DESIGN AND SYNTHESIS OF NOVEL SYNTHETIC ANTIOXIDANTS FOR THE TREATMENT OF OXIDATIVE STRESS RELATED DISEASES

Free radicals play an important role in many physiological processes that occur in the human body such as cellular defense responses to infectious agents and a variety of cellular signaling pathways. While at low concentrations free radicals are involved in many significant metabolic reactions, high levels of free radicals can have deleterious effects on biomolecules like proteins, lipids, and DNA. Many physiological disorders such as diabetes, ageing, neurodegenerative diseases, and ischemia-reperfusion (I/R) injury are associated with oxidative stress.1 In particular, the deleterious effects caused by I/R injury developed during organ transplantation, cardiac infarct, and stroke have become the main cause of death in the United States and Europe.1,2 In this context, we synthesized and characterized a series of novel indole-amino acid conjugates as potential antioxidants for I/R injury. The synthesis of indole-phenol conjugate compounds is also discussed. Phenolic derivatives such as caffeic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), resveratrol, and its analogues are known for their significant antioxidative properties. A series of resveratrol analogues have been designed and synthesized as potential antioxidants. The radical scavenging mechanisms for potential antioxidants and assays for the in vitro evaluation of antioxidant activities are also discussed.

Indole based antioxidants for the treatment of ischemia reperfusion injury

With the number of ischemia reperfusion (I/R) injuries on the rise, and a lack of pharmacological intervention aimed at reducing free radical damage associated with I/R, we have developed 30 indole phenolic antioxidants that were synthesized by click chemistry to couple our indole with a phenolic or anisole derivative. The total antioxidant activity of the analogues was tested in vitro using the ferric thiocyanate lipid emulsion method. Compounds containing hydroxyl or methoxy aromatics at the 3 or 4 position on the aromatic coupled to the indole exhibited increased antioxidant scavenging. 4-methoxyindole derivatives (8a-e) exhibited increased scavenging (p < 0.05) compared to the known antioxidant butylated hydroxyanisole (BHA).

Price risk management in the copper market using commodity derivatives and options strategies

