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Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor
Alexander Yurek-George1, Fay Habens, Matthew Brimmell
1School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.
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.
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