Total synthesis of burkholdacs A and B and 5,6,20-tri-epi-burkholdac A: HDAC inhibition and antiproliferative activity

Eur J Med Chem. 2014 Apr 9:76:301-13. doi: 10.1016/j.ejmech.2014.02.044. Epub 2014 Feb 18.

Abstract

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors burkholdacs A and B were efficiently synthesized in a highly convergent and unified manner. The synthesis features the amide coupling of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-methionine-containing segment to directly assemble the corresponding seco-acids, key precursors for macrolactonization. Using the same methodology, 5,6,20-tri-epi-burkholdac A was also synthesized. HDAC inhibitory assays and cell-growth inhibition analyses of the synthesized depsipeptides demonstrated the potency order of this class of bicyclic depsipeptides as compared to the clinically approved depsipeptide FK228 (romidepsin). Novel structure-activity relationships within this class of compounds were also revealed.

Keywords: Bicyclic depsipeptide; Burkholdacs; Histone deacetylase inhibitors; Natural products; Total synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects*
  • Depsipeptides / chemical synthesis*
  • Depsipeptides / pharmacology
  • Histone Deacetylase Inhibitors / chemical synthesis*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Spectrometry, Mass, Fast Atom Bombardment

Substances

  • Depsipeptides
  • Histone Deacetylase Inhibitors
  • burkholdac A
  • burkholdac B