UCLA

Peptidyl macrocycles are a compound class with a rich clinical history and great potential for drugging biological targets by mediating protein-protein interactions. Methods to forge S-S disulfide bonds largely rely on the oxidation of dithiol containing substrates. We have developed and implemented a sulfur transalkylative macrocyclization induced by an appended cinnamyl carbonate-based template. This is a mechanistically new method for the construction of peptide macrocycles. The resultant macrocyclic structures contain the functionality of the linear oligomer, while scaffolding this potential pharmacophore in a more conformationally rigid manner. We aim to improve these macrocyclic structure’s biological stability and pharmacology relative to the linear oligomer.

Chapter 2 details the synthesis of mono- and disulfides via sulfur transalkylation induced by a tethered cinnamyl cation. Scope, limitations, and competition with previously reported nucleophilic residues are discussed. Methods to synthetically elaborate these structures are demonstrated and attempted. Synthesis of a potential ghrelin O-acyl transferase inhibitor is disclosed.

Chapter 3 covers the synthesis and development of two new templates designed to forge two macrocyclic bonds in one linear oligomer molecule. The use of these templates in the synthesis of bimacrocycles with sulfur and aryl linkages is divulged.

Chapter 4 centers on the synthesis and chemistry macrocyclic trisulfides. Acidolysis of template capped peptides containing tert-butylate trisulfide residues furnishes a mixture of mono-, tri- and pentasulfide linked macrocyclic product. Confirmation of this S2 exchange event is demonstrated via independent synthesis of the relevant monosulfide congener obtained in these trisulfidation reactions. Additionally, our efforts toward the total synthesis of an antimicrobial trithiocane containing natural product via the trisulfidation reaction are detailed.