Cyclic peptides and peptidomimetics have gained considerable attention as therapeutics in the past decade, with arrays of natural and synthetic macrocycles being identified for their promising pharmacological activities. Extensive research efforts have been devoted to developing efficient synthetic strategies for accessing cyclopeptides and cyclopeptidomimetics.1 The nucleophilic aromatic substitution (SNAr) reaction has emerged as a valuable cyclisation method orthogonal to conventional peptide chemistries. While the assembly of alkyl-aryl or biaryl ether bridged peptide macrocycles through SNAr reaction is well documented, the focus of synthetic viability of SNAr macrocyclisation has primarily been on nitro activated substrates.2
We have recently showcased 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 with potent agonist activity and different receptor subtype selectivity.3 The orthogonality of this cyclisation method, along with the presence of functional group handles, has opened up exciting possibilities for further conjugations.
In pursuit to further broaden the utility of SNAr macrocyclisation, we attempted to harness the potential of the chemical handles, specifically the nitro, cyano, ethynyl and amino groups, for bioconjugation with various chemical entities. This effort resulted in the creation of 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 highlights their potential for applications in biomolecular imaging and theranostics for melanoma, where the overexpression of MC1R represents a promising biomarker.