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

Multi-cyclic peptides constrained by disulfide bonds (MDBs) or thioether bridges play a critical role on improving the biological and pharmaceutical activities of peptide drugs. The synthesis of correct MDBs and thioether-bridged bicyclic peptides still re-mains as a significant challenge task. In this work, benzeneseleninic acid (BA) used as an oxidant and deprotecting reagent for the synthesis of peptide MDBs and thioether-bridged bicyclic peptides has been investigated. Peptide disulfide bond can be formed by direct oxidation of two sulfhydryl groups by BA in neutral media or via two concerted steps, namely deprotecting two acetamidomethyl (Acm) groups and oxidation by BA in acidic media. As such, two disulfide bonds in a-conotoxin SI, apamin, a-conotoxin IMI and a peptide containing methionine residue were synthesized regioselectively by use of the BA oxidation and deprotection reactions (BA-ODr). Moreover, the relative positions of two Acm-protected cysteines and two free cysteines have no impact on the BA-ODr approach for the construction of two disulfide bonds in peptides. Utilization of the BA deprotection reaction, bicyclic peptides were synthesized based on the crosslinking of xylylene dibromide with sulfhydryl group giving satisfied yields. Furthermore, two disulfide bonds in a-conotoxin SI and three disulfide bonds in conotoxin mr3e, enterotoxin STp, μ-conotoxin KIIIA, linaclotide and ziconotide were also synthesized regioselectively with reasonable yields through oxidation of fully reduced peptides by BA. BA is readily accessible conferring efficient BA-ODr and oxidative folding strategies for preparation of MBDs and thioether bridges in peptides.