Oral Presentation 8th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2022

Application of alkylthioaryl linkage in macrocyclic peptidomimetic design (#5)

Wenxiao K Yue 1 , Tianxia Zhang 1 , Rekha Shandre Mugan 1 , Colin W Pouton 1 , Philip E Thompson 1
  1. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

The last decade has seen a transformation in the development of peptide therapeutics with an increasing number of approvals for peptide-based drugs. Of particular interest is the advancement of macrocyclic peptides and peptidomimetics. This class of compounds generally adopts well-defined conformations and exhibits enhanced metabolic stabilities, biological specificities and bioavailability.1 To date, many natural and non-natural macrocycles have been identified with promising pharmacological activities, and the interest in developing efficient synthetic strategies to access cyclopeptides and cyclopeptidomimetics has grown exponentially.2 Nucleophilic aromatic substitution (SNAr) is an effective cyclisation method that is orthogonal to conventional peptide chemistries. Application of this strategy for preparing alkyl-aryl ether or biaryl ether bridged peptide macrocycles is well documented, but focus has been primarily on nitro-activated SNArs.3 The synthetic applicability of SNAr macrocyclisation involving other substituents has been neglected.

With the aim to further broaden the scope and utility of SNAr macrocyclisation, we established a range of peptides bearing nitro-, cyano- and ethynyl-fluoroarenes as substrates for SNAr reaction mediated macrocyclisation with cysteine residues. The resultant alkylthioaryl-bridged macrocycles were subjected to further structural modification, providing new points for additional conjugation. The effects of those modifications were evaluated for their biological activities at melanocortin receptors (MCRs). Libraries of 19- to 22-membered heterodectic macrocyclic peptides were prepared. The synthetic make-up of the cyclic peptides and post-cyclisation functionalisation resulted in a diverse series of MCR agonists with high potency activity and different receptor subtype selectivity.

The successful extension of the domain of SNAr reactivity to substrates containing cyano and ethynyl groups and the feasibility of creating functionalised macrocyclic scaffolds boost the utility of SNAr in macrocyclic peptidomimetic design, expediting access to diversity-oriented ligand libraries with enhanced properties.

  1. White, C. J.; Yudin, A. K. Nat. Chem. 2011, 3, 509-524.
  2. (a) Mallinson, J.; Collins, I. Future Med. Chem. 2012, 4, 1409–1438. (b) Jiang, S.; Li., Z.; Ding, K.; Roller, P. P. Curr. Org. Chem. 2008, 12, 1502-1542.
  3. (a) Marsault, E.; Peterson, M. L. J. Med. Chem. 2011, 54, 1961-2004. (b) Peterson, M. L. The synthesis of macrocycles for drug discovery. In Macrocycles in drug discovery; Levin, J.; Eds.; The Royal Society of Chemistry: Cambridge, 2015; pp 398-486.