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Peer-reviewedCC BY 4.0Inorganic Chemistry

Synthesis, Cytotoxicity, and Mechanistic Evaluation of Thiazolium-Based Gold(I) Bis‑N‑Heterocyclic Carbene Complexes

  • Melanie E. Hoffmann1
  • Lisa C. Haas2
  • Fernanda Marques3
  • Sarah Sarwary2
  • Charlotte Theile4,5
  • Bakr Mustafa2,4
  • João D. G. Correia3
  • Aram Prokop2,4
  • Fritz E. Kühn1
5 affiliations
  1. 1TUM School of Natural Science, Department of Chemistry and Catalysis Research Centre, Molecular Catalysis, Technical University of Munich, Lichtenbergstr. 4, 85748 Garching bei München, Germany
  2. 2Department of Human Medicine, MSH Medical School Hamburg, am Kaiserkai 1, 20457 Hamburg, Germany
  3. 3Centro de Ciências e Tecnologias Nucleares and Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, CTN, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal
  4. 4Department of Pediatric Hematology/Oncology, HELIOS Clinics Schwerin, Wismarsche Strasse 393-397, 19055 Schwerin, Germany
  5. 5Universität Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany
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Abstract

Imidazole- and benzimidazole-based Au­(I) N-heterocyclic carbene (NHC) complexes show great potency as anticancer agents. However, other NHC scaffolds are only sparsely explored. Four gold­(I) NHC complexes featuring thiazolium-based ligands (NHCthia) with varying N-substituents were synthesized and evaluated for their biological activity. The complexes containing aromatic N-substituents demonstrate higher stability, higher TrxR inhibition, and activity against breast (MDA-MB-231 and MCF-7) and ovarian (A2780) cancer cell lines, compared to the tested alkyl N-substituted complexes. Specifically, mesityl-substituted complex 1 exhibits high activity with IC50 values in the nanomolar range, exceeding the potency of auranofin in MDA-MB-231 cells. Mechanistic studies in leukemia cells (Nalm-6) revealed that complex 1 induces ROS formation, activates BAX and BAK, and causes mitochondrial membrane potential loss, initiating intrinsic apoptosis. Notably, the ligand precursor L1 shows no significant cytotoxicity, confirming that the gold­(I) moiety drives the activity. Additionally, complex 1 can overcome resistance to etoposide and prednisolone without affecting healthy leukocytes, making Au­(I) bis-NHCthia complexes a compelling class of antiproliferative agents.

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Cite

BibTeXRIS
BibTeX
@article{hoffmann2026synthesis,
  title = {{Synthesis, Cytotoxicity, and Mechanistic Evaluation of Thiazolium-Based Gold(I) Bis‑N‑Heterocyclic Carbene Complexes}},
  author = {Melanie E. Hoffmann and Lisa C. Haas and Fernanda Marques and Sarah Sarwary and Charlotte Theile and Bakr Mustafa and João D. G. Correia and Aram Prokop and Fritz E. Kühn},
  journal = {Inorganic Chemistry},
  year = {2026},
  month = oct,
  doi = {10.1021/acs.inorgchem.6c02992},
  url = {https://doi.org/10.1021/acs.inorgchem.6c02992},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Synthesis, Cytotoxicity, and Mechanistic Evaluation of Thiazolium-Based Gold(I) Bis‑N‑Heterocyclic Carbene Complexes
AU  - Melanie E. Hoffmann
AU  - Lisa C. Haas
AU  - Fernanda Marques
AU  - Sarah Sarwary
AU  - Charlotte Theile
AU  - Bakr Mustafa
AU  - João D. G. Correia
AU  - Aram Prokop
AU  - Fritz E. Kühn
PY  - 2026
DA  - 2026/10/10
JO  - Inorganic Chemistry
DO  - 10.1021/acs.inorgchem.6c02992
UR  - https://doi.org/10.1021/acs.inorgchem.6c02992
AB  - Imidazole- and benzimidazole-based Au­(I) N-heterocyclic carbene (NHC) complexes show great potency as anticancer agents. However, other NHC scaffolds are only sparsely explored. Four gold­(I) NHC complexes featuring thiazolium-based ligands (NHCthia) with varying N-substituents were synthesized and evaluated for their biological activity. The complexes containing aromatic N-substituents demonstrate higher stability, higher TrxR inhibition, and activity against breast (MDA-MB-231 and MCF-7) and ovarian (A2780) cancer cell lines, compared to the tested alkyl N-substituted complexes. Specifically, mesityl-substituted complex 1 exhibits high activity with IC50 values in the nanomolar range, exceeding the potency of auranofin in MDA-MB-231 cells. Mechanistic studies in leukemia cells (Nalm-6) revealed that complex 1 induces ROS formation, activates BAX and BAK, and causes mitochondrial membrane potential loss, initiating intrinsic apoptosis. Notably, the ligand precursor L1 shows no significant cytotoxicity, confirming that the gold­(I) moiety drives the activity. Additionally, complex 1 can overcome resistance to etoposide and prednisolone without affecting healthy leukocytes, making Au­(I) bis-NHCthia complexes a compelling class of antiproliferative agents.
SN  - 0020-1669
SN  - 1520-510X
ER  -