Free Radical Synthesis Research Articles

Oxidative stress in Phenylketonuria: future directions

Phenylketonuria represents the most prevalent inborn error of amino acid metabolism. In early diagnosed patients adequate and continued dietary treatment results in a good neurologic outcome. Natural protein and phenylalanine-restricted diet, even if rich in fruits and vegetables, represents a serious risk for nutritional deficiencies, albeit universally accepted. In the last few years, a growing number of reports have been describing oxidative stress as a concern in phenylketonuric patients. The diet itself includes good sources of dietary antioxidants (phytochemicals, some vitamins and minerals) but also a risk factor for some deficiencies (selenium, zinc, ubiquinone-10 and L-carnitine). Additionally, the extreme stringency of the diet may impose a reduced synthesis of endogenous antioxidants (like ubiquinone-10 and glutathione). Furthermore, increased phenylalanine levels, and its metabolites, may enhance the endogenous synthesis of reactive species and free radicals and/or interfere with the endogenous synthesis of enzymatic antioxidants (like glutathione peroxidase). Therefore, oxidative stress will probably increase, mainly in late diagnosed patients or in those with bad metabolic control. Considering the known association between oxidative stress, obesity and cardiovascular disease, it seems advisable to look further to the impact of oxidative stress on body macromolecules and structures (like lipoprotein oxidation), especially in phenylketonuric patients with late diagnosis or bad metabolic control, in order to prevent future increased risks. Recommendations for PKU patient's clinical follow-up improvement and educational goals are included.

Towards Streamlining Conventional Radical Reactions Through Development of β-cyclodextrin based Batch, Flow-Through and “Teabag” Prototype Molecular Reactors

β-cyclodextrin based Batch, Flow-Through and “Teabag” Prototype Molecular Reactors have been assembled and used in variety of conventional synthetically useful free radical transformations (Hydrogen Transfer Reactions, Radical Cascade Reactions and Mn(OAc)3 mediated cascade/oxidation reactions. Reactions proceeded smoothly in all cases in good to excellent yields at ambient temperature in aqueous and organic media. The advantages of newly assembled setup are ease of setup, recyclability of the β-cyclodextrin media, flexibility and scope of the transformations to be performed and ease of scale-up of methodology. Keywords: free radical synthesis, molecular reactors, flow through chemistry, tea-bag methodology, streamlining, β-cyclodextrins, Radical chemistry, batch reactors, prototype flow-through, “teabag” molecular reactors

ChemInform Abstract: The Frequently Overlooked Importance of Solvent in Free Radical Syntheses

AbstractReview: 57 refs.

Protective effects of tryptophan on neuro-inflammation in rats after administering lipopolysaccharide

Tryptophan (TRP), which plays an important role in immune system regulation, protein synthesis, serotonin (5-HT) and melatonin production, is a potent endogenous free radical scavenger and antioxidant. The aim of this work was to determine the efficacy of TRP in neuro-inflammation induced by systemic administration of lipopolysacharide (LPS, 20mg/kg) which promotes the synthesis of free radical (LPO: MDA and 4-HDA), and pro-inflammatory cytokine Interferon-γ (IFN-γ) in different brain regions (cerebral cortex and hippocampus) of rats. Experiments were performed on adult female, pregnant and lactating rats fed with a diet of TRP content (0.5mg/100g protein), cerebral cortex and hippocampus were evaluated for lipid peroxidation (LPO) products, nitrites, nitrates and plasmatic concentration of IFN-γ. LPO levels in LPS+TRP groups were significantly decreased than that obtained in the LPS group. However, there were no observed differences in plasmatic levels of nitrites and nitrates as well as IFN-γ, neither in the cerebral cortex or hippocampus. The TRP has protective effect in the oxidative damage in a model of endotoxic shock in the breading nurslings induced by the systemic administration of LPS, acting as a scavenger of free radicals. So, it can be proposed as an innocuous protector agent in the endotoxic shock process.

