Macrocyclic NHC complexes of group 10 elements with enlarged aromaticity for biological studies.

Two sets of macrocyclic, bio-inspired, non-heme ligands are utilized for the synthesis of NiII, PdII and PtII complexes. The ligands consist of a 16-atom macrocycle, formed by four methylene bridged NHC moieties, with imidazole or benzimidazole as building blocks. The complexes exhibit a square planar coordination geometry and are characterized by NMR, ESI-MS, elemental analysis, SC-XRD and UV/Vis. For complexes incorporating benzimidazole, an evaluation of luminescence properties is performed, and is found that phosphorescence is present for the PdII derivative and there is fluorescence for the PtII derivative. Stability studies in cell culture medium are performed for subsequent MTT assays. Here, the NiII complexes show low to no activity, and PdII and PtII complexes exhibit remarkable low IC50 values in cisplatin resistant A2780cisR cells.

Mechanisms underlying the cytotoxic activity of syn/anti-isomers of dinuclear Au(I) NHC complexes.

The syn- and anti-isomers of dinuclear Au(I) complexes of the type Au2(RLOH)(PF6)2 (R = isopropyl or mesityl) bearing 2-hydroxyethane-1,1-diyl-bridged bisimidazolylidene ligands were separated by reversed phase high performance liquid chromatography (HPLC) and characterized by NMR spectroscopy, elemental analysis, ESI mass spectrometry as well as single crystal X-ray diffraction analysis. Evaluation of the antiproliferative activity of the isolated isomers has shown very small difference in their cytotoxic behavior in various cancer cell lines. Additional counter-anion exchange (hexafluorophosphate to chloride) allows to increase the water solubility of synAu2(MesLOH)(PF6)2 and leads to higher antiproliferative activity when compared to the hexafluorophosphate-complex. Both isomers were treated with l-cysteine as nucleophilic thiol source and only the anti-isomer shows dissociation of one bisimidazolylidene ligand after 24 h. In the case of the syn-isomer, density functional theory calculations indicate a lower reactivity due to the higher steric hindrance of the N-substituents and additional hydrogen bond interaction, which prevents a nucleophilic attack. When the N-substituent is replaced by the bulkier mesityl group, both conformations remain unreactive and result to be the most cytotoxic complexes in the above-mentioned cancer cell lines. Interestingly, synAu2(MesLOH)(PF6)2 exhibits a high selectivity in the MCF-7 cell line with a selectivity index (SI) of 19, which is superior to auranofin (SI < 1), making this compound an ideal candidate for further studies. Preliminary mechanistic studies reveal that the cytotoxic complexes possess mitochondrial-TrxR inhibition properties in the nanomolar range. Additionally, the cellular distribution studies by ICP-MS and nuclear microscopy have shown that the compound accumulates in the membranes. These results suggest that the mitochondrial membrane is the main target for this type of dinuclear complexes, causing oxidative stress by inhibiting mitochondrial thioredoxin reductase.

Visible-Light-Induced Dehydrohalogenative Coupling for Intramolecular α-Alkenylation: A Way to Build Seven- and Eight-Membered Rings.

A visible-light-induced intramolecular α-alkenylation has been developed via metal-free dehydrohalogenative C(sp2)-C(sp2) coupling reaction to afford seven- and eight-membered rings. Extensive mechanistic studies prove that this reaction proceeds through a [2 + 2]-photocycloaddition, elimination, and retro-[2 + 2]-photocycloaddition process, with cyclobutane and cyclobutene being involved as key intermediates. This transformation is broadly applicable and highly stereoselective, yielding exclusively cyclic (1Z,3Z)-1,3-diene via photochemically allowed disrotation. This protocol excavates new applications of [2 + 2]-photocycloadditions, which may find their way in future olefin-olefin coupling reactions and medium-sized ring synthesis.

Synthesis, characterization, and biological studies of multidentate gold(i) and gold(iii) NHC complexes.

The synthesis and characterization of a novel macrocyclic Au(iii) N-heterocyclic carbene (NHC) imidazolyl complex, a novel macrocyclic tetra-NHC benzimidazole ligand, and the corresponding Ag(i) and Au(i) complexes are presented. Single-crystal X-ray diffraction analysis of the Au(i) benzimidazolyl complex 3 reveals an unusual structure, differing from the respective Au(i) imidazolyl complex 4. Both complexes have a Au4L2 composition; however, 3 has two C-Au(i)-C units acting as a connection between the two ligands with two Au(i) atoms being linearly coordinated inside the cavity of the macrocyclic ligand. In the case of complex 4, the structure shows a box-type coordination with all four Au(i) atoms being located between the two ligands. Stability studies in cell culture medium are performed for subsequent MTT assays and they show an unprecedented proton-to-deuterium exchange of the methylene bridge of the Au(iii) imidazolyl complex. In MTT assays, the tetranuclear acyclic Au(i) complex 5 displays the lowest IC50 values in MCF-7, PC3, and A2780cisR cells with a selective cytotoxicity for MCF-7 and A2780cisR cells.