Physicochemical Properties and Pharmacological Activity of Mn(II), Fe(II), Co(II), Cu(II), AND Zn(II) Gluconates

Pharmaceutical Chemistry Journal -     

Complexes between pilocarpine and cobalt(II), nickel(II), copper(II), and zinc(II) ions

The properties of pilocarpine as a ligand toward the halides of cobalt(II), nickel(II), copper(II), and zinc(II) were investigated. Pilocarpine behaved as a monodentate ligand, giving rise to compounds with the general formula methyl(pilocarpine)2X2. The coordinating geometry at the metal ion was pseudotetrahedral in every case. PMR studies showed that the pyridine-type nitrogen of the imidazole ring of pilocarpine was the donor atom of the ligand.     

Self-inactivation of Fe(II)-bleomycin

Fe(II)-Bleomycin is activated in air to form an electron paramagnetic resonance (EPR)-active species, termed "activated bleomycin", that cleaves DNA, when present. When DNA is absent, the potential DNA cleavage activity is lost and the drug becomes self inactivated. A method is described for the preparation and purification of this self-inactivated product from bleomycin A2, together with some of its physical properties. It is shown that the loss of DNA cleavage activity parallels an alteration of bithiazole fluorescence, attributed to chemical change at this residue. EPR evidence is brought forth that the Cu(II) binding site of inactivated bleomycin in not altered, nor is the ability to form a species with Fe(II) and O2 having the identical spectroscopic signature as activated bleomycin.     

Cytotoxic and antimicrobial activities of Cu(II), Co(II), Pt(II) and Zn(II) Complexes with N,O-chelating heterocyclic carboxylates

A series of Cu(II), Co(II), Pt(II) and Zn(II) coordination compounds has been prepared by the reaction of the metal chlorides with pyrazine-2-carboxylic acid, pyridine-2-carboxylic acid, imidazole-4-carboxylic acid, benzimidazole-2-carboxylic acid and 1-methylimidazole-2-carboxylic acid. The complexes were characterized by IR, UV-VIS, elemental analysis, and some by (1) H-NMR, X-ray crystallography, HPLC and LC/MS spectroscopy. All complexes consist of a 2:1 ratio of ligand to metal ion. IR and X-ray crystallography show that coordination is through the nitrogen and carboxylate oxygen donor atoms of the ligand to form chelating rings. DFT calculations predict that the trans-coordinated isomers are thermodynamically more stable than their cis-forms. Only one of five complexes studied by X-ray crystallography, Cu(II) complex of 1-methylimidazole-2-carboxylic acid showed a cis-configured metal ion center. HPLC analysis indicated that Pt(II) complex of 1-methylimidazole-2-carboxylic acid is dominated (>90%) by the trans-configured complex. All other complexes showed one isomer, presumably the trans-form. The cytotoxic activity was investigated in human cancer cell lines in vitro; only the Pt(II) complexes were active. The antimicrobial activity against four bacterial strains and one fungi was estimated by the MIC method and best results were found amongst the Co(II) complexes. These results indicate that trans-coordinated bischelating N,O-heterocyclic carboxylates of Pt(II) are an interesting new class of potential antitumor agents.     

Simultaneous determination of zinc(II), manganese(II) and iron(II) in pharmaceutical preparations

The applicability of derivative spectrophotometry for simultaneous determination of zinc(II), manganese(II) and iron(II) in the form of PAR complexes was presented and discussed. Beer's law was obeyed in range 0.025-13 ppm for zinc 1-20, for manganese and 0.025-0.2 for iron ion. The elaborated method was applied successfully for determination of mentioned ions in pharmaceutical preparation without previous separation. The error of the determination did not exceed +/-3%.     

