Benzeneseleninic acid used as an oxidizing and deprotecting reagent for the synthesis of multi-cyclic peptides constrained by multiple disulfide bonds and thioether bridges

Abstract

Peptides constrained by multiple disulfide bonds (MDBs) or by thioether bridges play a critical role in improving the biological and pharmaceutical activities of peptide drugs. The synthesis of correct MDBs and thioether-bridged bicyclic peptides still remains a significant challenge. In this work, benzeneseleninic acid (BSA) acting as both an oxidant and a deprotecting reagent for the synthesis of MDB- and thioether-bridged bicyclic peptides has been investigated. Disulfide bonds in peptides can be formed by direct oxidation of two sulfhydryl groups by BSA in neutral media or via two concerted steps, namely deprotecting two acetamidomethyl (Acm) groups and oxidation by BSA in acidic media. As such, two disulfide bonds in α-conotoxin SI, apamin, α-conotoxin IMI and a peptide containing a methionine residue were synthesized regioselectively by the use of the BSA oxidation and deprotection reaction (BSA-ODr). By utilization of the BSA deprotection property, bicyclic peptides were synthesized based on the crosslinking of xylylene dibromide with sulfhydryl groups. Furthermore, two disulfide bonds in α-conotoxin SI and three disulfide bonds in conotoxin mr3e, enterotoxin STp, μ-conotoxin KIIIA, linaclotide and ziconotide were also synthesized regioselectively through oxidation of fully reduced peptides by BSA. All the reactions were carried out under mild conditions in a one-pot manner and peptides with satisfactory yields were achieved. In addition, the BSA-ODr is compatible with methionine residues in the peptides. Moreover, the relative positions of two Acm-protected cysteines and two free cysteines have no impact on the BSA-ODr approach for the construction of two disulfide bonds in peptides. The oxidative folding strategies based on BSA can be executed in peptide manufacture. BSA is readily accessible conferring efficient BSA-ODr and oxidative folding methodologies for the synthesis of MBDs and thioether bridges in peptides.