Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Aug 20;130(33):11219-22.
doi: 10.1021/ja8033763. Epub 2008 Jul 19.

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

Albert Bowers  1 , Nathan West, Jack Taunton, Stuart L Schreiber, James E Bradner, Robert M Williams
Affiliations

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

Albert Bowers et al. J Am Chem Soc. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structure of largazole (1), largazole thiol (2) and several known macrocyclic HDACi natural products containing the (S)-3-hydroxy-7-mercaptohept-4-enoic acid moiety.
Figure 2
Figure 2
Synthetic strategy to assemble largazole.
Figure 3
Figure 3
Inhibition of HDAC1 by largazole (filled circles), largazole thiol (open circles), SAHA (filled squares) and FK228 (open squares).
Figure 4
Figure 4
Comparative profiling of FK228 and the largazole thiol (2). Dose-ranging studies of FK228, largazole and the largazole thiol were performed against Class I HDAC proteins using the described kinetic, homogeneous assay (see Supporting Information). As a comparative measure of potency, compounds were studied in triplicate at a standard concentration (0.6 nM). Averaged data are presented for inhibition of HDAC1 (black), HDAC2 (gray) and HDAC3/NCoR2 (white). Error bars reflect one standard deviation from the mean.
Figure 5
Figure 5
Antiproliferative effects of largazole (red) and largazole thiol (blue). Effects on cell viability were evaluated using a panel of human malignant melanoma cell lines, using the standard, surrogate measurement of ATP content (Cell TiterGlo; Promega) in 384-well plate format. Replicate measurements were normalized to vehicle-only controls and IC50 calculations were performed by logistic regression (Spotfire DecisionSite). Largazole demonstrates a potent antiproliferative effect (IC50 45 nM – 315 nM) compared to largazole Thiol (IC50 360 nM – 2600 nM).
Scheme 1
Scheme 1
The total synthesis of largazole (1) and largazole thiol (2).
See this image and copyright information in PMC

References

    1. Taori K, Paul VJ, Luesch H. J Am Chem Soc. 2008;130:1806–1807. subsequent to the submission of the present manuscript on May 6, 2008, Luesch, et al. independently published a distinct synthesis of largazole; see: Ying Y, Taori K, Kim H, Homg J, Luesch H. J Am Chem Soc. 2008;130:0000. (published on-line May 29, 2008)

    1. Fujisawa Pharmaceutical Co., Ltd. 03141296. Jpn Kokai Tokkyo Koho JP. 1991
    2. Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T, Okuhara M. J Antibiot. 1994;47:301. - PubMed
    3. Shigematsu N, Ueda H, Takase S, Tanaka H. J Antibiot. 1994;47:311. - PubMed
    4. Ueda H, Manda T, Matsumoto S, Mukumoto S, Nishigaki F, Kawamura I, Shimomura K. J Antibiot. 1994;47:315. - PubMed
    1. Masuoka Y, Nagai A, Shin-ya K, Furihata K, Nagai K, Suzuki K, Hayakawa Y, Seto H. Tetrahedron Lett. 2001;42:41. - PubMed
    1. Townsend PA, Crabb SJ, Davidson SM, Johnson PWM, Packham G, Ganesan A. The bicyclic depsipeptide family of histone deacetylase inhibitors. In: Schreiber SL, Kapoor TM, Wess G, editors. Chemical Biology. Wiley-VCH Verlag GmbH & Co; Weinheim, Germany: 2007. pp. 693–720.

    1. Ref. 1b substantially corrected the error in ref. 1a with respect to the novelty of the (S)-3-hydroxy-7-mercaptohept-4-enoic acid moiety and also reported IC50 HDAC inhibitory data for Largazole.

Publication types

MeSH terms