Antimicrobial studies of hydrazone complexes of Hg(II) and Fe(II) divalent metal ions

The antibacterial, antifungal and antitubercular activities of Hg(II) and Fe(II) complexes of hydrazone were studied. All the complexes have been screened against Staphylococcus aureus, Salmonella typhi, Candida albicans, Aspergillus niger, Saccharomyces cerevisiae and Mycobacterium tuberculosis H37Rv and found to be more toxic than the parent ligand. The activity increased in the order [5-methyl-3-oximino-hexan-2-one-hydrazone]2 Fe(II) < [5-methyl-3-oximino-hexan-2-one-hydrazone]2 Hg(II) < 3-oximino-hexan-2-one-phenylhydrazone]2 Fe(II) < [5-methyl-3-oximino-hexan-2-one-phenylhydrazone]2 Hg(II) for antibacterial and antifungal activity.     

In vitro study of the interaction between omeprazole and the metal ions Zn(II), Cu(II), and Co(II)

The purpose of this study was to investigate the possibility of a chemical interaction between omeprazole (OM) and the metal ions Zn(II), Cu(II), and Co(II). Using UV absorption spectroscopy and elemental analysis, it was demonstrated that all of the studied metals form complexes with OM. The spectral changes associated with the complexation reaction were used to obtain the stoichiometry and formation constants of the complexes. In all cases complexes were found to form in 1:2 metal to OM ratio. In the case of cobalt another complex species which appeared as a green precipitate was also evident. Copper was shown to form the complex with the formula Cu3(OM)2 in addition to Cu(OM)2. The complexation of cobalt and copper to OM was found to be time dependent and the time required for the completion of the reaction was determined (about 6 h). Apparent binding constants were also determined.     

Tetraoxane antimalarials and their reaction with Fe(II)

Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4' ') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg.kg-1.day-1, and 2/5 mice at 50 mg.kg-1.day-1, showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO* radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO* radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.     

Synthesis, characterization, antibiogram and DNA binding studies of novel Co(II), Ni(II), Cu(II), and Zn(II) complexes of Schiff base ligands with quinoline core

A series of Co(II), Ni(II), Cu(II), and Zn(II) complexes of Schiff base ligands L¹H₃ and L²H have been prepared. The ligands are synthesized by the condensation of 2-hydroxy-3-formylquinoline with salicyloylhydrazide and 2-hydrazinobenzothiazole in absolute ethanol. The prepared complexes were characterized by the analytical and spectral techniques. The stoichiometry of the complexes is found to be 1:1. The presence of coordinated and lattice water is confirmed by the TG and DTA studies. Subsequently all the prepared complexes were screened for antimicrobial activity against bacteria and fungi. The Cu(II) complexes have been found to be more active than the ligand. In addition the DNA binding/cleaving capacity of the compounds was analyzed by absorption spectroscopy, viscosity measurement, thermal denaturation, and gel electrophoresis methods.     

Column solid phase extraction of iron(III), copper(II), manganese(II) and lead(II) ions food and water samples on multi-walled carbon nanotubes

A column solid phase extraction method for preconcentration of Fe(III), Cu(II), Mn(II) and Pb(II) on multi-walled carbon nanotubes (MWNTs) has been established. The adsorption was achieved quantitatively on carbon nanotube at pH 9.0, then the retained analyte contents on the column were quantitatively eluted with 1 M HNO₃ in acetone. The effects of analytical parameters including pH of the solution, eluent type, sample volume, flow rates of eluent, matrix ions, etc. were investigated for optimization of the presented procedure. The preconcentration factor was calculated as 20. The detection limits for the understudy analyte ions were found in the range of 3.5 μg/L (Mn)–8.0 μg/L (Pb). The validation of the presented procedure was checked by the analysis of TMDA 54.4 fortified lake water and HR-1 River Sediment certified reference materials. The method was applied to the determination of analyte ions in environmental samples.     

