Chemistry based on 3-nitro-2-pyridinesulfenyl (Npys) group gave us a new scenario on disulfide peptide synthesis [1]. Two topics will be discussed in the lecture, i.e., new solid- or none-solid-supported 3-nitro-2-pyridinesulfenates (Npys-OR) as disulfide bond-forming agents [2] and solid-phase-assisted disulfide ligation method [3].
The former realizes "on-resin" disulfide bond formation for preparing cyclic peptides in combination with the 2-mercaptoethanol treatment for the deprotection of tBu-thio groups from two Cys residues in SPPS, which can be applied to the automated solid-phase protocol. Moreover, by the combination with iodine oxidation, more complicated disulfide peptides like "α-conotoxin" with four Cys residues can be successfully synthesized on resin.
The latter give us a disulfide peptide from two kinds of Cys-containing peptide fragments in a simple solid-phase assisted procedure by using a “Npys-Cl resin”, which can lead to the syntheses of 1) cyclic peptides via the subsequent intra-molecular amide bond formation and 2) multi-connecting disulfide peptides via the repetitive disulfide ligation. Moreover, this chemistry is useful to construct a variety of disulfide conjugates. One of the typical examples is a conjugation between peptide and drug with a different solubility to the reaction solvent [4]. In the lecture, I will also discuss the development of a stable Npys-Cl surrogate to increase the efficiency of this technology.