New Variations on the Theme of Gold(III) C∧N∧N Cyclometalated Complexes as Anticancer Agents: Synthesis and Biological Characterization

Abstract

A series of novel (C^∧N^∧N) cyclometalated Au^III complexes of general formula [Au(bipy^dmb-H)X][PF₆] (bipy^dmb-H = C^∧N^∧N cyclometalated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine) were prepared with a range of anionic ligands X in the fourth coordination position, featuring C (alkynyl)-, N-, O-, or S-donor atoms. The X ligands are varied in nature and include three coumarins, 4-ethynylaniline, saccharine, and thio-β-d-glucose tetraacetate, the tripeptide glutathione (GSH), and a coumarin-substituted amide derived from 4-ethynylaniline. The gold(I) complex [Au(C₂ArNHCOQ)(PPh₃)] (HC₂ArNHCOQ = N-(4-ethynylphenyl)-2-oxo-2 H-chromene-3-carboxamide) was also prepared for comparison. The new compounds were fully characterized by means of analytical techniques, including NMR, absorption, and emission spectroscopy. The crystal structures of three cyclometalated Au^III complexes and of the Au^I derivative were solved by single-crystal X-ray diffraction. The antiproliferative activity of the new Au^III cyclometalated derivatives was evaluated against cancer cells in vitro. According to the obtained results, only complexes 3-PF₆ and 5-PF₆, featuring coumarins as ancillary ligands and endowed with high redox stability in solution, display antiproliferative effects, with 5-PF₆ being the most potent, while all of the others are scarcely active to nonactive in the selected cell lines. In order to study the reactivity of the compounds with biomolecules, the interaction of complexes 3-PF₆ and 5-PF₆ with the protein cytochrome c and the amino acids cysteine and histidine was analyzed by electrospray ionization mass spectrometry (ESI MS), showing adduct formation only with Cys after at least 1 h incubation. Furthermore, the parent hydroxo complex [Au(bipy^dmb-H)(OH)][PF₆] (1OH-PF₆) was investigated in a competitive assay to determine the protein vs oligonucleotide binding preferences by capillary zone electrophoresis (CZE) coupled to ESI-MS. Of note, the compound was found to selectively form adducts with the oligonucleotide over the protein upon ligand exchange with the hydroxido ligand. Adduct formation occurred within the first 10 min of incubation, demonstrating the preference of 1OH-PF₆ for nucleotides in this setup. Overall, the obtained results point toward the possibility to selectively target DNA with gold(III) organometallics.