Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor.
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.
Yurek-George
Alexander
A
School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
Habens
Fay
F
Brimmell
Matthew
M
Packham
Graham
G
Ganesan
A
A
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D011549:Pseudomonas / Q000737:chemistry
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C485419:spiruchostatin A