Download (.pdf) Microwave assisted radical organic syntheses
by Roy McBurney
Applications of microwave (MW)-assistance to radical-mediated organic preparations and procedures are reviewed.... more Applications of microwave (MW)-assistance to radical-mediated organic preparations and procedures are reviewed. Radical additions and cyclisations onto a wide range of acceptors benefited from the technique, as did organic halide reductions by tin hydrides and numerous cascade and sequential processes. Reaction times of chain processes initiated by AIBN were, in several cases, reduced to a few minutes. Regioselectivity in radical additions and ring closures was normally maintained under MW conditions, although stereoselectivities were usually poorer. MW methods have been developed for generation of C-, N-, O-, S- and P-centred radicals. As a result of this a notable number and diversity of heterocycles have been accessed. MW-methods have opened up several new and innocuous alternatives to toxic organotin reagents. Alkoxyamines smoothly release C-centred radicals and oxime ethers provide a variety of iminyl radicals on MW heating. In addition, several types of organo-element and organometallic precursors have yielded novel C-centred and hetero-radicals. To date applications of MW-assistance to homolytic processes are comparatively limited, but it is clear the alliance of the two holds a lot of promise.
The Computed EPR Parameters of the Tryptophan Radical: the Hyperfine Interaction Constants
Protein bound tryptophan free radicals play an important role in many enzymatic reactions. Identifying the sites of... more Protein bound tryptophan free radicals play an important role in many enzymatic reactions. Identifying the sites of free radical formation is essential for understanding the mechanism of catalysis. This work reports and analyses previously calculated electron paramagnetic resonance parameters of the tryptophan neutral radical focusing on the hyperfine interaction constants in relation to Mulliken atomic spin density distributions. This is investigated at a spectrum of twelve tryptophan indole ring rotation angles along with variable strengths of hydrogen bonding to the indole nitrogen atom. The hyperfine interaction constants are computed by density functional theory calculation at the B3LYP functional level for a tryptophan radical of optimised geometry. The hyperfine interaction depends on the indole ring rotation angle. This effect is greatly pronounced for the methylene protons of the Cα atom, due to the high unpaired electron spin density on the adjacent C3. The maximal hyperfine interaction of the methylene protons occurs at angles where the protons are perpendicular to the plane of the ring. The hyperfine interaction of the nitrogen atom is most significantly affected by the change of hydrogen bonding strength where a stronger hydrogen bonding strength reduces the hyperfine interaction on the ring atoms. These findings provide a basis for a new method of determining the location of a protein based tryptophan radical in proteins and enzymes. These data may well be used to derive a method of calculating electron paramagnetic resonance parameters of tryptophan radicals with sufficient accuracy to accurately simulate experimental electron paramagnetic resonance spectra.
The effect of AR inhibition by JMC-2004 on hyperglycemia-induced endothelial dysfunction
Authors: 7. Papežíková I., Pekarová M., Chatzopoulou M., Nicolaou I., Demopoulos V., Kubala L., Lojek A
Citation: Neuroendocrinol. Lett. 29 (5): 775-778 (2008)
OBJECTIVES: An increased glucose utilization by aldose reductase (ALR-2) has been implicated in the pathogenesis of... more OBJECTIVES: An increased glucose utilization by aldose reductase (ALR-2) has been implicated in the pathogenesis of diabetic vascular complications. In this process, several mechanisms are involved, including the depletion of cofactors required for the action of antioxidant enzymes or endothelial NO synthase. In this study, the effect of a novel ALR-2 inhibitor JMC-2004 on hyperglycemia-induced endothelial dysfunction was studied. METHODS: Bovine aortic endothelial cells (BAEC) were treated with glucose (30 mM), JMC-2004 (0.01mM), or glucose and JMC-2004 for 24 h. The cells were then stimulated with calcium ionophore A23187 after which NO production was measured electrochemically using a porphyrine-coated carbon NO electrode. Nitrite concentrations were determined in the cell supernatants. The peroxyl and hydroxyl radical-scavenging activity of JMC-2004 was measured with luminol-enhanced chemiluminescence. The expression of eNOS was determined by Western blotting. JMC-2004 IC50 for ALR-2 was determined colorimetrically with D-glyceraldehyde as a substrate. RESULTS: Incubating the cells with 30 mM glucose strongly diminished A23187- induced NO production. Treatment with JMC-2004 restored NO production by 40% without affecting eNOS expression. This effect was probably antioxidantindependent, since JMC-2004 did not have any antioxidant capacity. JMC-2004 exerted high selectivity towards ALR-2. CONCLUSIONS: ALR-2 inhibition with JMC-2004 was able to abolish hyperglycemia- induced endothelial dysfunction in bovine aortic endothelial cells.
