Gold(III) Aryl Complexes as Reagents for Constructing Hybrid Peptide-Based Assemblies via Cysteine S-Arylation

Abstract

Organometallic complexes have recently gained attention as competent bioconjugation reagents capable of introducing a diverse array of substrates to biomolecule substrates. Here, we detail the synthesis and characterization of an aminophosphine-supported Au(III) platform that provides rapid and convenient access to a wide array of peptide-based assemblies via cysteine S-arylation. This strategy results in the formation of robust C-S covalent linkages and is an attractive method for the modification of complex biomolecules due to the high functional group tolerance, chemoselectivity, and rapid reaction kinetics associated with these arylation reactions. This work expands upon existing metal-mediated cysteine arylation by introducing a class of air-stable organometallic complexes that serve as competent bioconjugation reagents enabling the synthesis of conjugates of higher structural complexity including macrocyclic stapled and bicyclic peptides, as well as a peptide-functionalized multivalent hybrid nanocluster. This organometallic-based approach provides a convenient, one-step method of peptide functionalization and macrocyclization, and has the potential to contribute to efforts directed towards developing efficient synthetic strategies of building new and diverse hybrid peptide-based assemblies of high complexity.

Thiolate-assisted copper(i) catalyzed C–S cross coupling of thiols with aryl iodides: scope, kinetics and mechanism

“…2 Recently, transition metal catalyzed C–S cross coupling reactions have emerged as a versatile strategy for the synthesis of aryl thioether and related sulfur containing compounds. 3 Various transition metals such as palladium, 4 nickel, 5 iron, 6 iridium, 7 ruthenium, 8 cobalt, 9 manganese, 10 gold 11 and silver 12 have been effectively employed as the catalyst in the C–S cross coupling reactions. However, the use of precious and expensive metals, the requirement of harsh reaction conditions, and high boiling point solvents in these reactions limit the applications of transition-metal catalysts from both economic as well as environmental viewpoints.…”

Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation

“…This can lead to a chemoselective reagent with favorable reaction rate with amino acids. Transition metal complexes such as Au, Ru, Pd, Ni, and Rh have been reported to modify amino acids via direct metalation or arylation. − Au complexes are known to modify cysteine significantly due to their inherent Lewis acidic character. , Au or Pd mediated cysteine arylation have been reported by Wong et al, Spokoyny et al , Casini et al, − and Buchwald–Pentelute et al Moreover, Au complex reactivity can be tuned to modify other amino acids as well . In our previous work, we reported lysine modification in c-MYC protein using Au-based probes .…”

Fundamental Basis for Implementing Oxidant‐Free Au(I)/Au(III) Catalysis

“…These complexes served as robust arylation reagents in a general protocol for cysteine S‐arylation of unprotected peptides and proteins. Further, in 2021 the same group used the tert ‐butyl‐substituted version of the MeDalphos ligand to develop (P,N)‐gold(III) platforms that work as efficient and selective cysteine arylation reagents, giving access to arylated bioconjugates of higher structural complexity including bicyclic peptides, stapled peptides and peptide‐functionalized hybrid nanoclusters [59] …”