Metals price risk management is a key issue related to financial risk in metal markets because of uncertainty of commodity price fluctuation, exchange rate, interest rate changes and huge price risk either to metals’ producers or consumers. Thus, it has been taken into account by all participants in metal markets including metals’ producers, consumers, merchants, banks, investment funds, speculators, traders and so on. Managing price risk provides stable income for both metals’ producers and consumers, so it increases the chance that a firm will invest in attractive projects. The purpose of this research is to evaluate risk management strategies in the copper market. The main tools and strategies of price risk management are hedging and other derivatives such as futures contracts, swaps and options contracts. Hedging is a transaction designed to reduce or eliminate price risk. Derivatives are financial instruments, whose returns are derived from other financial instruments and they are commonly used for managing financial risks. Although derivatives have been around in some form for centuries, their growth has accelerated rapidly during the last 20 years. Nowadays, they are widely used by financial institutions, corporations, professional investors, and individuals. This project is focused on the over-the-counter (OTC) market and its products such as exotic options, particularly Asian options. The first part of the project is a description of basic derivatives and risk management strategies. In addition, this part discusses basic concepts of spot and futures (forward) markets, benefits and costs of risk management and risks and rewards of positions in the derivative markets. The second part considers valuations of commodity derivatives. In this part, the options pricing model DerivaGem is applied to Asian call and put options on London Metal Exchange (LME) copper because it is important to understand how Asian options are valued and to compare theoretical values of the options with their market observed values. Predicting future trends of copper prices is important and would be essential to manage market price risk successfully. Therefore, the third part is a discussion about econometric commodity models. Based on this literature review, the fourth part of the project reports the construction and testing of an econometric model designed to forecast the monthly average price of copper on the LME. More specifically, this part aims at showing how LME copper prices can be explained by means of a simultaneous equation structural model (two-stage least squares regression) connecting supply and demand variables. A simultaneous econometric model for the copper industry is built: {█(Q_t^D=e^((-5.0485))∙P_((t-1))^((-0.1868) )∙〖GDP〗_t^((1.7151) )∙e^((0.0158)∙〖IP〗_t ) @Q_t^S=e^((-3.0785))∙P_((t-1))^((0.5960))∙T_t^((0.1408))∙P_(OIL(t))^((-0.1559))∙〖USDI〗_t^((1.2432))∙〖LIBOR〗_((t-6))^((-0.0561))@Q_t^D=Q_t^S )┤ P_((t-1))^CU=e^((-2.5165))∙〖GDP〗_t^((2.1910))∙e^((0.0202)∙〖IP〗_t )∙T_t^((-0.1799))∙P_(OIL(t))^((0.1991))∙〖USDI〗_t^((-1.5881))∙〖LIBOR〗_((t-6))^((0.0717) Where, Q_t^D and Q_t^Sare world demand for and supply of copper at time t respectively. P(t-1) is the lagged price of copper, which is the focus of the analysis in this part. GDPt is world gross domestic product at time t, which represents aggregate economic activity. In addition, industrial production should be considered here, so the global industrial production growth that is noted as IPt is included in the model. Tt is the time variable, which is a useful proxy for technological change. A proxy variable for the cost of energy in producing copper is the price of oil at time t, which is noted as POIL(t ) . USDIt is the U.S. dollar index variable at time t, which is an important variable for explaining the copper supply and copper prices. At last, LIBOR(t-6) is the 6-month lagged 1-year London Inter bank offering rate of interest. Although, the model can be applicable for different base metals' industries, the omitted exogenous variables such as the price of substitute or a combined variable related to the price of substitutes have not been considered in this study. Based on this econometric model and using a Monte-Carlo simulation analysis, the probabilities that the monthly average copper prices in 2006 and 2007 will be greater than specific strike price of an option are defined. The final part evaluates risk management strategies including options strategies, metal swaps and simple options in relation to the simulation results. The basic options strategies such as bull spreads, bear spreads and butterfly spreads, which are created by using both call and put options in 2006 and 2007 are evaluated. Consequently, each risk management strategy in 2006 and 2007 is analyzed based on the day of data and the price prediction model. As a result, applications stemming from this project include valuing Asian options, developing a copper price prediction model, forecasting and planning, and decision making for price risk management in the copper market.

An investigation of phenolic glycoside and condensed tannin homeostasis in Populus by salicyl alcohol feeding to cell cultures and by transgenic manipulation of the sucrose transporter, PTSUT4, in planta

Secondary metabolites play an important role in plant protection against biotic and abiotic stress. In Populus, phenolic glycosides (PGs) and condensed tannins (CTs) are two such groups of compounds derived from the common phenylpropanoid pathway. The basal levels and the inducibility of PGs and CTs depend on genetic as well as environmental factors, such as soil nitrogen (N) level. Carbohydrate allocation, transport and sink strength also affect PG and CT levels. A negative correlation between the levels of PGs and CTs was observed in several studies. However, the molecular mechanism underlying such relation is not known. We used a cell culture system to understand negative correlation of PGs and CTs. Under normal culture conditions, neither salicin nor higher-order PGs accumulated in cell cultures. Several factors, such as hormones, light, organelles and precursors were discussed in the context of aspen suspension cells’ inability to synthesize PGs. Salicin and its isomer, isosalicin, were detected in cell cultures fed with salicyl alcohol, salicylaldehyde and helicin. At higher levels (5 mM) of salicyl alcohol feeding, accumulation of salicins led to reduced CT production in the cells. Based on metabolic and gene expression data, the CT reduction in salicin-accumulating cells is partly a result of regulatory changes at the transcriptional level affecting carbon partitioning between growth processes, and phenylpropanoid CT biosynthesis. Based on molecular studies, the glycosyltransferases, GT1-2 and GT1-246, may function in glycosylation of simple phenolics, such as salicyl alcohol in cell cultures. The uptake of such glycosides into vacuole may be mediated to some extent by tonoplast localized multidrug-resistance associated protein transporters, PtMRP1 and PtMRP6. In Populus, sucrose is the common transported carbohydrate and its transport is possibly regulated by sucrose transporters (SUTs). SUTs are also capable of transporting simple PGs, such as salicin. Therefore, we characterized the SUT gene family in Populus and investigated, by transgenic analysis, the possible role of the most abundantly expressed member, PtSUT4, in PG-CT homeostasis using plants grown under varying nitrogen regimes. PtSUT4 transgenic plants were phenotypically similar to the wildtype plants except that the leaf area-to-stem volume ratio was higher for transgenic plants. In SUT4 transgenics, levels of non-structural carbohydrates, such as sucrose and starch, were altered in mature leaves. The levels of PGs and CTs were lower in green tissues of transgenic plants under N-replete, but were higher under N-depleted conditions, compared to the levels in wildtype plants. Based on our results, SUT4 partly regulates N-level dependent PG-CT homeostasis by differential carbohydrate allocation.

