Total synthesis of bicyclic depsipeptides spiruchostatins C and D and investigation of their histone deacetylase inhibitory and antiproliferative activities

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins C and D were synthesized for the first time in a highly convergent and unified manner. The method features the amide coupling of a d-leucine–d-cysteine- or d-valine–d-cysteine-containing segment with a d-alanine- or d-valine-containing segment to directly assemble the corresponding seco-acids, key precursors of macrolactonization. The HDAC inhibitory assay and cell-growth inhibition analysis of the synthesized depsipeptides determined the order of potency of spiruchostatins A–D in comparison with the clinically approved depsipeptide FK228 (romidepsin). Novel aspects of structure–activity relationships (SAR) were revealed. [Display omitted] ► Spiruchostatins C and D were synthesized for the first time. ► These compounds were evaluated against HDACs and 39 human cancer cell lines. ► Spiruchostatin D showed the most potent activities among the spiruchostatins family. ► Novel aspects of SAR were revealed.