The frequently overlooked importance of solvent in free radical syntheses

This tutorial review is designed to dispel the myth, still believed by many synthetic organic chemists, that radical-based syntheses are free from significant solvent effects. However, many synthetically valuable radical reactions do exhibit large kinetic solvent effects. It is therefore important to select the solvent for any proposed radical synthesis with considerable care if good product yields are to be achieved.

ChemInform Abstract: Synthesis of Stable Free Radicals: A Novel Family of Oligopyridine Based Nitronyl-Nitroxide Biradicals.

Abstract Diformyl substituted pyridines (at the 2,5 and 2,6 positions), 2,2′-bipyridines (at the 4,4′, 5,5′, and 6,6′ positions), 3,6-di-(6-carboxyaldehyde-2-pyridyl)-pyridazine and 2,9-dicarboxyaldehyde-1,10-phenanthroline react with N,N′-dihydroxy-2,3-diamino-2,3-dimethylbutane to yield the bis-N,N′-dihydroxyimidazolidine. Mild oxidation afforded the corresponding nitronyl-nitroxide biradicals 1 to 7. These ligands are highly colored and form very stable transition metal complexes.

Effect of COX-2 inhibitor meloxicam against traumatic brain injury-induced biochemical, histopathological changes and blood–brain barrier permeability

Objective: The overproduction of reactive oxygen species and resultant damage to cellular proteins or lipids of cell membranes and DNA by free radicals are the underlying mechanisms of many neuropathologies. Cyclooxygenase-2 (COX-2) inhibitors have been suggested to be neuroprotective by reducing prostanoid and free radical synthesis, or by directing arachidonic acid metabolism through alternate pathways. This study investigated the putative neuroprotective effect of the COX-2 inhibitor, meloxicam, in a rat model of diffuse brain injury.Methods: Sprague–Dawley rats were subjected to traumatic brain injury with a weight-drop device using 300 g−1 m weight–height impact. The groups were: control, meloxicam (2 mg/kg, i.p.), trauma and trauma + meloxicam (2 mg/kg, i.p.). Forty-eight hours after the injury, neurological examination scores were measured, the animals were decapitated and brain tissues were taken. Brain edema and blood–brain barrier (BBB) permeability were evaluated by wet–dry weight method and Evans blue (EB) extravasation respectively. In brain tissues, malonedialdehyde, glutathione, myeloperoxidase and Na/K-ATPase levels were measured.Results: The neurological examination scores mildly increased in trauma groups 48 hours after the induction of trauma. Meloxicam treatment improved the altered neurological status. The trauma caused a significant increase in brain water content that was partially reversed by meloxicam. Meloxicam also reduced the EB extravasation indicating the preservation of the BBB integrity. Meloxicam treatment also significantly reduced the increase in malondialdehyde and myeloperoxidase levels and restored glutathione content of the brains that had been significantly increased after trauma.Conclusion: Meloxicam exerts neuroprotective effect by preserving BBB permeability and by reducing brain edema (probably by its anti-inflammatory properties) in the diffuse brain injury model.

Streamlining Organic Free Radical Synthesis through Modern Molecular Technology: from Polymer Supported Synthesis to Microreactors and Beyond

Increasing emphasis has been placed on producing synthetic organic compounds faster and more efficiently than can be produced using conventional methodology. It is often observed that tried and true methods for performing synthesis, work-up, and purification on individual or low number of reactions do not scale up well even to a modest level of parallel synthesis. As a result, novel methodologies or parallel and combinatorial chemical synthesis continues be developed at a rapid pace. In general, the specific structure of the target molecule(s) guides the selection of the synthetic methodology (e.g., solid or solution phase) used in given reaction sequence. The phrase “Streamline Organic Synthesis” has been coined as descriptor for methodology that lends itself to efficient application to parallel organic synthesis. The advantages of the past few years in microreactors have demonstrated the miniaturizing of chemistry that significant advantage with respect to cost, safety, throughput, kinetics and scale-up. The use of chemical microreactors for broad spectrum of important chemical transformation has illustrated the utility and benefits for both chemical discovery and development of novel and unique applications. The main objective of this tutorial review article is to bring together two important topics of synthetic free radical chemistry and its applications and advancements to “Streamline Organic Synthesis” on the interface of conventional and alternative materials, such as polymer supported reagents/reactants, use of ultraporous materials (PolyHIPEs) as well as continuous microflow systems of natural zeolite and commercial man-made microreactors. Keywords: Polymer, Free Radical, Microreactors, Streamline, Organic Synthesis

