Synthesis, anticancer activity, and molecular docking of half-sandwich iron(II) cyclopentadienyl complexes with maleimide and phosphine or phosphite ligands.

In these studies, we designed and investigated the potential anticancer activity of five iron(II) cyclopentadienyl complexes bearing different phosphine and phosphite ligands. All complexes were characterized with spectroscopic analysis viz. NMR, FT-IR, ESI-MS, UV-Vis, fluorescence, XRD (for four complexes) and elemental analyses. For biological studies, we used three types of cells-normal peripheral blood mononuclear (PBM) cells, leukemic HL-60 cells and non-small-cell lung cancer A549 cells. We evaluated cell viability and DNA damage after cell incubation with these complexes. We observed that all iron(II) complexes were more cytotoxic for HL-60 cells than for A549 cells. The complex CpFe(CO)(P(OPh)3)(η1-N-maleimidato) 3b was the most cytotoxic with IC50 = 9.09 µM in HL-60 cells, IC50 = 19.16 µM in A549 and IC50 = 5.80 µM in PBM cells. The complex CpFe(CO)(P(Fu)3)(η1-N-maleimidato) 2b was cytotoxic only for both cancer cell lines, with IC50 = 10.03 µM in HL-60 cells and IC50 = 73.54 µM in A549 cells. We also found the genotoxic potential of the complex 2b in both types of cancer cells. However, the complex CpFe(CO)2(η1-N-maleimidato) 1 which we studied previously, was much more genotoxic than complex 2b, especially for A549 cells. The plasmid relaxation assay showed that iron(II) complexes do not induce strand breaks in fully paired ds-DNA. The DNA titration experiment showed no intercalation of complex 2b into DNA. Molecular docking revealed however that complexes CpFe(CO)(PPh3) (η1-N-maleimidato) 2a, 2b, 3b and CpFe(CO)(P(OiPr)3)(η1-N-maleimidato) 3c have the greatest potential to bind to mismatched DNA. Our studies demonstrated that the iron(II) complex 1 and 2b are the most interesting compounds in terms of selective cytotoxic action against cancer cells. However, the cellular mechanism of their anticancer activity requires further research.

1-(Pyridin-4-yl)-4-thiopyridine (PTP) in the crystalline state - pure PTP and a cocrystal and salt.

The first in situ preparation and single-crystal structure identification of pure 1-(pyridin-4-yl)-4-thiopyridine (PTP), C10H8N2S, a simple and basic derivative of mercaptopyridine, from a crystallization mixture is described. The same PTP was found in two multicomponent crystal forms with 3,5-dinitrobenzoic acid as a classic two-component cocrystal, namely, 1-(pyridin-4-yl)-4-thiopyridine-3,5-dinitrobenzoic acid (1/1), C7H4N2O6·C10H8N2S, and with 2-hydroxy-3,5-dinitrobenzoic acid as a salt formed via proton transfer from the hydroxy group of the acid to the pyridyl N atom of PTP, namely, 4-(4-sulfanylidene-1,4-dihydropyridin-1-yl)pyridin-1-ium 1-carboxy-3,5-dinitrophenolate, C10H9N2S+·C7H3N2O7-. The protonation energy of PTP is 944.64 kJ mol-1, indicating slightly greater N-basicity compared to pyridine, a well characterized and very basic chemical reference. A variety of molecular interactions can be observed in the three new crystal structures of PTP, which are all discussed in detail. Our findings confirm those of previous studies, indicating that PTP and 4-mercaptopyridine may, under suitable conditions, be chemically converted to one another, and that this process can be stimulated by light (UV-Vis).

2,2'-Dithiobispyrazine: about the disulfide bond.

X-ray diffraction studies reveal that pyrazine-2-thiol undergoes condensation to 2,2'-dithiobispyrazine [systematic name: 2-(pyrazin-2-yldisulfanyl)pyrazine], C8H6N4S2 (I), under aerial conditions. In the molecule of I, the pyrazine rings are arranged in an almost perpendicular manner, with an absolute value of the C-S-S-C torsion angle of -91.45 (6)°. A search in the Cambridge Structural Database confirmed that such a conformation is typical for disulfide compounds. Three different rotamers of disulfide I were studied using quantum theoretical studies. The rotamer of lowest energy was observed in the crystalline state in the structure stabilized by hydrogen-bond, chalcogen-bond and stacking interactions. Further quantum chemical computations confirm that 2,2'-dithiobispyrazine can react according to the SN2 mechanism.

Piano-stool ruthenium(II) complexes with maleimide and phosphine or phosphite ligands: synthesis and activity against normal and cancer cells.

