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Anti-Tumoural NHC(thiolato) Gold(I) Complexes Derived from HIF-1α Inhibitor AC1-004 Target the Mitochondrial Redox System and Show Antiangiogenic Effects in vivo

Title data

Schleser, Sebastian W. ; Köhler, Leonhard ; Riethmüller, Florian ; Reich, Sebastian ; Fertig, Robin ; Schlotte, Luca ; Seib, Jonathan ; Goller, Alexander ; Begemann, Gerrit ; Kempe, Rhett ; Schobert, Rainer:
Anti-Tumoural NHC(thiolato) Gold(I) Complexes Derived from HIF-1α Inhibitor AC1-004 Target the Mitochondrial Redox System and Show Antiangiogenic Effects in vivo.
In: ChemPlusChem. Vol. 88 (2023) Issue 5 . - e202300167.
ISSN 2192-6506
DOI: https://doi.org/10.1002/cplu.202300167

Official URL: Volltext

Project information

Project financing: Deutsche Forschungsgemeinschaft

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Keywords: antitumor agents; bioorthogonal click chemistry; gold, NHC complexes; medicinal chemistry
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Biology > Professor Developmental Biology > Professor Developmental Biology - Univ.-Prof. Dr. Gerrit Begemann
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors > Chair Organic Chemistry I - Univ.-Prof. Dr. Rainer Schobert
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Inorganic Chemistry II > Chair Inorganic Chemistry II - Univ.-Prof. Dr. Rhett Kempe
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Biology
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Biology > Professor Developmental Biology
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Former Professors
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Inorganic Chemistry II
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 21 Oct 2023 21:03
Last Modified: 23 Oct 2023 06:50
URI: https://eref.uni-bayreuth.de/id/eprint/87346