Twisted Amide-Mediated Synthesis and Rapid Structure-Activity Relationship Study of Medium-Sized Cyclic Peptides.

Abstract

Medium-sized cyclic peptides are expected to be ideal drug leads because these peptides combine the advantages, while compensating for the disadvantages, of small molecules and antibodies. Although medium-sized peptides can be produced by chemical synthesis, two major problems, namely (i) Cα-epimerization during C-terminal modification and (ii) side reactions in the cyclization, remain to be solved. These issues have hampered the synthesis of pure materials for bioassays, making it difficult to accomplish accurate structure-activity relationship (SAR) studies. Herein, we report an efficient synthesis of medium-sized cyclic peptides based on the twisted amide-mediated amidation strategy. First, a variety of linear peptides were synthesized by the "inverse" peptide synthesis and fragment coupling. Second, the C-terminus of the linear peptides were converted to twisted amides, which were then reacted with a variety of α-amino acyl sulfonamides, realizing the rapid C-terminal diversification of peptides. Finally, the resulting linear peptides were cyclized by the intramolecular twisted amide-mediated amidation to afford stereochemically pure cyclic peptides. Using this strategy, total synthesis of acyl-surugamide A, the stereoselective synthesis of 13 non-natural analogs, and the discovery of potent antimicrobial/antifungal peptides beyond the natural product were also achieved.