Investigation into the application of chiral organotin hydrides as enantioselective free radical reducing agents

Investigates the viability of selectively preparing molecules demonstrating the property of left or right "handedness" via free radical reactions. Experimental investigations suggested that a subtle interaction exists between the substituents of an organotin hydride and a target carbon radical during hydrogen atom transfer reactions.

Molecular and cellular aspects of copper transport in developing mammals

Copper is an essential trace element that requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects because of the ability of the metal ion to catalyze the formation of free radicals. The Cu-ATPases, ATP7A and ATP7B, play an important role in the physiological regulation of copper. Adequate supplies of copper are particularly important in developing animals, and in humans this is illustrated by mutations of ATP7A that cause the copper deficiency condition Menkes disease, which is fatal in early childhood. In contrast, mutations in ATP7B result in the genetic toxicosis, Wilson disease. We propose that the physiological regulation of copper is accomplished mainly by the intracellular copper-regulated trafficking of the Cu-ATPases. This process allows the overall copper status in the body to be maintained when levels of copper in the diet alter. A study of the defects in mouse models of Menkes and Wilson diseases has demonstrated that both ATPases play an important role in supplying copper to the developing fetus and neonate

Effects of purified herbal extract of Saliva miltiorrhiza on ischemic rat myocardium after acute myocardial infarction

In the current study, we compared purified Salvia miltiorrhiza extract (PSME) with Angiotensin-converting enzyme inhibitor, Ramipril, in in vitro experiments and also in vivo using animal model of myocardial infarction. PSME was found to have a significantly higher trolox equivalent antioxidant capacity which indicated a great capacity for scavenging free radicals. PSME could also prevent pyrogallo red bleaching and DNA damage.

After 2 weeks treatment with PSME or Ramipril, survival rates of rats with experimental myocardial infarction were marginally increased (68.2% and 71.4%) compared with saline (61.5%). The ratios of infarct size to left ventricular size in both PSME-and Ramipril-treated rats were significantly less than that in the saline-treated group. Activity of cardiac antioxidant enzyme superoxide dismutase (SOD) was significant higher while level of Thiobarbituric acid-reactive substances (TBARs) was lower in the PSME treated group. Purified and standardized Chinese herb could provide an alternative regimen for the prevention of ischemic heart disease.

Reducing the photocatalytic activity of zinc oxide quantum dots by surface modification

The use of zinc oxide (ZnO) nanoparticles as ultraviolet (UV) absorbers for many organic substrates is limited because of the high photocatalytic activity of ZnO. In this study, a facile and efficient technique for the preparation of a hybrid material of silica-coated ZnO nanoparticles was used to reduce the photocatalytic activity of ZnO. Monodispersed ZnO nanopartcles were prepared by wet chemistry and the particle surface was modified by tetraethylorthosilicate to form a silica coating via the Sto¨ ber method. ZnO samples, both before and after the coating process, were investigated by transmission electron microscopy, X-ray diffraction, dynamic light scanning, infrared, and UV-Vis absorption spectroscopy. The effect of the surface modification on the photocatalytic activity of ZnO was studied by monitoring the degradation of Rhodamine B caused by photo-generated free radicals. The results implied that the photo-generation of free-radicals was strongly quenched by the presence of silica on the particle surface.

The effect of dyes on photo-induced chemiluminescence emission from polymers

Weak photo-induced chemiluminescence (PICL) emission is observed when polymers are exposed to UVA or visible light. The presence of dyes can either increase PICL intensity via Type I photosensitisation which generates polymer free radicals, or reduce it via photo-protection. PICL studies on the eight Blue Wool Standards (BWSs) that are used commercially as lightfastness standards show higher PICL intensity from the least photostable BWSs that use triphenylmethane dyes and lower intensity from more photostable BWSs using UVA and visible wavelengths. The relative PICL intensities do not correlate in a stepwise manner with lightfastness ratings of the BWSs. However dye/polymer combinations that emit high levels of PICL relative to the undyed material are unlikely to have acceptable lightfastness. The xanthene dyes fluorescein and eosin Y are more strongly photosensitising than triphenylmethane dyes on wool and both produce higher PICL emission than undyed wool when irradiated with visible light.

