Chemoselective, Oxidation-Induced Macrocyclization of Tyrosine-Containing Peptides

Abstract

Inspired by nature’s wide range of oxidation-induced modifications to install cross-links and cycles at tyrosine (Tyr) and other phenol-containing residue side chains, we report a Tyr-selective strategy for the preparation of Tyr-linked cyclic peptides. This approach leverages N4-substituted 1,2,4-triazoline-3,5-diones (TADs) as azo electrophiles that react chemoselectively with the phenolic side chain of Tyr residues to form stable C–N1-linked cyclic peptides. In the developed method, a precursor 1,2,4-triazolidine-3,5-dione moiety, also known as urazole, is readily constructed at any free amine revealed on a solid-supported peptide. Once prepared, the N4-substituted urazole peptide is selectively oxidized using mild, peptide-compatible conditions to generate an electrophilic N4-substituted TAD peptide intermediate that reacts selectively under aqueous conditions with internal and terminal Tyr residues to furnish Tyr-linked cyclic peptides. The approach demonstrates good tolerance of native residue side chains and enables access to cyclic peptides ranging from 3- to 11-residues in size (16- to 38-atom-containing cycles). The identity of the installed Tyr-linkage, a stable covalent C–N1 bond, was characterized using NMR spectroscopy. Finally, we applied the developed method to prepare biologically active Tyr-linked cyclic peptides bearing the integrin-binding RGDf epitope.

Methodology of stable peptide based on propargylated sulfonium

“…One of the approaches delineated in the present investigation for the synthesis of Tyr-linked cyclic peptides bears resemblance to the method recently described in the literature [ [30] , [31] , [32] ], namely, the stable peptide approach for targeted Tyr modification. In contrast to the aforementioned approaches, the modification strategy exhibits a straightforward architecture, facile synthesis, and is conducted in an aqueous medium, rendering the reaction conditions more amenable to the physiological milieu.…”

Thermally Triggered Triazolinedione–Tyrosine Bioconjugation with Improved Chemo- and Site-Selectivity

“…Using this attractive approach, we prepared a small library of blocked TAD click reagents from 7 and a range of functional amines with classical cargoes for bioconjugation studies (Figure ). It should be noted that with classical strategies the synthesis of such functional TAD click reagents takes 5 or 6 steps starting from the amine-functional cargo molecule, where many transformations are marred by chemo-selectivity issues. , Functional urazoles are also notoriously hard to purify due to solubility issues. Even when they can be prepared and obtained in pure form, their chemo-selective oxidation can also be problematic.…”

Research progress on chemical modifications of tyrosine residues in peptides and proteins

“…Roberts and colleagues reported the construction of macrocyclic peptides through chemical selective oxidation of Tyr (Scheme 28) (Keyes et al, 2023). The method utilized N4‐substituted 1,2,4‐triazine‐3,5‐diones (TADs) as diazo electrophiles, which selectively reacted with the phenolic side chain of Tyr residues to form stable C‐N1 connected macrocycles.…”

“…The unprecedented ability of multicopper(II) clusters to chelate tethered diphenols and promote intramolecular over intermolecular coupling reactions demonstrates that copper clusters can catalyze redox transformations that cannot be accessed by smaller metal catalysts. The novel method was applied with high efficiency and selectivity to prepare biaryl-bridged and diaryl ether-linked mono-and bimacrocyclic peptides, including synthetic analogues of the GPAs and the cyclic core of the arylomycin-based antibiotic drugs.Roberts and colleagues reported the construction of macrocyclic peptides through chemical selective oxidation of Tyr (Scheme 28)(Keyes et al, 2023). The method utilized N4substituted 1,2,4-triazine-3,5-diones (TADs) as diazo electrophiles, which selectively reacted with the phenolic side chain of Tyr residues to form stable C-N1 connected macrocycles.…”