Inhibitory effects of loading with the calcium-chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) on amylase release and cellular ATP level in rat parotid cells.

Rat parotid cells were loaded with the Ca2(+)-chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), by incubation with the acetoxymethyl ester of BAPTA (BAPTA-AM). The BAPTA loading inhibited amylase release induced by beta-adrenergic receptor stimulation without affecting the basal release, and the IC50 value was 25 microM. Incubation of cells with BAPTA-AM also suppressed cellular ATP levels considerably. At 100 microM BAPTA-AM, the ATP level fell to about 50% of the control. A decrease in ATP levels by incubation with oligomycin, a mitochondrial inhibitor, correlated well with the inhibition of amylase release. Although these results do not exclude the possibility that cytosolic free Ca2+ is involved in the regulation of cyclic AMP-mediated amylase release, they suggest that the amylase release inhibition with BAPTA loading may be due, in part, to a decrease in cellular ATP levels. Therefore, the exact mode of the BAPTA action must be interpreted with caution.     

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.     

Spectrophotometric determination of oxprenolol hydrochloride as its Fe (III) complex

A spectrophotometric determination of oxprenolol hydrochloride in pharmaceutical preparations is described. The method is based on the reaction of oxprenolol hydrochloride with Fe (III) ion in the presence of ammonium thiocyanate, in acid media. The complex formed between oxprenolol hydrochloride and Fe (III) ion was extracted with chloroform and assayed spectrophometrically at 477 nm. The results obtained are reproducible and hence the method is suitable for the determination of oxprenolol hydrochloride in pharmaceutical dosage forms.     

Spectrophotometric determination of alendronate in pharmaceutical formulations via complex formation with Fe(III) ions

The formation of the complex between alendronate, non-chromophoric bisphosphonate drug important for the treatment of a variety of bone diseases, and iron(III) chloride in perchloric acid solution was studied. The stoichiometric ratio of alendronate to Fe(III) ions in the chromophoric complex was determined to be 1:1. The conditional stability constant was log K′_ave=4.50 (SD=0.15), indicating that the Fe(III)–alendronate complex is a complex of medium stability. The optimum conditions for this reaction were ascertained and a spectrophotometric method was developed for the determination of alendronate in the concentration range 8.1–162.5 μg ml⁻¹, the detection limit being 2 μg ml⁻¹. The method was validated for the direct determination of alendronate in tablet dosage formulations.     

In the search for new anticancer drugs. 17. Linear and cyclic polyether analogues of N,N:N',N':N',N'-tri-1,2-ethanediylphosphoric triamide and N,N:N',N':N',N'-tri-1,2-ethanediylphosphorothioic triamide

Linear and cyclic polyether derivatives of N,N:N',N':N',N'-tri-1, 2-ethanediylphosphoric triamide (TEPA) and N,N:N',N':N',N'-tri-1,2-ethanediylphosphorothioic triamide (thio-TEPA) are synthesized and evaluated for their antineoplastic activity against the murine lymphocytic leukemia P388. All compounds, except for 7d, were active ranging from 42% to 287% increase in life span (% ILS). All CD2F1 male mice treated with the most active compound (7a) at 90 mg/kg per day for 9 days were alive after 30 days, whereas all mice treated with the clinical drug thio-TEPA were dead. The % ILS for compound 7a on day 60 was 525. A correlation is presented between the structural features of compounds and their lipophilicities and antineoplastic activities.     

Preparation, X-ray structural and spectroscopic studies of some D-lactobionic acid complexes with Cs(I), Fe(III) and di-n-butyltin(IV)

D-Lactobionic acid (4-O-beta-D-galactopyranosyl-D-gluconic acid) complexes of Cs(I), Fe(III) and di-n-butyltin(IV)2+ ions were prepared in the solid state. The bonding sites of the ligands were verified by means of FTIR, Raman and 13C NMR spectroscopic measurements. The Cs(I)-D-lactobionate was obtained in single-crystal form. The X-ray crystallographic results on Cs(I)-D-lactobionate demonstarted that each Cs(I) ion is bonded to four D-lactobionate ions, forming an intricate 3D network. The asymmetric unit consists of one Cs(I), one D-lactobionate ion and one water molecule. For the di-n-butyltin(IV) complex, M?ssbauer pqs calculations indicated octahedral and trigonalbipyramidal stereochemistry around the central tin atom in the oligomeric compound. In DMSO solution, the polymeric structure does not remain as shown by 13C NMR measurement. One solvent molecule is coordinated additionally to the tin center, and the carboxylate group has become monodentate. According to the EPR measurement, the Fe(III) complexes obtained at different pH have at least dimeric or oligomeric structure.     

