Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor

Alexander Yurek-George; Fay Habens; Matthew Brimmell; Graham Packham; A Ganesan

doi:10.1021/ja039258q

Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor

J Am Chem Soc. 2004 Feb 4;126(4):1030-1. doi: 10.1021/ja039258q.

Authors

Alexander Yurek-George¹, Fay Habens, Matthew Brimmell, Graham Packham, A Ganesan

Affiliation

¹ School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom.

PMID: 14746465
DOI: 10.1021/ja039258q

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Histone Deacetylase Inhibitors*
Peptides, Cyclic / chemical synthesis*
Peptides, Cyclic / pharmacology
Pseudomonas / chemistry

Substances

Enzyme Inhibitors
Histone Deacetylase Inhibitors
Peptides, Cyclic
spiruchostatin A