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Ligand Basicity Governs Cysteine Reactivity in Au(I)–NHC Thiolate Complexes: A Computational Study

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide Gold–thiolate compounds have emerged as promising therapeutic agents, showing activity against parasites such as Leishmania amazonensis and Trypanosoma cruzi, as well as viruses including Mayaro, Zika, and SARS-CoV. However, their use is limited by speciation due to the rapid ligand exchange with thiolated biomolecules, and control of this reactivity is key for the design of drugs. This study explores the reactivity of linear Au(I) complexes featuring the NHC, 1,3-bis(mesityl)imidazole-2-ylidene (IMes), and thiol-donating ligands, specifically pyrimidine-2-thione (HSpym), 2-thiouracil (2tuH), 1,3-thiazolidine-2-thione (HStzn), and 1,3-benzothiazole-2-thione (HSbtz), along with a chloride complex, Au(IMes)Cl, focusing on their interaction with the biologically significant amino acid cysteine. Thiol-donor ligands were selected for their structural diversity, biological relevance, and presence in drug-like molecules, allowing a systematic comparison of their reactivity with cysteine. Using DFT, we calculated Gibbs free energy variations that corresponded well with experimental equilibrium data from the 1 H NMR measurements. Electronic structural parameters and ligand basicity provided insights into the observed thermodynamic trends, with complexes containing the most basic ligands, Stzn and 2tu, reacting more extensively with cysteine. Among three proposed reaction mechanisms, we identified a preferred pathway, suggesting that the leaving ligand may participate in cysteine deprotonation. In this mechanism, the initial exchange with protonated cysteine was most favorable for Au(IMes)Spym, while deprotonation of the intermediate proceeded most rapidly with Au(IMes)Cl. These findings elucidate the influence of ligand characteristics on heteroleptic Au(I)(NHC) complex reactivity, contributing to the understanding of these complexes as prospective therapeutic agents.

Source: Inorganic Chemistry

DOI: 10.1021/acs.inorgchem.5c02777

Authors: Gustavo Clauss, Igor Santos Oliveira, Camilla Abbehausen

Institution: Universidade Estadual de Campinas (UNICAMP)

Language: English

Topic: Metal complexes synthesis and properties

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

Open Access status: hybrid

Estimated APC paid: $4,500

Funders: Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico