5‐Hydroxypyrroloindoline Affords Tryptathionine and 2,2′‐bis‐Indole Peptide Staples: Application to Melanotan‐II

Abstract

AbstractWith peptides increasingly favored as drugs, natural product motifs, namely the tryptathionine staple, found in amatoxins and phallotoxins, and the 2,2’‐bis‐indole found in staurosporine represent unexplored staples for unnatural peptide macrocycles. We disclose the efficient condensation of a 5‐hydroxypyrroloindoline with either a cysteine‐thiol or a tryptophan‐indole to form a tryptathionine or 2‐2’‐bis‐indole staple. Judicious use of protecting groups provides for chemoselective stapling using α‐MSH, which provides a basis for investigating both chemoselectivity and affinity. Both classes of stapled peptides show nanomolar Ki’s, with one showing a sub‐nanomolar Ki value.