Oral Presentation 9th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2023

Developing the Allenamide as a Peptide Functional Group for Chemoselective Hetero-Michael Additions (97579)

Alan Cameron 1 2 3
  1. School of Chemical Sciences, University of Auckland, Auckland, New Zealand
  2. School of Biological Sciences, University of Auckland, Auckland, New Zealand
  3. The Maurice Wilkins Centre for Molecular Biodiscovery,, University of Auckland, Auckland, New Zealand

The allenamide was first reported in 2014 as an electrophilic Michael acceptor with chemoselective reactivity towards cysteine thiols1, allowing small molecules adorned with this functionality to be conjugated with peptides and proteins. Encouraged by this, we sought to further explore its applicability and developed the allenamide as a peptide functional group that could be introduced during Fmoc SPPS. In 2020, we demonstrated its use in preparing a cyclic peptide and conjugating a handful of thiols (beyond cysteine) selectively to peptides2. With the wealth of commercially available thiols, we set out to further harness the power of this approach as a peptide lipidation tool. Leveraging chemically diverse thiols as readily available building blocks, we have now prepared more than 20 antimicrobial lipopeptide derivatives of polymyxin B, utilising thia-Michael addition of substituted aromatic thiols, heterocyclic thiols, those bearing additional functional groups (e.g. amines) and less reactive alkyl thiols. In many instances, including with alkyl thiols, our newly optimised conditions afford near quantitative conversion within 3 min. This chemoselective lipidation approach offers unprecedented access to chemical diversity and partners excellently with a semi-synthetic approach, yielding new derivatives in up to 25% yield over five synthetic steps from commercially available polymyxin B. The activity profiles of the resultant lipopeptides are accordingly diverse and this strategy has afforded analogues with maintained antimicrobial potency and up to ten-fold attenuated nephrotoxicity in an organoid model. Through these studies, we have also revealed new and unexpected hetero-Michael applications of the allenamide. This talk will discuss these recent developments as both solution- and solid-phase reactions which afford potentially valuable products, and offer new approaches in green chemical synthesis. Mechanistic considerations and unique aspects of these hetero-Michael additions will be addressed employing density functional theory (DFT) calculations.

  1. 1. Abbas, A., Xing, B. and Loh, T.P., 2014. Allenamides as orthogonal handles for selective modification of cysteine in peptides and proteins. Angewandte Chemie, 126(29), pp.7621-7624.
  2. 2. Cameron, A.J., Harris, P.W. and Brimble, M.A., 2020. On‐Resin Preparation of Allenamidyl Peptides: A Versatile Chemoselective Conjugation and Intramolecular Cyclisation Tool. Angewandte Chemie, 132(41), pp.18210-18217.