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

Article abstract of DOI:10.1016/j.ejmech.2014.02.044

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.