Synthesis of Amide Analogs of Arenastatin A

In order to probe the metabolism of arenastatin A, a potent cytotoxic depsipeptide from the marine sponge Dysidea arenaria, we synthesized three analogs in which the ester linkages were replaced by amide bonds. Triamide analog-II and tetraamide analog, both of which contained a 15,20-amide linkage, showed stability in serum. However, arenastatin A and triamide analog-I, which both contained a 15,20-ester moiety, were readily metabolized in serum. Among the three amide analogs, only triamide analog-II exhibited potent cytotoxic activity against KB cells.