Total synthesis of largazole and its biological evaluation

Yoshitaka Numajiri, Takashi Takahashi, Motoki Takagi, Shin Ya Kazuo, Takayuki Doi

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

We achieved a total synthesis of largazole. The optically active β-hydroxycarbonyl unit was prepared from a modified Nagao's N-acetylthiazolidinethione. A 4-methylthiazoline-thiazole amino ester was prepared by both a step-by-step method and tandem cyclization from Cys-2-MeCys-containing tripeptide. Amidation of the activated β-hydroxycarbonyl unit and 4-methylthiazoline-thiazole-containing amino ester, followed by esterification with N-Fmoc valine afforded cyclization precursor after selective removal of the methyl ester at the C-terminus and the Fmoc group at the N-terminus. Macrolactamization, deprotection of thiol, and S-acylation provided largazole. Biological evaluation of its S-modified derivatives as well as the synthetic largazole exhibited strong inhibitory activity against histone deacetylases (HDAC).

Original languageEnglish
Pages (from-to)2483-2486
Number of pages4
JournalSynlett
Issue number16
DOIs
Publication statusPublished - 2008 Oct 1

Keywords

  • HDAC inhibitor
  • Macrolactamization
  • Natural products
  • Peptides
  • Total synthesis

ASJC Scopus subject areas

  • Organic Chemistry

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