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.
- Ying, Y; Taori, K; Kim, H; Hong, J; Luesch, H
- July 2008
Volume / Issue
- 130 / 26
Start / End Page
- 8455 - 8459
Electronic International Standard Serial Number (EISSN)
International Standard Serial Number (ISSN)
Digital Object Identifier (DOI)