title: Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor.
abstract: The total synthesis of spiruchostatin A was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction and as an activated acylating agent for amide formation, and macrolactonization by the Yamaguchi protocol. Spiruchostatin A is shown to have biological activity similar to that of FK228, a potent histone deacetylase (HDAC) inhibitor in clinical trials. The spiruchostatin A analogue, epimeric at the beta-hydroxy acid, is inactive, highlighting the importance of stereochemistry at this position for interactions with HDACs.
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: Fay
authors.initials: F
authors.lastname: Habens
authors.forename: Matthew
authors.initials: M
authors.lastname: Brimmell
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D011549:Pseudomonas / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C485419:spiruchostatin A