Chiral organotin hydrides as enantioselective reducing agents

This thesis reports on the feasibility of the utilization of organotin hydrides as enaantioselective free radical reducing agents. The chiral organotin hydrides prepared contain the bulky chiral (1R,2S,5R)-menthyl substituent and in some cases also contain a stereogenic tin centre. Reaction of (1R,2S,5R)-menthylmagnesium chloride (MenMgC1) with triphenyltin chloride in THF proceeds with epimerization of the C-1 carbon of the menthyl group and results in a mixture of (1R,2S,5R)-menthyltriphenyltin and (1S,2S.5R)-menthyltriphenyltin. Addition of Lewis bases such as triphenylphosphine to the THF solution of triphenyltin chloride prior to the addition of the Grignard reagent suppresses epimerization and enables isolation of pure (1R,2S,5R)-menthyltriphenyltin. (1R,2S,5R)-Menthyltriphenyltin is the precursor for the synthesis of (1R,2S,5R)-menthyldiphenyltin hydride as well as (1R,2S,5R)-menthyl-containing organotin halide derivatives. A crystal structure of (1R,2S,5R)-menthylphenyltin dibromide and (1R,2S,5R)-menthylphenyltin dichloride confirmed the configuration of the menthyl substituent in these compounds. Reaction of MenMgC1 with diphenyltin dichloride in THF proceeds with no epimerization of the C-1 carbon of the menthyl group and bis((1R,2S,5R)-menthyl)diphenyltin is formed. A crystal structure of (1R,2S,5R)-menthyltriphenyltin confirmed the configuration of the menthyl substituent. Bis((1R,2S,5R)-menthyl)diphenyltin is used to form bis((1R,2S,5R)-menthyl)phenyltin hydride as well as other bis(1R,2S,5R)-menthyl derivatives. A series of chiral non-racemic triorganotin halides and triorganotin hydrides containing one or two (1R,2S,5R)-menthyl substituents as well as various potentially intramolecular coordination substituents were synthesized and characterized. The intramolecular substituents include the 8-(dimethylamino)naphthyl, 2-[(1S)-1-dimethylaminoethyl]phenyl, 2-(4,4-dimethyl-2-oxazoline)-5-methylphenyl and the 2-(4-(S)isopropyl-2-oxazoline)-5-methylphenyl substituents. Each compound containing a stereogenic tin centre was synthesized as diastereomeric mixtures. AM1 calculations of these compounds provide good qualitative predictability of the molecular geometries observed in the solid state as well as the diastereomeric ratios observed in solution. X-ray analysis of some of the organotin halides containing intramolecular coordination substituents revealed a tendency towards penta-coordination at the tin centre as a result of N-Sn interactions. The chiral organotin hydrides synthesized were found to be poor enantioselective free radical reducing agents. However, the addition of one molar equivalent of achiral or chiral Lewis acids to the free radical reduction reactions involving these organotin hydrides results in remarkable increases in enantioselectivity. There are numerous examples in which enantioselectivities exceed 80% and three examples of enantioselectivites which are equal and above 90% with one outstanding enantioselective outcome of ≥99%. These results appear to be the highest enantioselectivites for organotin hydride radical reductions reported to date. There is strong evidence to suggest that the chiral menthyl group of the organotin hydride directs the stereochemical outcome in the reduced product. The results also suggest that an increase in the number of menthyl substituents attached to tin or the introduction of intramolecular coordination substituents does not necessarily results in a greater increase in enantioselectivity. Preliminary studies into the synthesis of organotin hydrides containing Lewis acid functionalities are also reported. A zirconium chloride functionality was found to be incompatible with organotin hydride. However, an organotin hydride containing a trialkylboron Lewis acid functionality attached via an alkyl chain was successfully synthesized. Although this reagent was only stable in the preparative THF solution, it was still found to be effective at reducing benzaldehyde to benzyl alcohol.

Metal-catalyzed oxidative damage and oligomerization of the amyloid-β peptide of Alzheimer’s disease

The most common form of dementia in old age is Alzheimer’s disease (AD). The presence in the brain of senile plaque is the major pathological marker of AD. The plaques are primarily composed of aggregated amyloid-β peptide (Aβ). Aβ is a 40–42 amino acid peptide that is a proteolytic product derived from the β-amyloid precursor protein. The function of Aβ and the exact mechanism of Aβ aggregation and neurotoxicity are unclear. However, metal coordination by Aβ plays an important role in inducing aggregation and the generation of reactive oxygen species, which appears to be at least partially responsible for Aβ neurotoxicity. In this review we examine the role of copper and zinc ions in Aβ neurotoxicity, especially with regards to the generation of free radicals. We discuss the role of copper or zinc ions in oxidative damage and Aβ conformational changes and the relationship of these metals to AD.

Methionine regulates copper/hydrogen peroxide oxidation products of Aβ

Metal-catalysed oxidation (MCO) may play a causative role in the pathogenesis of Alzheimer's disease (AD). Amyloid peptide (A), the major biomarker of AD, in the presence of copper ions reduces Cu2+ to Cu+ and catalyses the formation of H2O2 that subsequently induces radicals through Fenton chemistry. A is also subject to attack by free radicals, where the presence of Cu2+ in conjunction with H2O2 catalyses oxygenation, primarily at the methionine sulfur atom. This work investigates MCO of A, to gain further insight into the role of oxidative stress in AD. By combining a fluorescence assay with gel electrophoresis to monitor MCO reactions of A (1-28) in the presence and absence of methionine it was determined that methionine can both protect some residues against MCO and promote the oxidation of Tyr(10) specifically. Electrospray ionization mass spectrometric analysis of methionine MCO products indicated the formation of methionine sulfoxide, methionine sulfone and related hydroxylated products. Similar products could be formed from the oxidation of Met(35) of A and may relate to changes in properties of the peptide following MCO.

