Largazole: from discovery to broad-spectrum therapy

Abstract

The cyclic depsipeptide largazole from a cyanobacterium of the genus Symploca is a marine natural product with a novel chemical scaffold and potently inhibits class I histone deacetylases (HDACs). Largazole possesses highly differential growth-inhibitory activity, preferentially targeting transformed over non-transformed cells. The intriguing structure and biological activity of largazole have attracted strong interest from the synthetic chemistry community to establish synthetic routes to largazole and to investigate its potential as a cancer therapeutic. This Highlight surveys recent advances in this area with a focus on the discovery, synthesis, target identification, structure-activity relationships, HDAC8-largazole thiol crystal structure, and biological studies, including in vivo anticancer and osteogenic activities.

Fig. 1

Structure of largazole.

Fig. 2

Chemical degradation to determine the absolute configuration of stereogenic centers. a) O₃, CH₂Cl₂, 25 °C, 30 min; b) H₂O₂–HCO₂H (1:2), 70 °C, 20 min; c) 6 N HCl, 110 °C, 24 h.

Fig. 3

Putative mechanism of largazole action. A) Modes of action of largazole and FK228 to liberate potent HDAC inhibitors. B) Molecular docking of largazole thiol into an HDAC1 homology model. PG = Protecting group.

Fig. 4

Synthetic approaches to largazole.

Fig. 5

HDAC8–largazole thiol complex. The catalytic Zn²⁺ ion (red sphere) is coordinated by D178, H180, and D267 (blue sticks). Largazole thiol is shown as a stick figure (C = magenta, N = blue, O = red, and S = yellow). Structural K⁺ ions appear as green spheres. Reprinted with permission from K. E. Cole, D. P. Dowling, M. A. Boone, A. J. Phillips and D. W. Christianson, J. Am. Chem. Soc., 2011, 133, 12474–12477. Copyright 2011 American Chemical Society.

Fig. 6

Structure–activity relationships of largazole.

Fig. 7

In vitro and in vivo osteogenic activities of largazole. Arrows indicate the region of newly forming woven bone. Reprinted with permission from S.-U. Lee, H. B. Kwak, S.-H. Pi, H.-K. You, S. R. Byeon, Y. Ying, H. Luesch, J. Hong and S. H. Kim, ACS Med. Chem. Lett., 2011, 2, 248–251. Copyright 2011 American Chemical Society.