UC Riverside

Part one describes the synthesis and bioactivity of syrbactin derivatives. The syrbactins are a class of structurally similar natural products that were discovered to effectively induce apoptosis in various cancer cell lines through irreversible binding and inhibition of the constitutive proteasome. The success of proteasome inhibitors bortezomib and carfilzomib as cancer therapeutics has promoted further interest in the syrbactins. Previous work conducted by the Pirrung laboratory exploring the structure-activity relationship of syrbactin analogs has inspired the investigation into the synthesis of a unique set of syrbactin derivatives in efforts to create next-generation proteasome inhibitors with improved potency and enhanced overall efficacy. In this work, a novel set of syrbactin based derivatives have been proposed, synthesized, and the biological activities have been evaluated. Additionally, thiasyrbactin derivatives have been discovered to have unique properties resulting in rare and selective inhibition of the immunoproteasome. The immunoproteasome has been linked to a variety of diseases including various cancers, autoimmune, and neurodegenerative diseases, and is therefore, a novel therapeutic target.

Part two describes the development of peptide assembly by ligation of hydroxyl amino acids threonine and homoserine with mildly activated esters. Many advances in the field of peptide chemistry have occurred allowing for the synthesis and bioevaluation of complex peptides and proteins. The development of native chemical ligation (NCL), a chemoselective cysteine-based peptide-coupling technique, provided a breakthrough in the chemical synthesis of peptides. Cysteine is one of the least abundant amino acids in natural peptides; thus, additional ligation methods based on other amino acids are essential. Recently, the Pirrung laboratory has developed a method of peptide assembly reacting β-hydroxylamines including serine, with activated esters to form amide bonds. This strategy mimics the mechanism of NCL via transesterification and subsequent acyl transfer to form a native peptide bond at the ligation site. In this work, peptide assembly with mildly activated esters has been successfully extended to the hydroxyl amino acids threonine and homoserine, expanding the scope of this ligation method. The utility of this method was further demonstrated by the synthesis of the opossum peptide, antivenom lethal toxin neutralizing factor-10 (LTNF-10).