Publication in Applied Organometallic Chemistry

Gold(I) N-heterocyclic carbene (NHC) complexes containing 6-mercaptopurine derivatives and their in vitro anticancer and anti-inflammatory effects

 

Authors: Zdeněk Trávníček, Ján Vančo, Michal Čajan, Jan Belza, Igor Popa, Jan Hošek, René Lenobel, Zdeněk Dvořák

Full-text: https://doi.org/10.1002/aoc.7401

 

A series of eight N-heterocyclic carbenes (NHC) gold(I) complexes, involving 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (iPr) ligand in combination with 6-mercaptopurine derivatives (HL_1–8), has been prepared and thoroughly characterized, including elemental analysis, mass spectrometry, infrared and multinuclear NMR spectroscopy, and single crystal X-ray analysis. The com- plexes, showing general composition of [Au (iPr)(L_n)] 1–8, were evaluated for their in vitro cytotoxicity against four human cancer cell lines including A2780 (ovarian) and A2780R (ovarian Cisplatin resistant), PC3 (prostate) and MCF-7 (breast), and normal human MRC-5 cells (lung fibroblasts). The complexes revealed significant cytotoxicity, with the best IC₅₀ values ≈ 3.4–6.4 μM against A2780 and reasonable selectivity. Cellular effects of the selected complexes on the A2780 cells were evaluated using various flow cytometry assays. Com- plexes 1, 3, and 4 showed a strong pro-apoptotic effect and a strong effect on the loss of mitochondrial membrane potential. These findings indicate that their major mechanism of action is based on the collapse of the mitochondrial metabolism and activation of the intrinsic signaling pathway of apoptosis, con- sequently resulting in cell death. The complexes 1–8 revealed only negligible effect on the production of inflammatory-related cytokine (TNF-α), as well as the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) or peroxisome proliferator-activated receptor gamma (PPARγ). More- over, the shotgun proteomic analysis was performed, and the obtained results suggest that the mechanism of action of complexes 1, 3, and 4 differs somewhat from that of Auranofin.