ESI and MALDI mass spectrometry of large POSS oligomers

A series of Polyhedral Oligomeric Silsesquioxane (POSS) propylmethacrylate (PMA) and styryl oligomers were prepared from POSS monomers, R 7R'Si 8O 12, containing 1 functional R’ group for polymerization and 7 inert R-groups where R = isobutyl (i-butyl), phenyl (Ph), cyclohexyl (Cy) or cyclopentyl (Cp). Both standard atom transfer radical polymerization (ATRP) and free radical syntheses, the latter employing azoisobutylnitrile as the free radical initiator were used in the syntheses. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectra were obtained in a new matrix, 4,4′-dihydroxyoctafluoroazobenzene which was especially designed for insoluble and intractable polymeric materials. Well-resolved series of oligomers were observed out to n = ∼13 in both the linear and reflectron modes. Major peaks were assigned based on tandem mass spectrometry (MSMS) fragmentation patterns to give a consistent explanation of the observed spectra. In all cases, ionization of the ATRP products gave cationized parent ions in which the terminal Br atom was replaced by hydrogen. Additional observed peaks were due to loss of POSS side chains from the oligomer backbone. The free radical products were terminated with either one or two isobutylnitrile groups. Electrospray ionization (ESI) spectra were more complex than the MALDI-TOF but showed either identical parent ions or closely related hydroxylated parent ions.

H. pylori and mitochondrial changes in epithelial cells: The role of oxidative stress

Infection with H. pylori plays a role in the pathogenesis of gastritis, peptic ulcer, gastric carcinoma, and gastric lymphoma, but mechanisms leading to the various clinical manifestations remain obscure and are the primary focus of research in this field. Proliferation and apoptosis are essential in the maintenance of gastric tissue homeostasis, and changes seen in their balance may condition gastric mucosal changes during infection. Thus, excessive apoptosis or proliferation inhibition will result in cell mass loss, which is observed in gastric ulcers. On the other hand, accelerated epithelial cell turnover is characteristic of carcinogenic mucosas. There is also scientific evidence that demonstrates an association between H. pylori infection and exacerbated synthesis of free radicals, the latter being well known as a primary cause of cell death. A thorough review of the literature and the results of our experimental research lead to conclude that H. pylori-induced oxidative stress activates the intrinsic pathway of apoptosis. Structural and functional changes caused by this process on mitochondrial organelles lie at the origin of gastric mucosal toxicity, and lead to the development of the various manifestations associated with this infection. Based on these data we suggest that therapy with antioxidants should prove beneficial for the clinical management of patients with H. pylori infection.

Synthesis and electron paramagnetic resonance study of a nitroxide free radical covalently bonded on aminopropyl-silica gel

A solid spin-labeled material was obtained starting from 2-chloro-3,5-dinitro- N-(4-(2,2,6,6-tetramethyl-piperidine-1-oxyl)-benzamide) and aminopropyl-silica gel. Stability tests showed that even after several months the spin-labeled material had the same properties as immediately after synthesis. EPR properties of the TEMPO-derivatized silica were studied as a function of solvent polarity and temperature. Rotational correlation times were calculated from EPR spectra and correlated with solvent characteristics and temperature. Polar solvents induce a fast motion of the spin-label, clearly seen in the EPR spectra by the apparition of the well-known TEMPO radical triplet. The solid spin-labeled (dry) sample showed a high interspin interaction, which can be disrupted not only by different (liquid) solvents, but also by absorption of different solids, like cyclodextrins, dendrimers or polyethyleneglycols. Also, changes induced by the temperature were studied in the case of toluene wet sample. From 150 to 370 K, the spectrum is changing from a slow motion spectrum type to a fast motion regime. The preparative procedures to obtain the spin-labeled silica as well as some of its parameters are described.

