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

Abstract

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.

Unmasking latent thioesters under hydrophobic‐compatible conditions

“…The latent thioester in Figure 1 meets all of the desired criteria: compatibility with Fmoc SPPS and both aqueous and organic unmasking conditions. We have already demonstrated its suitability for Fmoc/t-Bu SPPS and subsequent aqueous ligation; 23,24 here, we establish that our latent thioester also functions under conditions compatible with hydrophobic materials, in addition to the previously reported aqueous conditions. As seen below, these organic reaction conditions can be employed to convert protected latent thioesters into thioesters or to enter directly into chemoselective ligations, if desired.…”

“…The solid-phase linker version of this material contains one latent thioester along with a carboxylic acid moiety. 24 )…”

“…Using the latent thioester that we demonstrated to function in aqueous media, 23,24 we envisioned adopting the reported ligation conditions for hydrophobic thioesters 21,22 to effect both transformations outlined in Figure 2. Esterification of C 2 -symmetrical diol 7 26 with protected amino acids to give 1a-c allowed us to test the functionality of our latent thioester.…”