An efficient one-pot synthesis of pyrazole complexes formed in situ: synthesis, crystal structure, Hirshfeld surface analysis and in vitro biological properties.

The molecular crystals of monomeric and dimeric pyrazole complexes were prepared via one-pot syntheses. These are dichloridobis(3,5-dimethyl-1H-pyrazole-κN1)cobalt/zinc(0.2/0.8), [Co0.20Zn0.80Cl2(C5H8N2)2] or [Co0.2Zn0.8Cl2(3,5-dmp)2] (1), and bis(µ-3,5-dimethyl-1H-pyrazole)-κ2N1:N2;κ2N2:N1-bis[bromido/chlorido(0.7/0.3)bis(3,5-dimethyl-1H-pyrazole-κN1)cobalt/zinc(0.1/0.9)], [Co0.20Zn1.80Br1.40Cl0.60(C5H7N2)2(C5H8N2)2] or [Co0.1Zn0.9Br0.7Cl0.3(µ-3,5-dmp)(3,5-dmp)]2 (2). The isolated complexes contain 3,5-dimethylpyrazole (3,5-dmp) ligands formed in situ from the decomposition of 1-hydroxymethyl-3,5-dimethylpyrazole. In both isolated complexes, some positional disorder is observed at the metal ions and halogen ligands. The molecular crystals of 1 and 2 are centrosymmetric, with the space groups C2/c and P-1, respectively. Additionally, in the dinuclear complex, the pyrazole ring has a bridging coordination function with respect to the metal ions. Both complexes have good biological activities against cancer cells. The results of an in vitro cytotoxicity study indicated that compounds 1 and 2 showed significant cytotoxicity for cancer cell lines, including hepatic (HepG2 cells), lung (A549 cells) and colon cancer cells (SW 480 and SW 620). Based on the calculated IC50 values against human cancer cell lines, it was found that both complexes demonstrated potent antiproliferative activity combined with great selectivity towards cancer cells. Complex 2 was a more effective cytotoxic agent which, at the same time, exhibited high cytocompatibility. The obtained data are very encouraging and could be useful for anticancer drug discovery.

Selective Cytotoxicity of Complexes with N,N,N-Donor Dipodal Ligand in Tumor Cells.

The present article demonstrates selective cytotoxicity against cancer cells of the complexes [Co(LD)2]I2∙CH3OH (1), [CoLD(NCS)2] (2) and [VOLD(NCS)2]∙C6H5CH3 (3) containing the dipodal tridentate ligand LD = N,N-bis(3,5-dimethylpyrazol-1-ylmethyl)amine), formed in situ. All tested complexes expressed greater anticancer activities and were less toxic towards noncancerous cells than cisplatin. Cobalt complexes (1 and 2) combined high cytotoxicity with selectivity towards cancer cells and caused massive tumour cell death. The vanadium complex (3) induced apoptosis specifically in cancer cells and targeted proteins, controlling their invasive and metastatic properties. The presented experimental data and computational prediction of drug ability of coordination compounds may be helpful for designing novel and less toxic metal-based anticancer species with high specificities towards tumour cells.

Systematic coordination chemistry and cytotoxicity of copper(II) complexes with methyl substituted 4-nitropyridine N-oxides.

Three new nitrato copper(II) complexes of dimethyl substituted 4-nitropyridine N-oxide were synthesized and characterized by elemental analysis, magnetic, spectroscopic, thermal and X-ray methods, respectively. They were isolated as trans isomers, mononuclear (µ=1.70-1.88 BM), five (1-2) and four (3) coordinate species of general formula [Cu(NO3)2(H2O)L2] where L=2,3-dimethyl-, 2,5-dimethyl-4-nitropyridine N-oxide and [Cu (NO3)2L2], L=3,5-dimethyl-4-nitropyridine N-oxide, respectively. The X-ray crystal structure of (1) (L=2,3-dimethyl-4-nitropyridine N-oxide) was determined. The organic ligands, the complexes and copper hexaqua ion as a reference were tested in vitro on the cytotoxic activity against human cancer cell lines: MCF-7 (breast), SW-707 (colon) and P-388 (murine leukemia). The complexes are relatively strong cytotoxic agents towards P-388 cell line. Comparative analysis was performed for all known copper(II) complexes containing methyl derivatives of the 4-nitropyridine N-oxide on the basis of their composition, structure and cytotoxic activities. To obtain the typical structure for these species (i.e., 4-coordinate mononuclear of the type trans-[Cu(inorganic anion)2L2]), two methyl groups must be situated on both sides of nitrogen atom(s) (i.e., NO and NO2) in the ligand. The biological activity was found to be strongly dependent upon the number of the methyl groups and the type of cell line. The best cytotoxic results were found for the complexes without substituents or with one methyl group. Generally, for all cell lines, the complexation increased cytotoxicity when compared with the free ligands.

