Cytotoxicity of pyrazine-based cyclometalated (C^Npz^C)Au(III) carbene complexes: Impact of the nature of the ancillary ligand on the biological properties

Bertrand, Benoît, Fernandez-Cestau, Julio, Angulo, Jesus ORCID: https://orcid.org/0000-0001-7250-5639, Cominetti, Marco M. D., Waller, Zoe A. E., Searcey, Mark ORCID: https://orcid.org/0000-0003-2273-8949, O'Connell, Maria A. ORCID: https://orcid.org/0000-0002-0267-0951 and Bochmann, Manfred ORCID: https://orcid.org/0000-0001-7736-5428 (2017) Cytotoxicity of pyrazine-based cyclometalated (C^Npz^C)Au(III) carbene complexes: Impact of the nature of the ancillary ligand on the biological properties. Inorganic Chemistry, 56 (10). 5728–5740. ISSN 0020-1669

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Abstract

The synthesis of a series of cyclometalated gold(III) complexes supported by pyrazine-based (C^N^C)-type pincer ligands is reported, including the crystal structure of a cationic example. The compounds provide a new platform for the study of antiproliferative properties of gold(III) complexes. Seven complexes were tested: the neutral series (C^Npz^C)AuX [X = Cl (1), 6-thioguanine (4), C≡CPh (5), SPh (6)] and an ionic series that included the N-methyl complex [(C^NpzMe^C)AuCl]BF4 (7) and the N-heterocyclic carbene complexes [(C^Npz^C)AuL]+ with L = 1,3-dimethylbenzimidazol-2-ylidene (2) or 1,3,7,9-tetramethylxanthin-8-ylidene (3). Tests against human leukemia cells identified 1, 2, 3, and 4 as particularly promising, whereas protecting the noncoordinated N atom on the pyrazine ring by methylation (as in 7) reduced the cytotoxicity. Complex 2 proved to be the most effective of the entire series against the HL60 leukemia, MCF-7 breast cancer, and A549 lung cancer cell lines, with IC50 values down to submicromolar levels, associated with a lower toxicity toward healthy human lung fibroblast cells. The benzimidazolylidene complex 2 accumulated more effectively in human lung cancer cells than its caffeine-based analogue 3 and the gold(III) chloride 1. Compound 2 proved to be unaffected by glutathione under physiological conditions for periods of up to 6 days and stabilizes the DNA G-quadruplex and i-motif structures; the latter is the first such report for gold compounds. We also show the first evidence of inhibition of MDM2–p53 protein–protein interactions by a gold-based compound and identified the binding mode of the compound with MDM2 using saturation transfer difference NMR spectroscopy combined with docking calculations.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Chemistry
Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Science > Research Groups > Drug Delivery and Pharmaceutical Materials (former - to 2017)
Faculty of Science > Research Groups > Pharmaceutical Materials and Soft Matter
Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017)
Faculty of Science > Research Groups > Pharmaceutical Cell Biology (former - to 2017)
Faculty of Science > Research Groups > Molecular and Tissue Pharmacology
Faculty of Science > Research Groups > Synthetic Chemistry (former - to 2017)
Faculty of Science > Research Groups > Chemistry of Light and Energy
Faculty of Science > Research Groups > Chemistry of Materials and Catalysis
Depositing User: Pure Connector
Date Deposited: 03 May 2017 05:10
Last Modified: 28 Jan 2024 02:24
URI: https://ueaeprints.uea.ac.uk/id/eprint/63349
DOI: 10.1021/acs.inorgchem.7b00339

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