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 fourth coordination position, featuring either C-(alkynyl), NO O-or S-donor atoms. The X ligands are varied in nature, and include three coumarins, 4-ethynylaniline, saccharine, thio-β-D-glucose tetraacetate, the tripeptide glutathione (GSH) and a coumarin-substituted amide derived from 4-ethynylanilyne. The gold(I) complex [Au(C2ArNHCOQ)(PPh3)] (HC2ArNHCOQ = N-(4-ethynylphenyl)-2-oxo-2Hchromene-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 the others are scarcely active to non-active 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 analysed 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 incubation, demonstrating the preference of 1OH-PF6 for nucleotides in this setup. Overall, the obtained results point towards the possibility to selectively target DNA with gold(III) organometallics.

Exploring the Chemoselectivity towards Cysteine Arylation by Cyclometallated AuIII Compounds: New Mechanistic Insights

“…Finally, compound 4 is completely unreactive even after 24 h incubation, further demonstrating its binding preference for cysteine containing peptides. [14] To confirm our observations, we also reacted the gold complexes with another cysteine-free peptide model, namely [Leu5]-enkephalin (YGGFL, LE). The obtained results showed that the main adduct is the mono-gold [LE + Au III C^NÀ H] + species obtained for compounds 1-3 (Table S5, Figures S23-S25).…”

Gold(I/III)-Phosphine Complexes as Potent Antiproliferative Agents

“…Whereas a lot of work has been conducted with linear phosphinogold(I), its high oxidation state counterpart gold(III) needs further exploration. Recent advancement of cyclometalated gold(III) in anticancer development show promising results 1,52–55 . These ligands impart strong σ-donating character to the gold center for stability and offer the possibility of different ligands around the metal center, given its square-planar geometry 56 .…”

Anticancer Gold(III) Compounds With Porphyrin or N-heterocyclic Carbene Ligands

“…In addition to the tetradentate porphyrin ligands, stabilization of the gold(III) ion can also be achieved by coordination with the tridentate (C ∧ N ∧ C, C ∧ N ∧ N or N ∧ C ∧ N) pincer ligand containing deprotonated C-donor atom(s) (C − ) and/or neutral σ-donating N-heterocyclic carbene (NHC) ligand(s), affording gold(III) complexes with high physiological stability and promising anticancer properties (Bertrand et al, 2017 ; Carboni et al, 2018 ; Bauer et al, 2019 ; Fares et al, 2020 ; Guarra et al, 2020 ). In this context, we have described the antitumor-active [Au III (C ∧ N ∧ C)(NHC)] + (H 2 C ∧ N ∧ C = 2,6-diphenylpyridine) complexes ( 5 and 6 ).…”