Synthetic and pharmacological studies on new simplified analogues of the potent actin-targeting Jaspamide

In the recent years, we focused our attention on the cyclodepsipeptide Jaspamide 1, an interesting marine metabolite, possessing a potent inhibitory activity against breast and prostate cancer, as a consequence of its ability to disrupt actin cytoskeleton dynamics. Although its biological profile has been well determined, many mechanistic details are still missing in terms of molecular target identification. For this reason, we decided to synthetically modify the natural metabolite, obtaining small arrays of unnatural variants useful to illuminate the structural requirements essential for the activity. Here, we report the synthesis of seven new Jaspamide analogues 2–8, containing, as the parent compound, a β-amino acid in the cyclopeptide backbone. Their biological profile is also described.

A new collection of simplified analogues of the actin-binding natural cyclodepsipeptide Jaspamide was designed and synthesized. The macrocycle closure has been accomplished through classic peptide bond formation or microwave supported RCM reaction.Figure optionsDownload as PowerPoint slide