Design, synthesis, and evaluation of a depsipeptide mimic of tendamistat

The cyclic hexadepsipeptide framework of enniatin B was identified as a template matching the beta-turn tripeptide of tendamistat. The modified analog 1 was synthesized as a tendamistat mimic and compared to the acyclic derivative 2 and the tripeptide Ac-Try-Arg-Tyr-OMe. These compounds were assembled from the dimeric esters 3-5. As an inhibitor of alpha-amylase, 1 is twice as potent as 2 and comparable to the tripeptide. NMR studies of 1 reveal four conformers in equilibrium in a 50:25:15:10 ratio; the ring conformation of the major component is similar to that of the enniatin B template, with the cis geometry of the alpha-hydroxyisovaleryl-N-methylvaline amide linkage; the other conformers differ in the position or presence of the cis amide linkage.