Harnessing Organometallic Au(III) Complexes as Precision Scaffolds for Next-Generation Therapeutic and Imaging Agents

Abstract

Au(III) organometallic complexes, particularly cyclometalated Au(III) compounds, have emerged as powerful tools in catalysis and bioinorganic chemistry, offering unique reactivity distinct from their Au(I) counterparts. Among their most interesting transformations, C-S cross-coupling reactions have become a selective strategy for cysteine arylation, enabling site-specific modifications of peptides and proteins. This review provides a comprehensive overview of cyclometalated Au(III) complexes in C-S bond formation, detailing the mechanistic insights, ligand effects, and electronic factors that dictate their reactivity. The role of ancillary ligands in tuning stability and selectivity is critically assessed, alongside advancements in structural modifications that enhance catalytic efficiency. Beyond fundamental C-S cross-coupling, the broader applications of these Au(III) complexes are explored, including enzyme inhibition, metabolic disruption, and transmembrane protein modulation, with implications in anticancer therapy, antimicrobial strategies, and in vivo catalytic transformations. By bridging fundamental organometallic reactivity with innovative biomedical applications, this review highlights the potential of cyclometalated Au(III) complexes as next-generation catalysts for both synthetic and therapeutic innovations.

Keywords: C–S cross‐coupling; bioinorganic catalysis; cyclometalated Au(III) complexes; cysteine arylation; metal‐based therapeutics.

Figure 1

Structures of cyclometalated Au(III) organometallic complexes highlighted in this review.

Scheme 1

Proposed mechanism of Cys arylation templated by Au(III) cyclometalated complexes.^{[ 38 ]}

Figure 2

Structures of organometallic Au(III) complexes used by Spokoyny and coworkers for the arylation of cysteine residues.^{[ 40} , ⁴¹ , ^{42 ]}

Figure 3

Structures of Au(III) C^N cyclometalated complexes bearing A) metformin or phenformin as ancillary ligands,^{[ 45 ]} and B) carboxylic acid as an anchoring group for proteomic studies.^{[ 46 ]}

Figure 4

A side‐view of the human AQP10 monomer. Inset: zoom image of the C^CON ligand covalently bound to Cys209 after reductive elimination. Figure generated using MOE software. Image from Pimpão, Catarina; Wragg, Darren, Mechanisms of irreversible aquaporin‐10 inhibition by organogold compounds studied by combined biophysical methods and atomistic simulations, Metallomics, 2021, 13, 9, mfab053, Reproduced with permission. Copyright 2021, Oxford University Press.

Figure 5

Structure of Au(III) conjugated organometallic complex Au‐Cou. Time‐course imaging of BALB/c nude mice (abdominal view) with liver and intestine‐selective fluorescence labeling treated with A) glycoalbumin (Sia) followed by Cy7.5‐OProp, B) Glyco‐Au (Sia) followed by Cy7.5‐OProp, and C) Glyco‐Au(Gal) followed by Cy7.5‐OProp. Adapted with permission from Tanaka et al. Angewandte Chemie International Edition, 2017, John Wiley and Sons.^{[ 52 ]}