Gold(I)-Mediated Rapid Cyclization of Propargylated Peptides via Imine Formation

Abstract

In fundamental research and drug discovery, there is still a need for effective and straightforward chemical approaches for generating cyclic peptides. The divergent synthesis of cyclic peptides remains a challenge, in particular when cyclization is carried out in the presence of unprotected side chains and a nonpeptidic component within the cycle is needed. Herein, we describe a novel and efficient strategy based on Au(I)-mediated cyclization of unprotected peptides through rapid (30–60 min) amine addition on a propargyl group to generate an imine linkage. Mechanistic insights reveal that the reaction proceeds via regioselective Markovnikov’s addition of the amine on the Au(I)-activated propargyl. This strategy was successfully applied to prepare efficiently (56–94%) over 35 diverse cyclic peptides having different sequences and lengths. We have also achieved stereoselective reduction of cyclic imines employing chiral ligands. The practicality of our method was extended for the synthesis of cyclic peptides that bind Lys48-linked di-ubiquitin chains with high affinity, leading to apoptosis of cancer cells.

Cyclic Peptides in Pipeline: What Future for These Great Molecules?

“…Another efficient strategy was developed by Vanjari et al [ 113 ] and consists of cyclizing propargylated peptides through imine formation mediated by gold ( Figure 3 J). This method allows the cyclization of peptides without the need for protecting groups and in a very short time (only 30 to 60 min).…”

“…A free amine of the peptide then acts as a nucleophile by attacking the gold-activated alkyne. This reaction occurs by a Markovnikov addition mechanism that is regioselective [ 113 ].…”

Metal-Mediated, Autolytic Amide Bond Cleavage: A Strategy for the Selective, Metal Complexation-Catalyzed, Controlled Release of Metallodrugs

“…Stimulus-responsive prodrugs that involve metal ions can exhibit similar limitations, where efficient prodrug activation with external stimuli and close control of pharmacokinetics remains challenging and therefore represents a current area of research interest. − Strategies such as transition metal-mediated, − cell-compatible catalysis, − or photodynamic triggering for drug activation or release have shown efficacy. − However, the dependence on an external stimulus or catalyst concentration can pose significant limitations on the accessibility or threshold abundance of the biological target. − …”

Gold-Mediated Multiple Cysteine Arylation for the Construction of Highly Constrained Bicycle Peptides

“…constrained bioactive peptides remains an area of interest to peptide medicinal chemists. 8,9 Direct cysteine arylation has been demonstrated as a potential method for generating Bicycle peptides with a high degree of constraint. 10 The Spokoyny group reported a method for selective gold mediated cysteine arylation under mild conditions, to form a Bicycle in 50% reported yield (Figure 1B).…”

“…Cyclization of peptides onto scaffolds such as TATA produces Bicycle peptides with a high degree of constraint, which often results in high affinity hits, as the resultant Bicycle is locked in the bioactive conformation. Identifying additional chemical transformations and scaffolds to enable delivery of constrained bioactive peptides remains an area of interest to peptide medicinal chemists. , Direct cysteine arylation has been demonstrated as a potential method for generating Bicycle peptides with a high degree of constraint …”