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Journal of the American Chemical Society DOI:10.1021/ja8033763

Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor.

Publication TypeJournal Article
Year of Publication2008
AuthorsBowers, A, West, N, Taunton, J, Schreiber, SL, Bradner, JE, Williams, RM
JournalJournal of the American Chemical Society
Volume130
Issue33
Pages11219-22
Date Published2008/08/20
ISSN0002-7863
Abstract

The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite 2, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and 2 have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances.

URLhttp://dx.doi.org/10.1021/ja8033763
DOI10.1021/ja8033763
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/18642817?dopt=Abstract