Acute effects of haemodialysis on biochemical modulators of endothelial function

To assess the acute effects of haemodialysis (HD) on biochemical factors modulating endothelial function. Academic medical centre. Forty patients (age 63.5 +/- 2.2 years, mean +/- SEM) undergoing HD. Folic acid (F), homocysteine (tHcy), asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (CRP) and malondialdehyde (MDA) were measured pre-HD, 1 h after commencing HD and within the last hour of HD (end-HD). Endothelium-dependent and -independent vasodilatation were measured by applanation tonometry (changes in augmentation index, AIx, postinhaled salbutamol and postsublingual nitroglycerin) in conjunction with biochemical measurements. Marked reductions in serum F (616 +/- 73 vs. 273 +/- 30 nmol L(-1), P < 0.001), tHcy (16.3 +/- 0.7 vs. 11.2 +/- 0.5 micromol L(-1), P < 0.001) and ADMA (0.64 +/- 0.02 vs. 0.47 +/- 0.02 micromol L(-1), P < 0.001) occurred end-HD, whereas CRP and MDA levels did not significantly change. There was no significant change in endothelium-dependent vasodilatation, whereas endothelium-independent vasodilatation improved end-HD (-23.1 +/- 1.9 vs. -17.3 +/- 1.3%, P = 0.018). Regression analysis showed that both higher ADMA (P = 0.029) and lower F levels (P = 0.040) end-HD were determinants of reduced endothelium-dependent vasodilatation end-HD (R(2) = 0.23). HD is associated with significant reductions in F, tHcy and ADMA serum concentrations. The lack of significant effects of HD on endothelium-dependent vasodilatation could be secondary to the concomitant loss of factors either enhancing (F) or impairing (ADMA) endothelial function.

Physiopathologie de la sclérodermie systémique: état des lieux sur une affection aux multiples facettes

Systemic sclerosis is a rare disease characterized by vascular hyperreactivity and collagen deposition. Endothelial cell, fibroblast and lymphocyte abnormalities have been reported in systemic sclerosis. Fibroblast dysfunction is characterized by uncontrolled activation of the transforming growth factor-beta (TGF-beta) pathway and excess synthesis of both connective tissue growth factor (CTGF) and free radicals. These promote the accumulation of extracellular matrix. Endothelial cells produce excess quantities of endothelin 1 and inducible NO synthase. They also undergo early apoptosis. Oxidative stress appears to play a major role in disease progression. Increased levels of interleukin 4, a profibrotic cytokine, have been detected in plasma and skin of systemic sclerosis patients. Autoantibodies are detectable in the serum of almost all systemic sclerosis patients. Some are directed against well-identified ubiquitous nuclear proteins and have no demonstrated pathogenic role. Other autoantibodies bind to endothelial cells or fibroblasts and may have a pathogenic role.

Review of In Vivo Static and ELF Electric Fields Studies Performed at Gazi Biophysics Department

In vivo effects of Static Electric and ELF Magnetic and Electric fields have been carried out for more than 20 years in the Bioelectromagnetic Laboratory at the Biophysics Department of the Medical Faculty of Gazi University. In this article, the results of in vivo ELF Electric field studies are presented as a review.Static and 50 Hz ELF (Extremely Low Frequency) Electric (E) fields effects on free radical synthesis, antioxidant enzyme level, and collagen synthesis were analyzed on tissues of guinea pigs, such as brain, liver, lung, kidney, spleen, testis, and plasma.Animals were exposed to static and ELF electric fields with intensities ranging from 0.3 kV/m to 1.9 kV/m in vertical and horizontal directions. Exposure periods were 1, 3, 5, 7, and 10 days. Electric fields were generated from a specially designed parallel plate capacitor system. The results indicate that the effects of electric fields on the tissues studied depend significantly on the type and magnitude of electric field and exposure period.

