Total Synthesis and Biological Mode of Action of Largazole: A Potent Class I Histone Deacetylase Inhibitor

Abstract

The efficient total synthesis of the recently described natural substance largazole (1) and it’s 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 largazole thiol (2) which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and the largazole thiol (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 being attributed to differences in cell permeability of the two substances, respectively.

Largazole as a Novel and Selective Anti-Breast Cancer Agent

“…The resulting N-terminal GFP-p27 fusion, detectable by fluorescence microscopy, was used to determine the levels of p27 expression upon treatment of cells with the compound libraries in 96-well format. Much to our surprise, the most potent hit that emerged from this screen was the natural compound Largazole (Figure 1), which was first described by Luesch and coworkers (15) and subsequently synthesized in several laboratories including ours (1,3,10,14,15,18,19). Largazole induced a robust and highly uniform upregulation of GFP-p27 at concentrations as low as 1 nM (Figure 2a) as compared to the expression levels after treatment with the proteasome inhibitor MG132.…”

Strategies in developing promising histone deacetylase inhibitors

“…Bowers and coworkers demonstrated that largazole is, in fact, a pro-drug, and largazole thiol (32) is its active form. 94 Their finding is supported by HDAC1, 2, 3, and 6 inhibitory activity data (K i , nM) of 0.07, 0.07, 0.17, and 25, respectively, for largazole thiol vs. 20, 21, 48, and 41000 for largazole.…”

Marine Natural Products: New Avenue in Treatment of Osteoporosis

“…exhibits in vitro and in vivo osteogenic activity by its histone deacetylases (HDACs) inhibition. Largazole is a 16 membered macrocycle possessing unusual structural features, includes a substituted 4-methylthiazoline linearly fused to a thiazole and a 3-hydroxy-7-mercaptohept-4-enoic acid unit (Bowers et al, 2008). Biological evaluation suggests that largazole and its key analogs are class I HDAC inhibitor.…”