Spectrophotometric investigations on protolytic equilibria of mefenamic acid and determination by means of Fe(III) in methanol-aqueous media

Studies have been carried out on the effect of pH (from pH 11.33 to H(O) = -4.65) on the UV spectrum of mefenamic acid. The dissociation constant pKa was found to be 4.55 +/- 0.06 and the protonation constant pK(2) was -1.78 +/- 0.18 in methanol-aqueous media. Mefenamic acid was determined spectrophotometrically by formation of a coloured complex (2:5) with Fe(III). At 495 nm Beer's law was followed for the concentration range 96.52 to 579.12 mug ml(-1).     

Synthesis, characterization, and comparative in vitro cytotoxicity studies of platinum(II), palladium(II), and gold(III) methylsarcosinedithiocarbamate complexes

This work reports on the synthesis, characterization, and in vitro cytotoxic activity of some new platinum(II), palladium(II), and gold(III) derivatives of methylsarcosinedithiocarbamate and its S-methyl ester, to study their behavior as potential antitumor agents. The biological activity of these compounds, as determined by growth inhibition and apoptosis induction, has been investigated in both human leukemic promyelocites HL60 and human squamous cervical adenocarcinoma HeLa cell lines, and their activity has been compared to the well-known platinum-based anticancer agent cisplatin. On the basis of these experimental results, [Pd(MSDT)X]n (MSDT = methylsarcosinedithiocarbamate; X = Cl, Br) complexes show a strong dose-dependent growth inhibition of both HL60 and HeLa cells, with IC(50) values slightly higher than those recorded for cisplatin; moreover, [Au(MSDT)X(2)] activity appears significantly higher or, at least, comparable to that of the reference drug. Exposure of both cell lines to [Pd(MSDT)X]n and [Au(MSDT)X(2)] complexes induces apoptosis, as determined by an Apo2.7 assay.     

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.     

In the search for new anticancer drugs. 19. A predictive design of N,N:N',N':N',N'-tri-1,2-ethanediylphosphorothioic triamide (TEPA) analogues

The nitroxyl-labeled analogues of N,N:N',N':N",N"-tri-1,2-ethanediylphosphoric triamide (TEPA), N,N:N',N'-bis(1,2-ethanediyl)-N"-[[(2,2,6,6-tetramethyl-1-oxypiperidi n-4- yl)amino]carbonyl]phosphoric triamide (5a) and N,N:N',N'-bis(1,2-ethanediyl)-N"-[[(2,2,5,5-tetramethyl-1-oxypyrrolid in-3- yl)amino]carbonyl]phosphoric triamide (11a), possess therapeutic indexes that are 8-12 times higher than those of thio-TEPA (1) and TEPA (2). The introduction of methyl groups into the aziridine ring, or the replacement of the nitroxyl moiety with hydroxylamine or amine derivatives, or with an adamantane moiety, results in compounds of lesser activity. An attempt is made to rationalize these results using a lipophilicity scale. A predictive design pattern is established.     

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.     

Antibacterial activity of morin and its complexes with La(III), Gd(III) and Lu(III) ions

The antibacterial activity of morin, sodium salt of morin-5"-sulfonic acid (NaMSA) and new complexes of La (II), Gd (III) and Lu (III) with morin were tested against three bacterial strains: Escherichia coli G (-), Klebsiella pneumoniae G (-), Staphylococcus aureus G (+) and compared with the activity of penicillin. All of the complexes possess inhibitory action against the tested strains. The activity of the studies compounds depends on their concentration. The complexes at a concentration of 10 microg/cylinder demonstrated higher activity than morin alone, but at a concentration of 100 microg/cylinder morin was the most effective inhibitor against the strains used in this investigation.     

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

Pharmaceutical Chemistry Journal -