Spectrophotometric determination of Fe(II) and Zn(II) in the pharmaceutical multivitamin preparations with microelements

3-mercapto-5-(3,4-dihydroxyphenylazo-1')-1,2,4-triazole (METRIAP), 3-mercapto-5-(2,4-dihydroxy-3-carboxyphenylazo-1)-1,2,4-triazole (METRIAREZ-gamma) and 2-mercapto-5-(2,4-dihydroxy-5-carboxyphenylazol-)-1,3,4-thiadiazole (METIDAREZ-beta), reagents synthesized in the Department of Medicinal Chemistry of Medical University in Lublin, have been used to determine Fe(II) and Zn(II) in Materna, Centrum, H-Pantoten pharmaceutical multivitamin preparations, containing other trace elements. Zn (II) with METRIAREZ-gamma at pH=7.35, and Fe(II) with METRIAP and METIDAREZ-beta at pH=10.30 or 7.40 constitute soluble in H2O colourful chelate compound at a mole ratio of 1:2 and 1:3, respectively. Volume stability constant of Fe(II) and Zn(II) complexes is equal to log K(METRIAP-Fe(II)) = 16.46; log K(METRIAREZ-beta-Fe(II)) = 14.253; log K(METRIAREZ-gammaZn(II)) = 11.47. Fe(III) and Zn(II) solutions were obtained by wet mineralisation of Materna, Centrum and H-Pantoten preparations with concentrated H2SO4 and 30% H2O2 added. Spectrophotometric determination was carried out in an aqueous-methanolic solution environment. Statistically evaluated results were compared with the results of the AAS (atomic absorption spectrophotometry) determination method. Advantages of the Fe(II) and Zn(II) determination method are its precision RSD = 0.23%-2.09% and repeatability as well as the possibility of Fe(II) determination without the necessity of masking or separating other trace elements.     

Ni(II), Cu(II), and Zn(II) diethyldithiocarbamate complexes show various activities against the proteasome in breast cancer cells

A series of three complexes with diethyldithiocarbamate ligand and three different metals (Ni, Cu, Zn) was prepared, confirmed by X-ray crystallography, and tested in human breast cancer MDA-MB-231 cells. Zinc and copper complexes, but not nickel complex, were found to be more active against cellular 26S proteasome than against purified 20S proteasome core particle. One of the possible explanations is inhibition of JAMM domain in the 19S proteasome lid.     

Spectrophotometric determination of Pb(II), Fe(III) and Bi(III) in complexes with 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (DACT)

A UV spectrophotometric method was developed for simultaneous determination of ions: Pb(II), Fe(III) and Bi(III) in complexes with DACT. Zero-order and derivative spectra were used for the determinations. Under the established experimental conditions the described method furnished reliable results with low limit of detection (from 0.09 microg x mL(-1) to 1.75 microg x mL(-1)), high recovery (from 96.08% to 97.81%) and broad range of linearity for the analyzed ions. Good precision of the method was confirmed in experiments on model solutions containing mixtures of ions studied at different concentrations and in statistical analysis of the data obtained.     

Spectroscopic,antiproliferative and antiradical properties of Cu(II), Ni(II), and Zn(II) complexes with amino acid based Schiff bases

Novel six Cu(II), Ni(II), and Zn(II) complexes with Schiff bases derived from 4-aminobenzoic acid with terephtaldehyde and amino acids (glycine, β-alanine). Structures have been proposed from elemental analysis, UV–Vis, IR, NMR, TGA, DTA, and magnetic measurements. Spectroscopic studies suggest that coordination occurs through azomethine nitrogen, hydroxyl group, and carbonyl oxygen of the ligands to the metal ions. The elemental analyses of the complexes where L is Schiff base ligands, are confined to the stoichiometry of the type M₂L₂(CH₃COO)₂ [M = Cu(II)]; and M₂L(CH₃COO)₂ [M = Ni(II) and Zn(II)]. The cytotoxicity activities of the compounds against human breast carcinoma MCF-7 cell line have been studied. Ligands and their Zn(II) compounds inhibited cell proliferation of MCF-7 cancer cell lines in a dose- and time-dependent manner. The free radical scavenging activity was measured by 1,1-diphenyl-2-picryl-hydrazil. Our results show that the synthesized compounds induced oxidative damage by increasing the lipid peroxidation in yeast since MDA formation was increased, and it could be concluded that the synthesized compounds caused oxidative stress. In addition, the antioxidant activities of the synthesized compounds were very much lower than those of standard antioxidants.