A versatile resin for the generation of thioether-bonded head-to-tail cyclized peptides

Abstract

Thioether-bonded cyclic peptide is widely present in current peptide-based drug discovery, and the diversification of its topological structure is conducive to the optimization of its biological activity. In this paper, we report a facile strategy for the synthesis of thioether-bonded head-to-tail cyclized peptides containing cross-linking arms of different length. The key of our strategy is the development of AMDMBT-based 2-chlorotrityl resins, which are prepared by the treatment of 2-chlorotrityl chloride resin with aminoethanethiol, dibromomethylbenzene and dithiol. The AMDMBT 2-chlorotrityl resin allows us to conveniently obtain peptides containing bromoacetyl group at the N-terminus and structurally diverfied sulfhydryl group at the C-terminus. The peptides can undergo head-to-tail cyclization in solution to form thioether-bonded head-to-tail cyclized peptides. The reported method will facilitate the in-depth optimization of the structure and activity of thioether-bonded head-to-tail cyclized peptides.