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1.
Molecules ; 25(15)2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32751474

RESUMO

The present study describes the coordination properties of a reduced Schiff base, N-(2-hydroxybenzyl)alanine, towards cobalt(II) using potentiometric as well as spectroscopic (UV-Vis and ESI-MS) methods. The results indicate the formation of six mononuclear complexes showing high stability in aqueous solution. Coordination occurs in the {O-phenolic,N,O-carboxyl} and {N,O-carboxyl} chelation modes, depending on the degree of ligand deprotonation. Examination of the complexation equilibria at pH ca 7, which is important from a biological point of view, allowed to identify two species: [CoL] and [CoL2H]-. The kinetic analysis showed a structural change of those cobalt(II) complexes from octahedral to tetrahedral in accordance with a first-order time relationship. The antimicrobial properties of N-(2-hydroxybenzyl)alanine, cobalt(II) nitrate and of the Co(II) - ligand complexes were determined against Gram-positive bacteria (Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis), Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Helicobacter pylori) and a fungal strain (Candida). The results indicate that the complexes are more active for more strains than the ligand alone. Nevertheless, the complexes induce a higher decrease in the metabolic activity of cells but without damage to nuclei. Tetrahedral structures show stronger anti-cellular toxicity than octahedral complexes, which is most likely due to the higher accessibility of the cobalt(II) center.

2.
J Biol Inorg Chem ; 25(6): 875-885, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32719971

RESUMO

L-ascorbic acid 2-phosphate magnesium (APMg) salt is a vitamin C derivative frequently used as a raw material in cell and tissue therapy. APMg is not only used as a replacement of the unstable ascorbate, but also shows additional cell-biological functionalities. However, its unknown structural characteristics hamper the mechanistic elucidation of its biological role. Therefore, different techniques were applied for APMg structure characterization. Firstly, the stoichiometric composition was characterized by its solvent, ligand and magnesium content. No crystals of APMg could be obtained; however, a single crystal of APNa, the sodium salt of l-ascorbic acid 2-phosphate, was successfully obtained and its crystal structure was elucidated. FT-IR was applied to further clarify the structure of solid APMg. Finally, the structure of APMg in aqueous solution was explored by potentiometric titration as well as FT-IR.

3.
BMC Chem ; 13(1): 57, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31384805

RESUMO

Background: Thanks to its specific chemical and physical properties, graphene has aroused growing interest in many fields of Science and Technology. The present study focuses on the properties of microcrystalline chitosan (MCCh): a compound known to increase the biocompatibility of various matrices, including those made of graphene layers, enabling the controlled release of molecules of therapeutic compounds. The study exploits the potential of MCCh to complex with metal ions, in this case Mg2+, and attempts to describe such interactions when the system is enriched with graphene oxide (GO). These findings would open completely new areas of knowledge about GO as a drug carrier. Results: Potentiometric analysis found that in the GO-Mg system, complexes of ML' type were formed, where M = Mg2+; L' = GO (log ß 11'0 = 9.5 (3)) and ML'2 (log ß 12'0 = 13.2 (4)), whereas in the GO-Mg2+-MCCh system, a mixed-type complex MLL' was also formed, in which L = MCCh: this complex demonstrated the overall stability constants log ß 111' = 11.2 (3) for degree of deacetylation DD 74.4% and log ß 111' = 12.4 (4) for DD 97.7%. FT-IR analysis showed interactions in the GO-Mg2+-MCCh (DD = 97.7%) system. In addition, the amide II-NH band was displaced from 1623 cm-1 to two bands at 1633 cm-1 and 1648 cm-1, resulting from the interaction of the metal ion, and the absorption band of the corresponding NH in the chitosan acetyl group was shifted from 1304 to 1351 cm-1. When chitosan with a deacetylation degree lower than 74.4% was applied, the amide bands I and II differed only in their intensity. A greater impact on absorption was observed for the acetyl NH group of chitosan, for which the corresponding band shifted from 1319 to 1361 cm-1. Conclusions: The results confirm the ability of GO-Mg2+-MCCh to create complex arrangements. It can form a basic complex of one metal ion and one ligand molecule (GO) in the case of ML' (where L' = GO), or two molecules of GO with a metal ion M (Mg2+) in the case of ML'2. A mixed complex of MLL' type is also formed, with two ligands: L = MCCh with deacetylation degrees DD = 74.4% and 97.7% and graphene oxide L' = GO. In the latter case, FT-IR spectroscopy was used to confirm the mode of interaction. The GO-Mg2+-MCCh system may be used as carrier in modern magnesium containing medicines or as auxiliary substances in pharmacy.

4.
J Pharm Biomed Anal ; 165: 338-345, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30579234

RESUMO

l-ascorbic acid 2-phosphate magnesium (APMg) salt is a vitamin C derivative frequently used in cell culture media for research purposes. It is also used as a raw material in the GMP-manufacturing of gene-, cell- and tissue advanced therapy medicinal products (ATMPs). However, quality methods are currently lacking. Therefore, a LC method was developed, based on hydrophilic interaction (HILIC)-ion exchange (IE) mixed-mode liquid chromatography. The final method consisted of an isocratic system with 15 mM KH2PO4 buffer (pH 2.5 with HCl) acetonitrile (30:70, v/v) mobile phase on a zwitterionic HILIC column, containing an hydrophilic ligand embedded cation-exchange functionality and a surface anion-exchange group. A flow rate of 0.4 mL/min and UV detection at 240 nm was applied. The assay method of APMg was validated, obtaining adequate linearity (R2 = 0.999), precision (RSD of 0.49%) and accuracy (overall recovery of 100.4%). The developed method was successfully applied on five currently marketed products from different suppliers, showing different related substance impurity profiles. Using atomic absorption spectroscopy (AAS), magnesium was found to be bound on the stationary phase, requiring a strong mobile phase to rinse the column. Finally, related impurities were identified using MS/MS and high resolution MS, and found to be ascorbic acid as well as ethyl derivatives, which was further confirmed by NMR.


Assuntos
Ácido Ascórbico/análogos & derivados , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Ácido Ascórbico/análise , Ácido Ascórbico/química , Ácido Ascórbico/normas , Interações Hidrofóbicas e Hidrofílicas , Controle de Qualidade , Reprodutibilidade dos Testes , Espectrofotometria Atômica/métodos
5.
J Inorg Biochem ; 187: 62-72, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30055397

RESUMO

The coordination properties of 2-picolinehydroxamic acid towards cobalt(II) in aqueous solution were determined by a pH-metric method and confirmed by spectroscopic (UV-Vis and ESI-MS) studies. The results show the formation of mononuclear complexes, as well as of metallacrowns (MC). All methods indicate a high tendency of 2-picolinehydroxamic acid to form cobalt(II) metallacrown 12-MC-4. ESI-MS additionally confirms 15-MC-5 and 18-MC-6, stabilized by a sodium ion and methanol. The complexes observed in the speciation model at a pH about 7.2 were studied for their DNA-binding ability. The decrease of absorbance in the range of ca 310-400 nm indicates effective binding to calf thymus DNA by 2-picolinehydroxamic acid complexes, via intercalative mode. The antimicrobial properties of 2-picolinehydroxamic acid, cobalt(II) ions and of the complexes formed in the Co(II) - ligand system were determined against Gram-positive bacteria (Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Helicobacter pylori) and fungal strains (Candida, Aspergillus niger). The results indicate that the complexes demonstrate greater antibacterial and antifungal activity for most strains than the ligand. Both the complexes and the ligand induce a slight decrease in the metabolic activity of cells, while the complexes do not damage the cell nuclei. The 2-picolinehydroxamic acid complexes activate the human monocytic cells, suggesting they have immunomodulating properties, which are particularly important in combating infections caused by strains resistant to other drugs.


Assuntos
Antibacterianos , Antifúngicos , Cobalto , Complexos de Coordenação , Citotoxinas , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Aspergillus niger/crescimento & desenvolvimento , Candida/crescimento & desenvolvimento , Linhagem Celular , Cobalto/química , Cobalto/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Camundongos , Monócitos/citologia , Monócitos/metabolismo , Células THP-1
6.
Chem Cent J ; 11(1): 90, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-29086874

RESUMO

BACKGROUND: The paper examines Co(II)-amino acid-imidazole systems (where amino acid = L-α-amino acid: alanine, asparagine, histidine) which, when in aqueous solutions, activate and reversibly take up dioxygen, while maintaining the structural scheme of the heme group (imidazole as axial ligand and O2 uptake at the sixth, trans position) thus imitating natural respiratory pigments such as myoglobin and hemoglobin. The oxygenated reaction shows higher reversibility than for Co(II)-amac systems with analogous amino acids without imidazole. Unlike previous investigations of the heteroligand Co(II)-amino acid-imidazole systems, the present study accurately calculates all equilibrium forms present in solution and determines the [Formula: see text]equilibrium constants without using any simplified approximations. The equilibrium concentrations of Co(II), amino acid, imidazole and the formed complex species were calculated using constant data obtained for analogous systems under oxygen-free conditions. Pehametric and volumetric (oxygenation) studies allowed the stoichiometry of O2 uptake reaction and coordination mode of the central ion in the forming oxygen adduct to be determined. The values of dioxygen uptake equilibrium constants [Formula: see text] were evaluated by applying the full mass balance equations. RESULTS: Investigations of oxygenation of the Co(II)-amino acid-imidazole systems indicated that dioxygen uptake proceeds along with a rise in pH to 9-10. The percentage of reversibility noted after acidification of the solution to the initial pH ranged within ca 30-60% for alanine, 40-70% for asparagine and 50-90% for histidine, with a rising tendency along with the increasing share of amino acid in the Co(II): amino acid: imidazole ratio. Calculations of the share of the free Co(II) ion as well as of the particular complex species existing in solution beside the oxygen adduct (regarding dioxygen bound both reversibly and irreversibly) indicated quite significant values for the systems with alanine and asparagine-in those cases the of oxygenation reaction is right shifted to a relatively lower extent. The experimental results indicate that the "active" complex, able to take up dioxygen, is a heteroligand CoL2L'complex, where L = amac (an amino acid with a non-protonated amine group) while L' = Himid, with the N1 nitrogen protonated within the entire pH range under study. Moreover, the corresponding log  [Formula: see text] value at various initial total Co(II), amino acid and imidazole concentrations was found to be constant within the limits of error, which confirms those results. The highest log [Formula: see text] value, 14.9, occurs for the histidine system; in comparison, asparagine is 7.8 and alanine is 9.7. This high value is most likely due to the participation of the additional effective N3 donor of the imidazole side group of histidine. CONCLUSIONS: The Co(II)-amac-Himid systems formed by using a [Co(imid)2]n polymer as starting material demonstrate that the reversible uptake of molecular oxygen occurs by forming dimeric µ-peroxy adducts. The essential impact on the electron structure of the dioxygen bridge, and therefore, on the reversibility of O2 uptake, is due to the imidazole group at axial position (trans towards O2). However, the results of reversibility measurements of O2 uptake, unequivocally indicate a much higher effectiveness of dioxygenation than in systems in which the oxygen adducts are formed in equilibrium mixtures during titration of solutions containing Co(II) ions, the amino acid and imidazole, separately.

7.
Chem Cent J ; 10: 14, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27042204

RESUMO

BACKGROUND: Heteroligand Co(II) complexes involving imidazole and selected bio-relevant L-α-amino acids of four different groups (aspartic acid, lysine, histidine and asparagine) were formed by using a polymeric, pseudo-tetrahedral, semi-conductive Co(II) complex with imidazole-[Co(imid)2]n as starting material. The coordination mode in the heteroligand complexes was unified to one imidazole in the axial position and one or two amino acid moieties in the appropriate remaining positions. The corresponding equilibrium models in aqueous solutions were fully correlated with the mass and charge balance equations, without any of the simplified assumptions used in earlier studies. Precise knowledge of equilibria under oxygen-free conditions would enable evaluation of the reversible oxygen uptake in the same Co(II)-amino acid-imidazole systems, which are known models of artificial blood-substituting agents. RESULTS: Heteroligand complexes were formed as a result of proton exchange between the two imidazole molecules found in the [Co(imid)2]n polymer and two functional groups of the amino acid. Potentiometric titrations were confirmed by UV/Vis titrations of the respective combinations of amino acids and Co-imidazole. Formation of MLL' and ML2L' species was confirmed for asparagine and aspartic acid. For the two remaining amino acids, the accepted equilibrium models had to include species protonated at the side-chain amine group (as in the case of lysine: MLL'H, ML2L'H2, ML2L'H) or at the imidazole N1 (as in the case of histidine: MLL'H and two isomeric forms of ML2L'). Moreover, the Δlog10 ß, log10 ß stat, Δlog10 K, and log10 X parameters were used to compare the stability of the heteroligand complexes with their respective binary species. The large differences between the constant for the mixed-ligand complex and the constant based on statistical data Δlog10 ß indicate that the heteroligand species are more stable than the binary ones. The parameter Δlog10 K, which describes the influence of the bonded primary ligand in the binary complex Co(II)(Himid) towards an incoming secondary ligand (L) forming a heteroligand complex, was negative for all the Amac ligands (except for histidine, which shows stacking interactions). This indicates that the mixed-ligand systems are less stable than the binary complexes with one molecule of imidazole or one molecule of amino acid, in contrast to Δlog10 ß, which deals with binary complexes Co(II)(Himid)2 and Co(II)(AmacH-1)2 containing two ligand molecules. The high positive values of the log10 X disproportionation parameter were in good agreement with the results of the Δlog10 ß calculations mentioned above. CONCLUSION: The mixed-ligand MLL'-type complexes are formed at pH values above 4-6 (depending on the amino acid used), however, the so-called "active" ML2L'-type complexes, present in the equilibrium mixture and known to be capable of reversible dioxygen uptake, attain maximum share at a pH around nine. For all the amino acids involved, the greater the excess of amino acid, the lower the pH where the given heteroligand complex attains maximum share. The results of our equilibrium studies make it possible to evaluate the oxygenation constants in full accordance with the distribution of species in solution. Such calculations are needed to drive further investigations of artificial blood-substituting systems.

8.
Eur J Med Chem ; 46(12): 5917-26, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22047642

RESUMO

Here we present the synthesis of the new Ni(II) complexes with chelating ligands 1-benzothiazol-2-yl-3,5-dimethyl-1H-pyrazole (a), 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyrazole-4-carboxylic acid methyl ester (b) and 1-benzothiazol-2-yl-5-(2-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carboxylic acid methyl ester (c). These ligands a-c create solid complexes with Ni(II). The crystal and molecular structures of two complexes were determined by X-ray diffraction method. Thermal stability of two complexes with ligand c by TG/DTG and DSC methods were also shown. Cytotoxic activity of all the complexes against three tumour cell lines and to normal endothelial cells (HUVEC) was also estimated. Complexes with ligand c exhibited relatively high cytotoxic activity towards HL-60 and NALM-6 leukaemia cells and WM-115 melanoma cells. Cytotoxic effectiveness of one of these complexes against melanoma WM-115 cells was two times higher than that of cisplatin. The protonation constant log K=9.63 of ligand b corresponding to the phenol 2-hydroxy group has been determined in 10% (v/v) DMSO/water solution (25°C). The coordination modes (formation of two monomeric species: NiL and NiL(2)) in the complexes with Ni(II) are discussed for b on the basis of the potentiometric and UV/Vis data.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Níquel/química , Níquel/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quelantes/síntese química , Quelantes/química , Quelantes/farmacologia , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Neoplasias/tratamento farmacológico , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia
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