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

Abstract

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 (HL1–8), has been prepared and thoroughly characterized, including elemental analysis, mass spectrometry, infrared and multinuclear NMR spectroscopy, and single crystal X‐ray analysis. The complexes, showing general composition of [Au (iPr)(Ln)] 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. Complexes 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, consequently 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). Moreover, 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.

Gold(I) N-Heterocyclic Carbene Complexes with 7-Azaindoles Demonstrates In Vitro Antiproliferative Effects on Ovarian Cancer Cells and Anti-inflammatory Activity

“…The data in Table 2 shows that the Au−N and Au−C bond distances are very close not only in the case of complexes 1 and 4 but also quite comparable with those determined for similar Au(I)-NHC complexes with 6-mercaptopurine derivatives. 17 On the other side, the N−Au−C bond angles differ significantly within each of the groups, but it can be taken as a logical consequence associated with a different degree of substitution of the corresponding N-donor ligand together with the concrete noncovalent intra/intermolecular bonding. As for complex 1, the individual molecules are connected through C−H•••N, C−H•••C hydrogen bonds into infinite 1Dpolymeric chains (see Figure S27 in Supporting Information), while the molecules of complex 4 form noncovalent centrosymmetric dimmer are connected via the same types of noncovalent bonds (see Figure S28 in Supporting Information).…”

“…In our recent work, 17 we have prepared a series of NHC gold(I) complexes involving 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene (iPr) ligand in combination with 6mercaptopurine derivatives (HPur), with the general composition of [Au(iPr)(Pur)]. The complexes revealed significant in vitro cytotoxicity, with the best IC 50 values of 3.4−6.4 μM against A2780 and reasonable selectivity; however, on the other side, they showed only negligible effects on the production of inflammatory-related cytokine (TNF-α), the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and peroxisome proliferatoractivated receptor gamma (PPARγ).…”