The Structurally diverse and complex naturally derived cyclopeptides and cyclodepsipeptides have received intense recent interest from the medicinal chemistry community driven in part by their activity in biological systems, such as those mediated by protein–protein interactions, that are difficult to prosecute with more typically drug-like small molecules. In addition, the selectivity afforded by their complexity and the remarkable ability of some of these peptide-containing macrocycles to provide significant systemic exposures on oral dosing despite physical properties that lie substantially outside of normal parameters for achieving oral bioavailability, make them an attractive chemical class. Thus, cyclic peptides are of great value not only for their own intrinsic pharmacological activity but also for their potential as tools used to understand how to design molecules with the properties necessary to produce highly effective therapeutics for the treatment of human disease.
We have been interested in macrocyclic secondary metabolites and view their syntheses as playing a key role in structural confirmation, structural modification, and subsequent activity control. Over the past ten years, we have completed the total synthesis of 48 natural products, which included over 26 cyclopeptides/cyclodepsipeptides.
The presentation will focus on our recent progress in the development of elongation factor 1 inhibitors based on the core structure of the natural product nannocystins.