Motivated by the clinical success of gold(I) metallotherapeutic Auranofin in the effective treatment of both inflammatory and cancer diseases, we decided to prepare, characterize, and further study the [Au(kin)(PPh3)] complex (1), where Hkin = kinetin, 6-furfuryladenine, for its in vitro anti-cancer and anti-inflammatory activities. The results revealed that the complex (1) had significant in vitro cytotoxicity against human cancer cell lines (A2780, A2780R, PC-3, 22Rv1, and THP-1), with IC50 ≈ 1-5 μM, which was even significantly better than that for the conventional platinum-based drug Cisplatin while comparable with Auranofin. Although its ability to inhibit transcription factor NF-κB activity did not exceed the comparative drug Auranofin, it has been found that it is able to positively influence peroxisome-proliferator-activated receptor-gamma (PPARγ), and as a consequence of this to have the impact of moderating/reducing inflammation. The cellular effects of the complex (1) in A2780 cancer cells were also investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential, and shotgun proteomic analysis. Proteomic analysis of R2780 cells treated with complex (1) and starting compounds revealed possible different places of the effect of the studied compounds. Moreover, the time-dependent cellular accumulation of copper was studied by means of the mass spectrometry study with the aim of exploring the possible mechanisms responsible for its biological effects.

• Keywords
• PPAR, ROS, anti-inflammatory, anticancer, apoptosis, cell cycle, gold(I) complex, in vitro, kinetin,
• MeSH
• Apoptosis MeSH
• Auranofin pharmacology   MeSH
• Kinetin pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Ovarian Neoplasms * metabolism   MeSH
• PPAR gamma MeSH
• Proteomics MeSH
• Plant Growth Regulators pharmacology   MeSH
• Gold * pharmacology   chemistry   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Auranofin MeSH
• Kinetin MeSH
• PPAR gamma MeSH
• Plant Growth Regulators MeSH
• Gold * MeSH

A series of gold(I) complexes of the general composition [Au(naza)(PPh₃)] (1-8) was prepared and thoroughly characterized (e.g., electrospray ionization (ESI) mass spectrometry and multinuclear nuclear magnetic resonance (NMR) spectroscopy). The N1-deprotonated anions of 7-azaindole or its derivatives (naza) are coordinated to the metal centre through the N1 atom of their pyrrole ring, as proved by a single crystal X-ray analysis of the complexes [Au(3I5Braza)(PPh₃)] (7) and [Au(2Me4Claza)(PPh₃)]·½H₂O (8'). The in vitrocytotoxicity of the complexes 1-8 was studied against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the MRC-5 human normal fibroblast cell line. The complexes 4, 5, and 8, containing deprotonated 3-iodo-7-azaindole, 5-bromo-7-azaindole, and 2-methyl-4-chloro-7-azaindole (2Me4Claza), respectively, showed significantly higher potency (IC50 = 2.8-3.5 µM) than cisplatin (IC50 = 20.3 µM) against the A2780 cells and markedly lower effect towards the MRC-5 non-cancerous cells (IC50 = 26.0-29.2 µM), as compared with the mentioned A2780 cancer cells. The results of the flow cytometric studies of the A2780 cell cycle perturbations revealed a G₂-cell cycle phase arrest of the cells treated by the representative complexes 1 and 5, which is indicative of a different mechanism of action from cisplatin (induced S-cell cycle phase arrest). The stability of the representative complex 8 in the water-containing solution as well as its ability to interact with the reduced glutathione, cysteine and bovine serum albumin was also studied using ¹H and 31P-NMR spectroscopy (studied in the 50% DMF-d₇/50% D₂O mixture) and ESI+ mass spectrometry (studied in the 50% DMF/50% H₂O mixture); DMF = dimethylformamide. The obtained results are indicative for the release of the N-donor azaindole-based ligand in the presence of the used biomolecules.

• Keywords
• 7-azaindole, antitumor activity, crystal structures, gold(I) complexes, in vitro, triphenylphosphane,
• MeSH
• Cell Death drug effects   MeSH
• Cell Cycle drug effects   MeSH
• Phosphines chemical synthesis   chemistry   pharmacology   MeSH
• Indoles chemical synthesis   chemistry   pharmacology   MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Antineoplastic Agents pharmacology   MeSH
• Proton Magnetic Resonance Spectroscopy MeSH
• Water chemistry   MeSH
• Gold pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 7-azaindole dimer MeSH Browser
• Phosphines MeSH
• Indoles MeSH
• Antineoplastic Agents MeSH
• Water MeSH
• Gold MeSH