Ascophyllum compositions and methods

The invention provides extracts of brown seaweed of the genus Ascophyllum that have valuable pharmacological properties. In particular, compositions of the invention are useful for e.g.: inhibiting alpha-glucosidase activity; preventing or treating conditions mediated by alpha-glucosidase activity; reducing blood glucose levels; preventing or treating diabetes; modulating glucose uptake in adipocytes; preventing or treating obesity; scavenging free radicals; stimulating the immune system; activating macrophages; preventing or treating condition mediated by macrophage activation; and modulating nitric oxide production by macrophages. Methods for using the Ascophyllum extracts of the invention are provided, as are kits comprising Ascophyllum extracts of the invention and instructions for using the extracts.

From bivalves to birds : oxidative stress and longevity

1. The oxidative stress theory of ageing predicts that animals living longer will have less cumulative oxidative damage together with structural characteristics that make them more resistant to oxidative damage itself.
2. Although a general relationship between body size, metabolism and longevity does not exist in marine invertebrates, they are generally characterized by low rates of metabolism and reactive oxygen species (ROS) formation associated with lower antioxidant enzyme activities compared to vertebrates.
3. Birds and mammals have very similar size-affected metabolic rates and their metabolic intensity explains only some of the variation in maximum lifespan potential (MLSP).Within each class, smaller animals have higher rates of metabolism and ROS production and membranes that are more susceptible to oxidative damage and autocatalytic propagation of free radicals than larger ones.
4. Although the high variation in life-history strategies is accompanied by substantial variation in MLSP, there is a consistent positive correlation between rates of ROS formation and antioxidant levels among most animals examined so far for these traits. The consensus of these studies is that ROS and antioxidant levels are inversely related to MLSP.
5. The lack of a clear stoichiometric relation between variables contributing to oxidative stress limits our capacity to infer longevity consequences from measures of pro-oxidant or antioxidant status among or within species

Theobroma cacao (cocoa) supplementation in the treatment of Non-alcoholic Steatohepatitis

Non-alcoholic Steatohepatitis (NASH) is a chronic disease that results from accumulation of fat within the liver that subsequently stimulates free radicals to damage the cells of the liver. Cocoa is a rich source of antioxidants and it was found that its consumption could slow the development of NASH.

Links between pollen, atopy and the asthma epidemic

Pollen allergy has been found in 80–90% of childhood asthmatics and 40–50% of adult-onset asthmatics. Despite the high prevalence of atopy in asthmatics, a causal relationship between the allergic response and asthma has not been clearly established. Pollen grains are too large to penetrate the small airways where asthma occurs. Yet pollen cytoplasmic fragments are respirable and are likely correlated with the asthmatic response in allergic asthmatics. In this review, we outline the mechanism of pollen fragmentation and possible pathophysiology of pollen fragment-induced asthma. Pollen grains rupture within the male flowers and emit cytoplasmic debris when winds or other disturbances disperse the pollen. Peak levels of grass and birch pollen allergens in the atmosphere correlated with the occurrence of moist weather conditions during the flowering period. Thunderstorm asthma epidemics may be triggered by grass pollen rupture in the atmosphere and the entrainment of respirable-sized particles in the outflows of air masses at ground level. Pollen contains nicotinamide adenine dinucleotide phosphate (reduced) oxidases and bioactive lipid mediators which likely contribute to the inflammatory response. Several studies have examined synergistic effects and enhanced immune response from interaction in the atmosphere, or from co-deposition in the airways, of pollen allergens, endogenous pro-inflammatory agents, and the particulate and gaseous fraction of combustion products. Pollen and fungal fragments also contain compounds that can suppress reactive oxidants and quench free radicals. It is important to know more about how these substances interact to potentially enhance, or even ameliorate, allergic asthma.

Determination of antioxidants using chemiluminescence detection

Antioxidants are produced within the body or obtained from dietary sources. Their main role is to counter the detrimental effects of free radicals, but they are also essential for numerous metabolic processes. This thesis describes novel detection methods for the determination of antioxidants in plant based materials and physiological fluids.

Influence of trace-metals on the colour and photostability of wool

This study expands the knowledge of the mechanisms that cause wool to yellow. It established that metals in wool influence the production of free radicals and the extent of degradation and yellowing of photo-irradiated wool. It also examined the relationship between the colour and trace metal content of fleece wool.