Cyclic peptides and peptidomimetics have gained enormous attention as therapeutics in the past decade, with numerous natural and non-natural macrocycles being identified for their promising pharmacological activities. Extensive research efforts have been dedicated to developing efficient synthetic strategies for accessing cyclopeptides and cyclopeptidomimetics.1 Nucleophilic aromatic substitution (SNAr) reaction is an effective cyclisation method orthogonal to conventional peptide chemistries. While the assembly of alkyl-aryl or biaryl ether bridged peptide macrocycles utilising SNAr reaction is well documented, the synthetic viability of SNAr macrocyclisation has focused primarily on nitro activated substrates.2
We have recently demonstrated the expansion of SNAr reactivity to include substrates featuring nitro-, cyano-, ethynyl-fluoroarenes and fluoroheteroarenes, and established a library of alkylthioaryl-bridged melanocortin peptide ligands possessing high agonist activity and different receptor subtype selectivity.3 The orthogonality of this cyclisation method, coupled with the presence of functional moieties, has introduced new avenues for additional conjugations.
In pursuit to further broaden the utility of SNAr macrocyclisation, we attempted to harness the potential of the chemical handles, namely the nitro, cyano, ethynyl and amino group, for bioconjugation with various chemical entities, and subsequently created a diverse collection of melanocortin peptide conjugates. The resultant peptide conjugates bearing DOTA-based chelators and fluorescent labels exhibited profound agonist activity at the melanocortin 1 receptor (MC1R) with varying degrees of receptor subtype selectivity. This underscores their potential for applications in biomolecular imaging and theranostics in melanoma, where the overexpression of MC1R serves as a promising biomarker.