1,3-Dichloroacetone: A Robust Reagent for Preparing Bicyclic Peptides

Qingqing Lin; Denham Hopper; Haoyue Zhang; Jordan Sfyris Qoon; Zihan Shen; John A Karas; Richard A Hughes; Susan E Northfield

doi:10.1021/acsomega.9b03152

1,3-Dichloroacetone: A Robust Reagent for Preparing Bicyclic Peptides

ACS Omega. 2020 Jan 17;5(4):1840-1850. doi: 10.1021/acsomega.9b03152. eCollection 2020 Feb 4.

Authors

Qingqing Lin¹, Denham Hopper¹, Haoyue Zhang¹, Jordan Sfyris Qoon¹, Zihan Shen¹, John A Karas¹, Richard A Hughes¹, Susan E Northfield¹

Affiliation

¹ Department of Pharmacology & Therapeutics, School of Biomedical Sciences, The University of Melbourne, Melbourne, Victoria 3010, Australia.

Abstract

The chemical synthesis of cyclic peptides is a well-established area of research. This has been further expanded by development of bio-orthogonal reactions that enable access to peptides of greater structural complexity. One approach utilizes 1,3-dichloroacetone to selectively link free cysteine side-chains with an acetone-like bridge via an S_N2 reaction. Here, we have used this reaction to dimerize cyclic peptide monomers to create novel bicyclic dimeric peptides. We investigated a range of reaction parameters to identify the optimal dimerization conditions for our model systems. One of the acetone-linked dimeric peptides was analyzed for proteolytic stability in human serum and was observed to still be fully intact after 48 h. This study provides valuable insights into the application of 1,3-dichloroacetone as a tool in the synthesis of complex, multicyclic peptides.