Cytotoxicity of Pyrazine-Based Cyclometalated (C^Npz^C)Au(III) Carbene Complexes: Impact of the Nature of the Ancillary Ligand on the Biological Properties

• Published in: Inorganic chemistry Vol. 56; no. 10; pp. 5728 - 5740
• Main Authors: Bertrand, Benoît, Fernandez-Cestau, Julio, Angulo, Jesus, Cominetti, Marco M. D, Waller, Zoë A. E, Searcey, Mark, O’Connell, Maria A, Bochmann, Manfred
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15-05-2017
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical Sciences; Coordination chemistry; Cristallography; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fluorescence Polarization; Humans; Life Sciences; Ligands; Medicinal Chemistry; Methane - analogs & derivatives; Methane - chemistry; Methane - pharmacology; Models, Molecular; Molecular Structure; Organogold Compounds - chemical synthesis; Organogold Compounds - chemistry; Organogold Compounds - pharmacology; Pyrazines - chemistry; Pyrazines - pharmacology; Structure-Activity Relationship
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.7b00339

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.