In these studies, we designed and investigated cyto- and genotoxic potential of five ruthenium cyclopentadienyl complexes bearing different phosphine and phosphite ligands. All of the complexes were characterized with spectroscopic analysis (NMR, FT-IR, ESI-MS, UV-vis, fluorescence and XRD (for two compounds)). For biological studies, we used three types of cells - normal peripheral blood mononuclear (PBM) cells, leukemic HL-60 cells and doxorubicin-resistance HL-60 cells (HL-60/DR). We compared the results obtained with those obtained for the complex with maleimide ligand CpRu(CO)2(η1-N-maleimidato) 1, which we had previously reported. We observed that the complexes CpRu(CO)(PPh3)(η1-N-maleimidato) 2a and CpRu(CO)(P(OEt)3)(η1-N-maleimidato) 3a were the most cytotoxic for HL-60 cells and non-cytotoxic for normal PBM cells. However, complex 1 was more cytotoxic for HL-60 cells than complexes 2a and 3a (IC50 = 6.39 µM vs. IC50 = 21.48 µM and IC50 = 12.25 µM, respectively). The complex CpRu(CO)(P(OPh)3)(η1-N-maleimidato) 3b is the most cytotoxic for HL-60/DR cells (IC50 = 104.35 µM). We found the genotoxic potential of complexes 2a and 3a only in HL-60 cells. These complexes also induced apoptosis in HL-60 cells. Docking studies showed that complexes 2a and CpRu(CO)(P(Fu)3)(η1-N-maleimidato) 2b have a small ability to degrade DNA, but they may cause a defect in DNA damage repair mechanisms leading to cell death. This hypothesis is corroborated with the results obtained in the plasmid relaxation assay in which ruthenium complexes bearing phosphine and phosphite ligands induce DNA breaks.

Effect of a Substituent on the Properties of Salicylaldehyde Hydrazone Derivatives.

The present study investigates the effect of the substitution of salicylaldehyde hydrazones at two selected positions, i.e., the para-position with regard to the proton-donating and proton-accepting centers forming the hydrogen bridge. A detailed analysis of structural data obtained by theoretical approaches and X-ray experiments, together with original resonance Hammett's constants, indicates that the strength of the intramolecular hydrogen bonding present in salicylaldehyde hydrazones can be selectively modulated by substitution of the parent molecular system with the chemical group of known π-electron-donating or -accepting properties. Our findings provide an insight into planning synthesis pathways for salicylaldehyde hydrazone species and predicting their result with regard to their H-bonding and related physical and chemical properties.

X-ray studies of three 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine cocrystals: an unexpected molecular conformation stabilized by hydrogen bonds.

The results of the X-ray structure analysis of three novel 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine cocrystals are presented. These are 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine-2,4,6-tribromophenol (1/2), C12H8N6·2C6H3Br3O, 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine-isonicotinic acid N-oxide (1/2), C12H8N6·2C6H5NO3, and 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine-4-nitrobenzenesulfonamide (1/1), C12H8N6·C6H6N2O4S. Special attention is paid to a conformational analysis of the title tetrazine molecule in known crystal structures. Quantum chemistry methods are used to compare the energetic parameters of the investigated conformations. A structural analysis of the hydrogen and halogen bonds with acceptor aromatic tetrazine and pyrazine rings is conducted in order to elucidate factors responsible for conformational stability.

A novel hydrogen-bonding N-oxide-sulfonamide-nitro N-H...O synthon determining the architecture of benzenesulfonamide cocrystals.

The structures of novel cocrystals of 4-nitropyridine N-oxide with benzenesulfonamide derivatives, namely, 4-nitrobenzenesulfonamide-4-nitropyridine N-oxide (1/1), C5H4N2O3·C6H6N2O4S, and 4-chlorobenzenesulfonamide-4-nitropyridine N-oxide (1/1), C6H6ClNO2S·C5H4N2O3, are stabilized by N-H...O hydrogen bonds, with the sulfonamide group acting as a proton donor. The O atoms of the N-oxide and nitro groups are acceptors in these interactions. The latter is a double acceptor of bifurcated hydrogen bonds. Previous studies on similar crystal structures indicated competition between these functional groups in the formation of hydrogen bonds, with the priority being for the N-oxide group. In contrast, the present X-ray studies indicate the existence of a hydrogen-bonding synthon including N-H...O(N-oxide) and N-H...O(nitro) bridges. We present here a more detailed analysis of the N-oxide-sulfonamide-nitro N-H...O ternary complex with quantum theory computations and the Quantum Theory of Atoms in Molecules (QTAIM) approach. Both interactions are present in the crystals, but the O atom of the N-oxide group is found to be a more effective proton acceptor in hydrogen bonds, with an interaction energy about twice that of the nitro-group O atoms.

Ionic cocrystals of dithiobispyridines: the role of I...I halogen bonds in the building of iodine frameworks and the stabilization of crystal structures.

