Synthesis and Conformational Analysis of Stevastelin C3 Analogues and Their Activity Against the Dual‐Specific Vaccina H1‐Related Phosphatase

Abstract

The biological activity of macrocyclic natural products depends on their conformational properties. For both the elucidation of enzyme binding affinities as well as the development of selective drugs, rigid macrocyclic scaffolds carry high potential. In this study, 13-membered cyclodepsipeptides based on the structure of naturally occurring stevastelins were studied in detail. Six diastereomeric stevastelin C3 analogues and four phosphorylated derivatives were synthesized. The synthesis of linear precursors was achieved on solid support by starting from stereoisomerically pure 2-methyl-3-hydroxy acids. Subsequent macro-lactamization gave the cyclic depsipeptides in very good yields (36-62%). The conformational space of these stevastelin C3 analogues was computationally investigated. On the basis of NMR spectroscopic data, homogeneous conformations were determined for each benzylated depsipeptide and the influence of phosphorylation on the overall conformation was investigated. Importantly, phosphorylation was found to significantly weaken the conformational preferences of the 13-membered depsipeptides. Finally, the cyclic depsipeptides were tested for activity against phosphatases. Inhibitory activity on vaccina H1-related phosphatase was observed depending on the derivatization of the cycles. The activity profiles are discussed in the light of the structural data.