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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Ying, Y; Taori, K; Kim, H; Hong, J; Luesch, H

Published Date

  • July 2008

Published In

Volume / Issue

  • 130 / 26

Start / End Page

  • 8455 - 8459

PubMed ID

  • 18507379

Electronic International Standard Serial Number (EISSN)

  • 1520-5126

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja8013727


  • eng