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Total synthesis and molecular target of largazole, a histone deacetylase inhibitor.

Publication ,  Journal Article
Ying, Y; Taori, K; Kim, H; Hong, J; Luesch, H
Published in: Journal of the American Chemical Society
July 2008

Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the preparation of a series of key analogues, and the molecular target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biological evaluation of largazole and its key analogues, including an acetyl analogue, a thiol analogue, and a hydroxyl analogue, suggested that histone deacetylases (HDACs) are molecular targets of largazole and largazole is a class I HDAC inhibitor. In addition, structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.

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Published In

Journal of the American Chemical Society

DOI

EISSN

1520-5126

ISSN

0002-7863

Publication Date

July 2008

Volume

130

Issue

26

Start / End Page

8455 / 8459

Related Subject Headings

  • Thiazoles
  • Structure-Activity Relationship
  • Histone Deacetylase Inhibitors
  • General Chemistry
  • Enzyme Inhibitors
  • Depsipeptides
  • Cyclization
  • Antineoplastic Agents
  • 40 Engineering
  • 34 Chemical sciences
 

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Ying, Y., Taori, K., Kim, H., Hong, J., & Luesch, H. (2008). Total synthesis and molecular target of largazole, a histone deacetylase inhibitor. Journal of the American Chemical Society, 130(26), 8455–8459. https://doi.org/10.1021/ja8013727
Ying, Yongcheng, Kanchan Taori, Hyoungsu Kim, Jiyong Hong, and Hendrik Luesch. “Total synthesis and molecular target of largazole, a histone deacetylase inhibitor.Journal of the American Chemical Society 130, no. 26 (July 2008): 8455–59. https://doi.org/10.1021/ja8013727.
Ying Y, Taori K, Kim H, Hong J, Luesch H. Total synthesis and molecular target of largazole, a histone deacetylase inhibitor. Journal of the American Chemical Society. 2008 Jul;130(26):8455–9.
Ying, Yongcheng, et al. “Total synthesis and molecular target of largazole, a histone deacetylase inhibitor.Journal of the American Chemical Society, vol. 130, no. 26, July 2008, pp. 8455–59. Epmc, doi:10.1021/ja8013727.
Ying Y, Taori K, Kim H, Hong J, Luesch H. Total synthesis and molecular target of largazole, a histone deacetylase inhibitor. Journal of the American Chemical Society. 2008 Jul;130(26):8455–8459.
Journal cover image

Published In

Journal of the American Chemical Society

DOI

EISSN

1520-5126

ISSN

0002-7863

Publication Date

July 2008

Volume

130

Issue

26

Start / End Page

8455 / 8459

Related Subject Headings

  • Thiazoles
  • Structure-Activity Relationship
  • Histone Deacetylase Inhibitors
  • General Chemistry
  • Enzyme Inhibitors
  • Depsipeptides
  • Cyclization
  • Antineoplastic Agents
  • 40 Engineering
  • 34 Chemical sciences