N-MethyIation as a Synthetic Resource for Increasing Stability in Depsipeptides

摘要

Many depsipeptides of natural origin display high biological activities. [1] However, only a few of these compounds have entered clinical trials because of problems associated with bioavailability as well as low stability in plasma favored by the presence of the ester bonds. Another key feature of natural peptides and depsipeptides is the presence of TV-methylated residues in their sequence. Cyclosporin, for example, bears six TV-methyl amino acids. [2] Since the presence of TV-methyl groups confers resistance to proteolytic cleavage, [3] the introduction of these groups has been widely used to prevent enzymatic degradation. Nevertheless, to date, TV-methylation has been limited mostly to the backbone but has not been extensively studied as the replacement of the ester bond into a depsipeptide [4]. Here we describe the application of this strategy to two distinct depsipeptides of marine origin: (i) thiocoraline, [5] a bicyclic thiodepsipeptide which acts as bisintercalator to DNA; and (ii) kahalahide F, [6] which is now in preclinical stage.