It has been confirmed that mercaptopyridines undergo spontaneous condensation in redox reaction with iodine-forming dithiopyridines. In the solid state, these compounds are protonated at the N atoms and cocrystallize with iodine forming salt structures, namely, 2-[(pyridin-2-yl)disulfanyl]pyridinium triiodide sesquiiodine, C10H9N2S2+·I3-·1.5I2, and 4,4'-(disulfanediyl)dipyridinium pentaiodide triiodide, C10H10N2S22+·I5-·I3-. Dithiopyridine cations are packed among three-dimensional frameworks built from iodide anions and neutral iodine molecules, and are linked by hydrogen, halogen and chalcogen interactions. Quantum chemical computations indicated that dithiopyridines exhibit anomalously high nitrogen basicity which qualify them as potential proton sponges.

A rare case of a 2:2:1 ternary cocrystal of pyridine sulfides and trithiocyanuric acid.

We report a rare case of a 2:2:1 ternary cocrystal consisting of two trithiocyanuric acid molecules, two bis(pyridin-4-yl) sulfide molecules and 1,4-bis(pyridin-4-yl)tetrasulfane, namely, 1,3,5-triazinane-2,4,6-trithione-4-(pyridin-4-ylsulfanyl)pyridine-1,4-bis(pyridin-4-yl)tetrasulfane (2/2/1), 2C3H3N3S3·2C10H8N2S·C10H8N2S4. This interesting crystal structure with five neutral molecules per asymmetric unit was synthesized and characterized by means of X-ray diffraction (XRD) experiments and quantum-chemical modelling. Among various specific interactions, hydrogen and halogen bridges have a significant role in stabilizing the crystal structure. In particular, the role played by stacking interactions has been revealed by structure analysis and theoretical calculations. Crystallization was spontaneous and reproducible. One of the components, 1,4-bis(pyridin-4-yl)tetrasulfane, has been characterized by XRD for the first time.

Trithiocyanuric acid: novel cocrystals and analysis of its tautomeric forms.

Cocrystals of trithiocyanuric acid with 2,2'-bipyridyl [1,3,5-triazinane-2,4,6-trithione-2,2'-bipyridine (2/1), 2C3H3N3S3·C10H8N2, (I)] and 4-methylbenzohydrazide [1,3,5-triazinane-2,4,6-trithione-4-methylbenzohydrazide (1/1), C8H10N2O·C3H3N3S3, (II)] crystallize in the monoclinic crystal system. In the crystals, molecules of both components are linked by hydrogen bonds. The trithiocyanuric acid molecules are connected by N-H...S hydrogen bonds forming R22(8) synthons, which are further organized into chain motifs. Computations based on quantum chemistry methods have been performed for a more detailed description of the observed tautomerism of trithiocyanuric acid.

Pyrazine-2(1H)-thione.

The title compound, C4H4N2S, was obtained by the reduction of 2-mercapto-pyrazine (during its crystallization with 2-mercapto-pyrazine and isonicotinic acid N-oxide in ethanol solution. It crystallizes in the monoclinic space group P21/m. In the crystal, the mol-ecules are linked by N-H⋯N and C-H⋯S hydrogen bonds.

C-Br...S halogen bonds in novel thiourea N-oxide cocrystals: analysis of energetic and QTAIM parameters.

Cocrystals of thiourea with 4-nitropyridine N-oxide, C5H4N2O3·2CH4N2S, (I), and 3-bromopyridine N-oxide, C5H4BrNO·CH4N2S, (II), crystallize in the monoclinic space group P21/c. In the crystals, molecules of both components are linked by N-H...O hydrogen bonds, creating R21(6) synthons. The bromine substituent of the N-oxide component in (II) is a centre for C-Br...S halogen bonding to the thiourea molecule. Computations based on quantum chemistry methods (quantum theory of atoms in molecules, QTAIM) and atoms in molecules (AIM) theory were performed for a more detailed description of the observed type of halogen-bonding interaction.

Crystal structure of 3,6-bis-(pyridin-2-yl)-1,4-di-hydro-1,2,4,5-tetra-zine.

The structure of the title compound, C12H10N6, at 100 K has monoclinic (P21/n) symmetry. Crystals were obtained as a yellow solid by reduction of 3,6-bis-(pyridin-2-yl)-1,2,4,5-tetra-zine. The structure displays inter-molecular hydrogen bonding of the N-H⋯N type, ordering mol-ecules into infinite ribbons extending along the [100] direction.

N-Oxide-N-oxide interactions and Cl...Cl halogen bonds in pentachloropyridine N-oxide: the many-body approach to interactions in the crystal state.

Pentachloropyridine N-oxide, C5Cl5NO, crystallizes in the monoclinic space group P21/c. In the crystal structure, molecules are linked by C-Cl...Cl halogen bonds into infinite ribbons extending along the crystallographic [100] direction. These molecular aggregates are further stabilized by very short intermolecular N-oxide-N-oxide interactions into herringbone motifs. Computations based on quantum chemistry methods allowed for a more detailed description of the N-oxide-N-oxide interactions and Cl...Cl halogen bonds. For this purpose, Hirshfeld surface analysis and the many-body approach to interaction energy were applied.