Search Results (5)

Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, (H₂O)MnTnHex-2-PyP⁵⁺ (MnHex) carrying long hexyl chains, is a lipophilic mimic of superoxide dismutase (SOD) and a redox-active drug candidate. MnHex crosses the blood–brain barrier, and improved neurologic outcome and decreased infarct size and inflammation in a rat middle cerebral artery occlusion (MCAO) ischemic stroke model. Yet, the dose and the therapeutic efficacy of Mn porphyrin were limited by an adverse effect of arterial hypotension. An equally lipophilic Fe analog, (OH)FeTnHex-2-PyP⁴⁺ (FeHex), is as redox-active and potent SOD mimic in vitro. With different coordination geometry of the metal site, FeHex has one hydroxo (OH) ligand (instead of water) bound to the Fe center in the axial position. It has ~2 orders of magnitude higher efficacy than MnHex in an SOD-deficient E. coli model of oxidative stress. In vivo, it does not cause arterial hypotension and is less toxic to mice. We thus evaluated FeHex versus MnHex in a rodent MCAO model. We first performed short- and long-term pharmacokinetics (PK) of both porphyrins in the plasma, brain, and liver of rats and mice. Given that damage to the brain during stroke occurs very rapidly, fast delivery of a sufficient dose of drug is important. Therefore, we aimed to demonstrate if, and how fast after reperfusion, Fe porphyrin reaches the brain relative to the Mn analog. A markedly different plasma half-life was found with FeHex (~23 h) than with MnHex (~1.4 h), which resulted in a more than 2-fold higher plasma exposure (AUC) in a 7-day twice-daily treatment of rats. The increased plasma half-life is explained by the much lower liver retention of FeHex than typically found in Mn analogs. In the brain, a 3-day mouse PK study showed similar levels of MnHex and FeHex. The same result was obtained in a 7-day rat PK study, despite the higher plasma exposure of FeHex. Importantly, in a short-term PK study with treatment starting 2 h post MCAO, both Fe- and Mn- analogs distributed at a higher level to the injured brain hemisphere, with a more pronounced effect observed with FeHex. While a 3-day mouse MCAO study suggested the efficacy of Fe porphyrin, in a 7-day rat MCAO study, Mn-, but not Fe porphyrin, was efficacious. The observed lack of FeHex efficacy was discussed in terms of significant differences in the chemistry of Fe vs. the Mn center of metalloporphyrin; relative to MnHex, FeHex has the propensity for axial coordination, which in vivo would preclude the reactivity of the Fe center towards small reactive species. Full article

Metalloporphyrins have attracted great attention in the potential application of biomimetic catalysis. Especially, they were widely investigated as green catalysts in the chemical oxidation of various hydrocarbons through the catalytic activation of molecular oxygen. The structural properties of active central metal ions were reported to play a decisive role in catalytic activity. However, those delicate structural changes are difficult to be experimentally captured or elucidated in detail. Herein, we explored the electronic structural properties of metalloporphyrins (metal porphyrin (PM^II, PM^IIICl)) and their corresponding catalytically active intermediates (metal(III)-peroxo(PM^III-O₂), metal(III)-hydroperoxo(PM^III-OH), and metal(IV)-oxo(PM^IV=O), (M=Fe, Mn, and Co)) through the density functional theory method. The ground states of these intermediates were determined based on the assessment of relative energy and the corresponding geometric structures of ground states also further confirmed the stability of energy. Furthermore, our analyses of Mulliken charges and frontier molecular orbitals revealed the potential catalytic behavior of reactive metalloporphyrin intermediates. Full article

Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. We hypothesized that targeting oxidative stress-induced inflammation with MnP would assuage liver complications and enhance insulin sensitivity and glucose tolerance in a high-fat diet (HFD)-induced mouse model of T2D. During 12 weeks of feeding, we saw significant improvements in weight, hepatic steatosis, and biomarkers of liver dysfunction with redox modulation by MnP treatment in HFD-fed mice. Additionally, MnP treatment improved insulin sensitivity and glucose tolerance, while reducing serum insulin and leptin levels. We attribute these effects to redox modulation and inhibition of hepatic NF-κB activation, resulting in diminished ROS and pro-inflammatory cytokine production. This study highlights the importance of controlling oxidative stress and secondary inflammation in obesity-mediated insulin resistance and T2D. Our data confirm the role of NF-κB-mediated inflammation in the development of T2D, and demonstrate the efficacy of MnP in preventing the progression to disease by specifically improving liver pathology and hepatic insulin resistance in obesity. Full article

The present work is concerned with the manganese complexes of 5,10,15,20-tetraphenylporphyrin and of 5,10,15,20-tetra(3-hydroxyphenyl)porphyrin, which were prepared by metallation of the corresponding porphyrin ligands, and the study of their spectroscopic and photophysical behavior under strongly acidic and alkaline conditions. The second objective was to obtain and study some new hybrid materials, with special optoelectronic and surface properties, by impregnation of silica gels obtained by one step acid and by two steps acid-base catalysis with these Mn-porphyrins. The resulting nanomaterials exhibited interesting bathochromic and hyperchromic effects of their second band in the emission spectra in comparison with the Mn-porphyrins and also they have distinct orientation of the aggregates on surfaces, as shown by AFM images, making them useful for applications in medicine, formulation of sensors and for environmental-friendly catalysts for photodegradation of organic compounds. Full article

An amperometric metronidazole (MTZ) sensor using a glycosylated metalloporphyrin as a recognition element, which was incorporated in a carbon paste electrode, is reported. For the preparation of a MTZ-sensitive active material, 5, 10, 15, 20-tetrakis [2-(2, 3, 4, 6-tetraacetyl-β-D-glucopyranosyl)-1-O-phenyl]porphyrin (T(oglu) PPH2) and its Mn(III) complex MnT(o-glu)PPCl were synthesized from the reaction of pyrrole with ortho-acetylglycosylated benzaldehyde by Lindsay’s method. The MnT(oglu) PPCl-modified electrode showed excellent selectivity toward MTZ with respect to a number of interferents and exhibited stable response. The calibration graph obtained with the proposed sensor was linear over the range of 2.9×10^-3-5.8×10^-8 M/L, with a detection limit of 5.8×10^-8 M/L for MTZ. Cyclic voltammetric measurements indicated that MnT(oglu) PPCl included in graphite-epoxy resin matrices could efficiently mediate electron transfer from the base electrode to MTZ causing a decrease of reduction potential for MTZ detection. The sensor could be regenerated by simply polishing with an alumina paper, with an excellent reproducibility (RSD=1.6%). The experimental conditions such as pH and applied working potential were optimized. The prepared sensor is applied for the determination of MTZ in pharmaceutical preparations and the results agreed with the values obtained by the pharmacopoeia method. Full article