Hyperbranched (Co)Polymers via Free Radical Polymerization of Polymerizable Barton Esters

The free radical synthesis of hyperbranched polymer architectures using a thermally and photochemically labile styrenic Barton ester monomer of the AB type, designed to combine the functions of initiator, monomer, and branch unit, is described. Highly branched poly(styrene)s were obtained in one step by copolymerizing this monomer with styrene. Residual Barton ester functionality in the hyperbranched products enabled their use as macroinitiators in subsequent polymerizations. Linear PMMA was thus successfully grafted from the hyperbranched poly(styrene) cores. This approach is a versatile route for the synthesis of hyperbranched homopolymers and copolymers via free radical polymerization chemistry.

An appreciation of free radical chemistry part 5: Free radicals in organic synthesis

Free radical synthetic methodology has grown by leaps and bounds in just about two decades. The limit to which the scope of free radical synthesis can go is restricted only by the imagination of the synthetic chemist. It greatly simplifies a synthetic sequence, makes use of readily available, relatively inexpensive reactants and reagen-ts; the transformations are selective, involve fewer steps, the yields are good, the reaction conditions are mild, etc. Therefore, such free radical reactions truly qualify to be called “Green Chemistry”.

Free Radical Synthesis of Benzofused Tricyclic β‐Lactams by Intramolecular Cyclization of 2‐Azetidinone‐Tethered Haloarenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Free radical synthesis of benzofused tricyclic β-lactams by intramolecular cyclization of 2-azetidinone-tethered haloarenes

o-Halogenophenyl- and o-halogenobenzyl-4-alkenyl-β-lactams can be prepared both in the racemic form and in optically pure form using the ketene–imine cyclization. These 2-azetidinone-tethered haloarenes were used for the regio- and stereoselective preparation of benzofused tricyclic β-lactams including benzocarbapenems and benzocarbacephems via intramolecular aryl radical cyclisation.

Oxidative stress and preeclampsia: rationale for antioxidant clinical trials.

Preeclampsia remains a frequent and potentially dangerous complication of pregnancy. The cause remains largely unknown, but oxidative stress and a generalized inflammatory state are features of the maternal syndrome. The placenta appears to be the principal source of free radical synthesis but maternal leukocytes and the maternal endothelium are also likely contributors. Recent reports have suggested an important role for placental trophoblast NAD(P)H oxidase in free radical generation in preeclampsia. The antioxidant vitamin E is now known to have multiple actions in addition to prevention of lipid peroxidation (ie, inhibition of NAD(P)H oxidase activation and the inflammatory response). In view of the abnormally low plasma vitamin C concentrations in preeclampsia, a combination of vitamins C and E is a promising prophylactic strategy for prevention of preeclampsia. Several multicenter randomized clinical trials are now underway. The potential use of antioxidants and the recognized, albeit modest, benefit of low-dose aspirin prophylaxis have heightened the need for a reliable predictive test for preeclampsia. A combination test involving several relevant biomarkers is likely to provide the best predictive potential.

Antioxidant vitamins and blood pressure.

Synthesis of free radicals might play a role in the cellular process of atherosclerosis. This process can be stopped by antioxidants such as beta-carotene, vitamin C, or vitamin E, which will inactivate the effects of free radicals. Although antioxidant vitamins have not been proven to prevent cardiovascular diseases through the modulation of lipid peroxidation, it has been suggested that peroxidation might be a pathway to such prevention, mediated through the effects of antioxidants on blood pressure (BP) and arterial stiffness. Several observational epidemiologic studies and some clinical trials have suggested an inverse association between dietary intake of fruits and vegetables, and BP. An inverse link between serum levels of vitamin C and BP has also been determined in observational epidemiologic settings. Some relations between other antioxidant vitamins (retinol and beta-carotene) and BP are reported; they confer the same inverse association. However, results from clinical trials testing the effect of a single, or a combination of antioxidants at high pharmacologic doses have revealed inconsistent BP findings. So far, no evidence confirms that oral antioxidant supplementation is effective in preventing or treating high BP. Additional large studies should be conducted to determine the effect on BP of antioxidant supplementation at nutritional doses.