University of Melbourne
Talk Session: SESSION 11: SCAFFOLDS AND PEPTIDOMIMETICS
Date: Wednesday, June 15, 2022
Talk Time: 11:35 am - 11:55 am
Talk Title: Exploiting Thioamide Reactivity in Peptide Synthesis
Exploiting Thioamide Reactivity in Peptide Synthesis
We have developed a new method for peptide synthesis through the Ag(I)-promoted coupling of thioamides with carboxylic acids. This process generates an isoimide, which can undergo a 1,3-acyl transfer to generate an imide. The peptide imide can be hydrolysed to generate a native amide bond, or can undergo subsequent acyl transfer reactions to generate a range of modified peptides. Alternatively, the isoimide can be trapped by internal or external nucleophiles to generate a range of functionalised peptide motifs. We are investigating applications in peptide ligation, peptide residue excision/insertion, and peptide thioester synthesis.
Radiolabelled Amino Acids and Peptides for PET Imaging of Cancer
We are collaborating with Dr Peter Roselt and Prof Rod Hicks at the Peter MacCallum Cancer Centre on the preparation of radiolabelled peptides for cancer imaging. We have developed a one-step method for preparation of the radiolabelled synthon, p-nitrophenyl 2-F-fluoropropionate, and incorporated this into the synthesis of gold-standard radiotracers using a fully automated, 2-stage radiochemistry module.
Biologically Active Cyclic Peptide Natural Products
Current efforts are being directed towards the synthesis of several complex cyclic peptide natural products. The ustiloxins & celogentins are tubulin-binding cyclic peptides that have shown potent in vitro anti-tumour activity. The echinocandins and microsclerodermins are antifungal cyclic peptides that contain several poly-hydroxylated amino acids, with several now in clinical use for the treatment of fungal infections. The general synthetic strategy involves developing methods for the stereocontrolled synthesis of the highly functionalised amino acid residues present in these peptides, followed by the development of procedures for the assembly of the amino acid components into the final cyclic peptides. We have recently prepared the dityrosine-containing cyclic peptide natural product mycocyclosin, combining our interests in dityrosine crosslinks and peptide natural products!
Cross-linked Tyrosine Derivatives in Peptides and Proteins
We are developing novel methods for the preparation of cross-linked tyrosine derivatives, such as dityrosine, trityrosine and pulcherosine. In addition to their presence in small peptides, the formation of these tyrosine derivatives in proteins has been associated with a variety of diseases and disorders, including Alzheimer’s and Parkinson’s diseases. We are investigating the relationship between oxidatively cross-linked Aβ peptide oligomers and the progression of Alzheimer’s disease, in collaboration with Assoc Prof Kevin Barnham, Dept of Pathology and Bio21 Institute.
Our investigations both in the Petasis reaction and the use of tyrosine boronates had led to an interest in organoboron chemistry, particularly the efficient interconversion of boronate protecting groups. We have developed several methods for the cleavage of pinacol boronate esters to generate boronic acids under mild conditions.
In recent years a range of novel amide ligation strategies have been developed, many incorporating sulfur-containing reagents as thioesters and other carboxylic acid surrogates.
We have recently reported novel methods for peptide cyclization and functionalization based on the reaction of thioamides with carboxylic acids in the presence of silver(I).
These methods involve the initial generation of isoimide intermediates, which can undergo a range of acyl transfer processes to generate modified peptides. Recent progress in this area will be highlighted, including novel strategies for macrocyclization, ring expansion and glycosylation of peptide thioamides.