42 views
RAGE: A MULTI-LIGAND RECEPTOR UNVEILING NOVEL INSIGHTS IN HEALTH AND DISEASE
Authors: Alexiou, P.*; Chatzopoulou, M.; Pegklidou, K.; Demopoulos, V.J.*;
Citation: Curr. Med. Chem. 2010, 17, 2232-2252
Receptor for advanced glycation end products (RAGE), expressed in a range of cell types such as endothelial cells,... more
Receptor for advanced glycation end products (RAGE), expressed in a range of cell types such as endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons, is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Their repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterin and S100/calgranulins. This variety of ligands allows RAGE to be implicated in a wide spectrum of pathological conditions such as diabetes and its complications, Alzheimer's disease, cancer and inflammation, processes via numerous cascades of signaling pathways. Additionally, over the last decade, extended studies have also been conducted as regards genetic
polymorphisms in the RAGE gene and their possible impacts on the functional activity of the receptor.
It becomes obvious that studies on the RAGE pathway is not at all an easy task and the question of whether blockade of RAGE is a feasible and safe strategy for prevention/stabilization of chronic diseases is of high interest for the pharmaceutical community.
In this review the biology of RAGE and the triggered signaling cascades involved, as well as its role in health and disease will be presented through an intellectual journey with a vision to the research hallmarks in this area over the last decades. Additionally, its potentiality as an attractive pharmacotherapeutic target will be explored by pointing out the pharmacotherapeutic agents that have already been developed for RAGE blockage and are under clinical trials.
Two Mechanisms for Toxic Effects of Hydroxylamines In Human Erythrocytes: Involvement of Free Radicals and Risk of Potentiation
by Chris Evelo
C T Evelo, A A Spooren, R A Bisschops, L G Baars, J M Neis (1998) Two mechanisms for toxic effects of hydroxylamines in human erythrocytes: involvement of free radicals and risk of potentiation. Blood Cells Mol Dis 24: 3. 280-295 Sep
The toxic potency of three industrially used hydroxylamines was studied in human blood cells in vitro. The parent... more The toxic potency of three industrially used hydroxylamines was studied in human blood cells in vitro. The parent compound hydroxylamine and the O-ethyl derivative gave very similar results. Both compounds induced a high degree of methemoglobin formation and glutathione depletion. Cytotoxicity was visible as Heinz body formation and hemolysis. High levels of lipid peroxidation occurred, in this respect O-ethyl hydroxylamine was more active than hydroxylamine. In contrast H2O2 induced lipid peroxidation was lowered after O-ethyl hydroxylamine or hydroxylamine treatment, this is explained by the ferrohemoglobin dependence of H2O2 induced radical species formation. Glutathione S-transferase (GST) and NADPH methemoglobin reductase (NADPH-HbR) activities were also impaired, probably as a result of the radical stress occurring. The riboflavin availability was decreased. Other enzyme activities glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PDH), glucose phosphate isomerase and NADH methemoglobin reductase, were not or only slightly impaired by hydroxylamine or O-ethyl hydroxylamine treatment. A different scheme of reactivity was found for N,O-dimethyl hydroxylamine. This compound gave much less methemoglobin formation and no hemolysis or Heinz body formation at concentrations up to and including 7 mM. Lipid peroxidase induction was not detectable, but could be induced by subsequent H2O2 treatment. GST and NADPH-HbR activities and riboflavin availability were not decreased. On the other hand GR and G6PDH activities were inhibited. These results combined with literature data indicate the existence of two different routes of hematotoxicity induced by hydroxylamines. Hydroxylamine as well as O-alkylated derivatives primarily induce methemoglobin, a process involving radical formation. The radical stress occurring is probably responsible for most other effects. N-alkylated species like N,O-dimethyl hydroxylamine primarily lead to inhibition of the protective enzymes G6PDH and GR. Since these enzymes play a key role in the protection of erythrocytes against oxidative stress a risk of potentiation during mixed exposure does exist.