Mononuclear copper(II) nitrato complexes with methyl-substituted 4-nitropyridine N-oxide. Physicochemical and cytotoxic characteristics.

Three new complexes, products of the interaction of Cu(NO(3))(2) and methyl-substituted 4-nitropyridine N-oxides were synthesized and characterized by elemental analysis, magnetic, spectroscopic (IR, FIR and EPR), thermal and X-ray methods. The complexes (magnetic moments 1.70-1.81 BM at 300K) of general formula [Cu(H(2)O)(NO(3))(2)L(2)], L=2-methyl-4-nitropyridine N-oxide and [Cu(NO(3))(2) L'(2)], where L'=2,6-dimethyl- and 2,3,6-trimethyl-4-nitropyridine N-oxide were obtained. The compounds were unstable upon dissolution. The X-ray single crystal structure of Cu(II) complex with 2,6-dimethyl-4-nitropyridine N-oxide was determined and analysed. The compounds and free ligands were tested in vitro on the cytotoxic activity against MCF-7 and SW-707 human cancer cell lines. The complexes with 4-nitropyridine N-oxide (a reference) and 2-methyl-4-nitropyridine N-oxide show a significant anti-proliferative activity against studied cell lines. A reciprocal relationship between the activity and the number of methyl groups was observed. Both ligands and complexes are cytotoxic active but to the different cell lines.

Atypical calcium coordination number: Physicochemical study, cytotoxicity, DFT calculations and in silico pharmacokinetic characteristics of calcium caffeates.

Two complexes of calcium ions containing monodeprotonated caffeate ligands were synthesized and physicochemically (IR, FIR, NMR, thermal analysis) and theoretically (DFT and pharmacokinetical parameters) characterized. [Ca(C(9)H(7)O(4))(2)].2H(2)O 1a and [Ca(C(9)H(7)O(4))(2)].2H(2)O KNO(3)1b are compounds with unusual four coordinate calcium ion containing the ligand coordinated to the metal ion through two carboxylic groups arranged with tetrahedrally-like mode (CaO(4)). Two water molecules are outside the first coordination sphere bound non-equivalently to the ligand through a net of hydrogen bonding. The compounds were found to be cytotoxically inactive. Finally, in silico parameters predict the potential application of the compound as a supplement and/or drug.

Methyl-substituted 4-nitropyridine N-oxides as ligands: structural, spectroscopic, magnetic and cytotoxic characteristics of copper(II) complexes.

Seven new mono- and dinuclear Cu(II) complexes containing various methyl substituted 4-nitropyridine N-oxides as ligands were isolated and characterized physicochemically and biologically. The characterization included elemental analysis, magnetic and spectroscopic methods (diffuse reflectance and UV-visible absorption, IR, FIR). A single crystal X-ray diffraction analysis was performed for the complex with 2,5-dimethyl-4-nitropyridine N-oxide. Trans- and cis-square planar configuration around Cu ion was established for mono- and dinuclear species, respectively. In methanolic solutions the dinuclear species decompose into mononuclear ones with increasing 4-->6 coordination number with attachment of two solvent molecules. The IR spectra showed that the strength of the Cu-ligand bond gauged by the degree of N-O elongation changed irregularly with position and number of methyl groups. Cytotoxic studies on the MCF-7 human breast cancer line revealed a structure-activity relationship: double blocking of the NO(2) group with two CH(3) groups rendered the complex completely inactive.

Synthesis, physicochemical and pharmacokinetic characterization of calcium uronates.

Four calcium compounds containing uronic acids (D(+)-galacturonic and D(+)-glucuronic) in L:M ratio = 2 and 3 were isolated by applying novel (except for one complex) synthetic procedures. The compounds were characterized by elemental analysis, spectroscopic methods (diffuse reflectance and absorption UV-visible, IR, FIR), mass spectrometry, fast atom bombardment (FAB), thermal decomposition, thermogravimetry/derivative thermogravimetry (TG/DTG) data and differential scanning calorimetric studies (DSC). Two modes of water binding in the complexes, i.e., hydration and coordination-like, were established. Computer-aided analysis has shown that further investigations are needed in order to determine the applicability of calcium uronates as calcium carriers.