Synthesis and Biological Evaluation of a Depsipeptidic Histone Deacetylase Inhibitor via a Generalizable Approach Using an Optimized Latent Thioester Solid-Phase Linker

We
describe the synthesis of Xyzidepsin, a depsipeptidic analogue
of HDAC inhibitor Romidepsin (FK228), using a solid-phase strategy.
Our latent thioester solid-phase linker was synthesized in 92% yield
(three steps). Chemoselective conditions unmasked the thioester functionality
and cyclized the depsipeptidic macrocycle. An IC50 value
of 0.50 μM ± 0.05 was obtained for U937 cells. This synthetic
route, well-suited to SAR, represents a generalizable route toward
all manner of analogues, including structures with acidic and basic
amino acids.