PUBLICATION
Anti-tumoural [NHC(thiolato)]Au(I) complexes derived from HIF-1α inhibitor AC1-004 target the mitochondrial redox system and show antiangiogenic effects in vivo
- Authors
- Schleser, S.W., Köhler, L.H.F., Riethmüller, F., Reich, S., Fertig, R., Schlotte, L., Seib, J., Goller, A., Begemann, G., Kempe, R., Schobert, R.
- ID
- ZDB-PUB-230510-44
- Date
- 2023
- Source
- ChemPlusChem 88(5): e202300167 (Journal)
- Registered Authors
- Begemann, Gerrit
- Keywords
- NHC complexes, antitumor agents, bioorthogonal click chemistry, gold, medicinal chemistry
- MeSH Terms
-
- Animals
- Cell Proliferation
- Coordination Complexes*/chemistry
- Gold/chemistry
- Humans
- Ligands
- Neoplasms*
- Oxidation-Reduction
- Thioredoxin-Disulfide Reductase/metabolism
- Thioredoxin-Disulfide Reductase/pharmacology
- Zebrafish/metabolism
- PubMed
- 37161701 Full text @ Chempluschem
Citation
Schleser, S.W., Köhler, L.H.F., Riethmüller, F., Reich, S., Fertig, R., Schlotte, L., Seib, J., Goller, A., Begemann, G., Kempe, R., Schobert, R. (2023) Anti-tumoural [NHC(thiolato)]Au(I) complexes derived from HIF-1α inhibitor AC1-004 target the mitochondrial redox system and show antiangiogenic effects in vivo. ChemPlusChem. 88(5):e202300167.
Abstract
AC1-004 is a potent inhibitor of the hypoxia-inducible factor alpha (HIF-1α) pathway, essential for tumour growth, angiogenesis and metastasis. We modelled a series of gold(I) complexes on AC1-004, retaining its 5-carboalkoxybenzimidazole as an NHC ligand while replacing its 2-aryloxymethyl residue with modified thiolato gold(I) fragments. The intention was to augment a potential HIF-1α inhibition by conducive effects typical of NHC gold complexes, such as an inhibition of tumoural thioredoxin reductase (TrxR), an increase in reactive oxygen species (ROS), and cytotoxic and antiangiogenic effects. We report on the synthesis and biological effects of twelve such N,N'-dialkylbenzimidazol-2-ylidene gold(I) complexes, obtained in average yields of 65% for the thiophenolato and 45% for the novel 4-(adamant-2-yl)benzenethiol complexes. The structure of one complex was validated via single-crystal X-ray diffraction. Structure-activity relationships (SAR) were derived by variation of the N-substituents (Me, Et, iPr, pentyl, Bn) and the thiolato ligand. Their cytotoxicity against various human cancer cell lines of different entities reached IC50 values in the single-digit micromolar range. The complexes were also assayed for the induction of tumour cell apoptosis (activation of caspase-3/7), TrxR inhibition and antiangiogenic effects in zebrafish. Cyclopropene-bearing congeners were employed in click reactions to examine the subcellular accumulation of the complexes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping