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

•Burkholdacs A and B and 5,6,20-tri-epi-burkholdac A were synthesized.•These compounds were evaluated against HDACs and 39 human cancer cell lines.•Burkholdacs A and B showed potent HDAC1 inhibitory and antiproliferative activities.•Burkholdacs A and B showed very high HDAC1 (class I) isoform selectivity.•Novel aspects of SAR were revealed.

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.

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