurek-George
authors.forename: Alexander Richard Liam
authors.initials: AR
authors.lastname: Cecil
authors.forename: Alex Hon Kit
authors.initials: AH
authors.lastname: Mo
authors.forename: Shijun
authors.initials: S
authors.lastname: Wen
authors.forename: Helen
authors.initials: H
authors.lastname: Rogers
authors.forename: Fay
authors.initials: F
authors.lastname: Habens
authors.forename: Satoko
authors.initials: S
authors.lastname: Maeda
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
mesh_terms: D000613:Aminobutyrates / Q000737:chemistry; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000613:Aminobutyrates; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D018942:Macrolides; D010456:Peptides, Cyclic; C088694:dehydrobutyrine; C087123:romidepsin; C110550:HDAC1 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases