The behaviour of three vanadium(V) systems, namely the pyridinone (V
V-dmpp), the salicylaldehyde (V
V-salDPA) and the pyrimidinone (V
V-MHCPE) complexes, is studied in aqueous solutions, under ...aerobic and physiological conditions using
51V NMR, EPR and UV–Visible (UV–Vis) spectroscopies. The speciations for the V
V-dmpp and V
V-salDPA have been previously reported. In this work, the system V
V-MHCPE is studied by pH-potentiometry and
51V NMR. The results indicate that, at pH ca. 7, the main species present are (V
VO
2)L
2 and (V
VO
2)LH
−1 (L
=
MHCPE
−) and hydrolysis products, similar to those observed in aqueous solutions of V
V-dmpp. The latter species is protonated as the pH decreases, originating (V
VO
2)L and (V
VO
2)LH. All the V
V-species studied are stable in aqueous media with different compositions and at physiological pH, including the cell culture medium. The compounds were screened for their potential cytotoxic activity in two different cell lines. The toxic effects were found to be incubation time and concentration dependent and specific for each compound and type of cells. The HeLa tumor cells seem to be more sensitive to drug effects than the 3T3-L1 fibroblasts. According to the IC
50 values and the results on reversibility to drug effects, the V
V-species resulting from the V
V-MHCPE system show higher toxicity in the tumor cells than in non-tumor cells, which may indicate potential antitumor activity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In this work we report biochemical
ex vivo studies with a vanadium compound containing a pyridinone ligand, the bis(1,2-dimethyl-3-hydroxy-4-pyridinonate)oxovanadium (IV), V
IVO(dmpp)
2, which has ...shown to have promising antidiabetic activity. The experiments were carried out on primary adipocytes of 6–8
week old Wistar rats. Insulin-stimulated glucose uptake studies were performed using a radioactive assay by measuring the (U)–
14C–glucose taken up by the isolated adipocytes for 30
min. Adipocytes were incubated with and without insulin and in the presence and absence of different concentrations of V
IVO(dmpp)
2 (100–500
μM) for 45
min. We observed that in a nontoxic concentration, as demonstrated by the Alamar Blue test, V
IVO(dmpp)
2 significantly increases glucose uptake, in the absence of insulin, by 5-folds higher than basal, and it has a significant inhibitory effect of 78% on free fatty acid release in isolated adipocytes from normal rats. We also demonstrated that it promotes the phosphorylation of Akt1, a key protein in the insulin signaling cascade. These results were compared with those obtained with another vanadium compound reported in the literature, with a similar structure, the bis(maltolato)oxovanadium (IV) (BMOV), which is now in clinical trials. Our
ex vivo results clearly indicate that V
IVO(dmpp)
2 is a good candidate to be a promising drug for the treatment of diabetes and other metabolic disorders.
The vanadium compound bis(1,2-dimethyl-3-hydroxy-4pyridinonate)oxovanadium(IV), V
IVO(dmpp)
2, has shown, through
ex vivo studies with isolated adipoytes, to have promising antidiabetic activity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The Schiff base N,N′‐ethylenebis(pyridoxylideneiminato) (H2pyr2en, 1) was synthesized by reaction of pyridoxal with ethylenediamine; reduction of H2pyr2en with NaBH4 yielded the reduced Schiff base ...N,N′‐ethylenebis(pyridoxylaminato) (H2Rpyr2en, 2); their crystal structures were determined by X‐ray diffraction. The totally protonated forms of 1 and 2 correspond to H6L4+, and all protonation constants were determined by pH‐potentiometric and 1H NMR titrations. Several vanadium(IV) and vanadium(V) complexes of these and other related ligands were prepared and characterized in solution and in the solid state. The X‐ray crystal structure of VVO2(HRpyr2en) shows the metal in a distorted octahedral geometry, with the ligand coordinated through the N‐amine and O‐phenolato moieties, with one of the pyridine‐N atoms protonated. Crystals of (VVO2)2(pyren)2⋅2 H2O were obtained from solutions containing H2pyr2en and oxovanadium(IV), where Hpyren is the “half” Schiff base of pyridoxal and ethylenediamine. The complexation of VIVO2+ and VVO2+ with H2pyr2en, H2Rpyr2en and pyridoxamine in aqueous solution were studied by pH‐potentiometry, UV/Vis absorption spectrophotometry, as well as by EPR spectroscopy for the VIVO systems and 1H and 51V NMR spectroscopy for the VVO2 systems. Very significant differences in the metal‐binding abilities of the ligands were found. Both 1 and 2 act as tetradentate ligands. H2Rpyr2en is stable to hydrolysis and several isomers form in solution, namely cis–trans type complexes with VIVO, and α‐cis‐ and β‐cis‐type complexes with VVO2. The pyridinium‐N atoms of the pyridoxal rings do not take part in the coordination but are involved in acid–base reactions that affect the number, type, and relative amount of the isomers of the VIVO–H2Rpyr2en and VVO2–H2Rpyr2en complexes present in solution. DFT calculations were carried out and support the formation and identification of the isomers detected by EPR or NMR spectroscopy, and the strong equatorial and axial binding of the O‐phenolato in VIVO and VVO2 complexes. Moreover, the DFT calculations done for the VIVO(H2Rpyr2en) system indicate that for almost all complexes the presence of a sixth equatorial or axial H2O ligand leads to much more stable compounds.
Vanadium complexes of Schiff‐base and reduced‐Schiff‐base ligands derived from the reaction of pyridoxal and ethylenediamine are remarkable examples of the complexity of the types of isomers that may form in solutions containing VIVO and VVO2 complexes (see picture for the NMR spectra).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Double quantum and triple quantum filtered
23
Na nuclear magnetic resonance techniques were used to characterise in detail the isotropic and anisotropic binding and dynamics of intra- and ...extracellular Na
+
in different cellular systems, in the absence and presence of Li
+
. The kinetics of Li
+
influx by different cell types was evaluated. At steady state, astrocytes accumulated more Li
+
than red blood cells (RBCs), while a higher intracellular Li
+
concentration was found in chromaffin than in SH-SY5Y cells. Anisotropic and isotropic motions were detected for extracellular Na
+
in all cellular systems studied. Isotropic intracellular Na
+
motions were observed in all types of cells, while anisotropic Na
+
motions in the intracellular compartment were only detected in RBCs.
23
Na triple quantum signal efficiency for intracellular Na
+
was SH-SY5Y > chromaffin > RBCs, while the reverse order was observed for the extracellular ions.
23
Na double quantum signal efficiency for intracellular Na
+
was non-zero only in RBCs, and for extracellular Na
+
the order RBCs > chromaffin > SH-SY5Y cells was observed. Li
+
loading generally decreased intracellular Na
+
isotropic movements in the cells, except for astrocytes incubated with a low Li
+
concentration and increased anisotropic intracellular Na
+
movements in RBCs. Li
+
effects on the extracellular signals were more complex, reflecting Li
+
/Na
+
competition for isotropic and anisotropic binding sites at the extracellular surface of cell membranes and also at the surface of the gel used for cell immobilisation. These results are relevant and contribute to the interpretation of the in vivo pharmacokinetics and sites of Li
+
action.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The binding of the VV oxidation products of two vanadium(IV) compounds, VO(dmpp)2 and VO(maltolato)2, which have shown promising anti‐diabetic properties, to human serum albumin (HSA) in aqueous ...aerobic solution has been studied by 1H saturation transfer difference (STD) NMR spectroscopy and computational docking studies. Group epitope mapping and docking simulations indicate a preference of HSA binding to the 1:1 VO2(dmpp)(OH)(H2O)– and 1:2 VO2(maltol)2– vanadium(V) species. By using known HSA binders, competition NMR experiments revealed that both complexes preferentially bind to drug site I. Docking simulations carried out with HADDOCK together with restraints derived from the STD results led to three‐dimensional models that are in agreement with the NMR spectroscopic data, providing useful information on molecular interaction modes. These results indicate that the combination of STD NMR and data‐driven docking is a good tool for elucidating the interactions in protein–vanadium compounds and thus for clarifying the mechanism of drug delivery as vanadium compounds have shown potential therapeutic properties.
1H STD NMR analysis complemented by HADDOCK studies have revealed that the VO2(dmpp)(H2O)(OH)– species, resulting from the oxidation of the potential insulin mimetic VO(dmpp)2, binds preferentially to HSA site I. These findings corroborate the involvement of this serum protein in the transport of vanadium species in the blood stream and their delivery to target cells.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective:
The mood stabilizing drugs lithium, carbamazepine and valproate modulate brain adenosine monophosphate (cAMP) levels, which are assumed to be elevated in bipolar disorder patients. The ...aim of this work was to investigate how these three mood stabilizing agents affect the regulation of cAMP levels by dopamine D
2
‐like receptors
in vitro
in rat cortical neurons in culture and
in vivo
in the rat prefrontal cortex.
Methods:
The production of cAMP was measured in the cultured cortical neurons or in microdialysis samples collected from the prefrontal cortex of freely moving rats using the 8‐
3
H and
125
I radioimmunoassay kits.
Results:
In vitro
and
in vivo
data showed that the treatment with the mood stabilizing drugs had no effect on basal cAMP levels
in vitro
, but had differential effects
in vivo
. Direct stimulation of adenylate cyclase (AC) with forskolin increased cAMP levels both
in vitro
and
in vivo
, and this effect was significantly inhibited by all three mood stabilizers. Activation of dopamine D
2
‐like receptors with quinpirole partially inhibited forskolin‐induced increase in cAMP in untreated cultures, but no effect was observed in cortical neuron cultures treated with the mood stabilizing drugs. Similar results were obtained by chronic treatment with lithium and valproate in the prefrontal cortex
in vivo
. However, surprisingly, in carbamazepine‐treated rats the activation of dopamine D
2
‐like receptors enhanced the responsiveness of AC to subsequent activation by forskolin, possibly as a consequence of chronic inhibition of the activity of the enzyme.
Conclusions:
It was shown that each of these drugs affects basal‐ and forskolin‐evoked cAMP levels in a distinct way, resulting in differential responses to dopamine D
2
‐like receptors activation.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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•Mn(III)-porphyrins are promising alternatives for Gd-based MRI contrast agents.•Their relaxivities are higher at clinically most applied magnetic fields (0.5–1.5 T).•Pharmacokinetics ...and toxicity are tunable by substituents at the porphyrin skeleton.•Accumulation of Mn(III) porphyrins in tumors is ideal for MRI-guided therapies.•Ester derivatives are very promising cell-tracking contrast agents.
Mn(III) porphyrins have great potential as Gd-free MRI contrast agents because both the cation and the ligand have interesting properties. The redox properties of the Mn(III)-ion can be exploited for the preparation of reactive oxygen species for therapy. Moreover, the porphyrin ligand allows these complexes to have a high affinity for tumor tissues. The inherent properties of the porphyrin ligands make these systems attractive for photothermal, photodynamic, and sonodynamic therapies. Therefore, these systems are attractive for the development of theranostics for MRI-guided therapy. For the magnetic field strengths at which most clinical MRI machines operate at present (0.5–1.5 T), the longitudinal relativity of low-molecular-weight complexes is even higher than that of the classical Gd-based contrast agents. This review gives an overview of the developments in the field of Mn(III) porphyrin contrast agents during the last 30 years.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Metal-based complexes can provide relaxation and paraCEST redox responsive probes.•Some ligand-based and metal-based T1 and paraCEST redox probes work in small animals.•Mn-based nanoparticles - have ...a strong redox-active relaxation response in animals.•Ratiometric methods can provide quantitative redox evaluation of cells in vitro.
Given their potential in a better characterization and diagnosis of major pathologies like cancer or chronic inflammation, redox-activated Magnetic Resonance Imaging (MRI) probes have recently attracted much interest from chemists. Such redox responsive probes are capable of reporting on specific biomarkers that are related to tissue redox potential disruption or hypoxia. Lately, this research area has experienced remarkable development, including redox-responsive metal complexes and nanoparticles. Here we critically review the progress with a specific focus on metal-based probes and some nanoparticle examples. We demonstrate, via representative cases, the different molecular mechanisms that can generate a redox-modulated MRI response. They can be based on the redox activity of either the ligand or the metal center, provided the different oxidation states of the metal ion are endowed with different magnetic properties. A particular emphasis is given to recent advances and to the imaging probes that have attained in vivo validation. In overall, we aim to provide the reader with a comprehensive view of how intracellular or extracellular redox buffer systems can be assessed by using MRI contrast agents based on lanthanide or transition metal ions using T1-weighted, T2-weighted, paraCEST 1H or 19F MRI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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