Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: Synthesis and biological evaluation

Pravin Bhansali, Christin L. Hanigan, Robert A. Casero, L. M.Viranga Tillekeratne

Research output: Contribution to journalArticlepeer-review

Abstract

The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn 2+ were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin.

Original languageEnglish (US)
Pages (from-to)7453-7463
Number of pages11
JournalJournal of medicinal chemistry
Volume54
Issue number21
DOIs
StatePublished - Nov 10 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: Synthesis and biological evaluation'. Together they form a unique fingerprint.

Cite this