Syntheses and characterization of monomeric Mo(VI) complexes with bidentate phosphine oxide ligands and dimeric and tetrameric Mo(V) clusters with benzoic acid and phosphinic acid derivatives, containing MoO2, Mo2O2(μ-O)2 and Mo4O4(μ3-O)4

Mo(VI) oxo complexes have been persistently sought after as epoxidation catalysts. Further, Mo(V) oxo clusters of the form M4(µ3-X)4 (M = transition metal, X = O, S) have been rigorously studied due to their remarkable structures and also their usefulness as models for electronic studies. The syntheses and characterizations of new Mo(VI) and Mo(V) oxo complexes have been described in this dissertation. Two new complexes MoO2Cl2Ph2P(O)CH2COOH and MoO2Cl2Ph2P(O)C6H4tBuS(O) were synthesized from reactions of “MoO2Cl2” with ligands Ph2P(O)CH2COOH and Ph2P(O)C6H4tBuS(O). Tetrameric packing arrangements comprised of hydrogen bonds were obtained for the complex MoO2Cl2Ph2P(O)CH2COOH and the ligand Ph2P(O)CH2COOH. Further the stability of an Mo-O bond was preferred over the Mo-S bond even though this resulted in the formation of a more strained seven membered ring. Tetranuclear Mo(V) complexes of the form [Mo4(µ3-O)4(µ-O2PR2)4O4], (PR2 = PPh2, PMe2) were synthesized using reactions of MoO2(acac)2 with diphenyl and dimethyl phosphinic acids, in ethanol. In the crystal structure of these complexes four Mo=O units are interconnected by four triply bridging oxygen atoms and bridging phosphinate ligands. The complex exhibited fourfold symmetry as evidenced by a single 31P NMR peak for the P atoms in the coordinated ligands. Reaction of WO2(acac)2 with Ph2POOH in methanol resulted in a dimeric W(VI) complex [(CH3O)2(O)W(µ-O)( µ-O2PPh2)2W(O)(CH3O)2] which contained a packing disorder in its crystal structure. Similar reactions of MoO2(acac)2 with benzoic acid derivatives resulted in dimeric complexes of the form [Mo2O2(acac)2(µ-O)(µ-OC2H5)(µ-O2CR)] (R = C6H5, (o-OH)C6H4, (p-Cl)C6H4, (2,4-(OH)2)C6H3, (o-I)C6H4) and one tetrameric complex [Mo2O2(acac)2(µ-O)(µ-OC2H5)(µ-O2C)C6H4(p-µ-O2C)Mo2O2(acac)2(µ-O)(µ-OC2H5)] with terephthalic acid. 1H NMR proved very useful in the prediction of the formation of dimers with the substituted benzoic acids, which were also confirmed by elemental analyses. The reductive capability of ethanol proved instrumental in the syntheses of Mo(V) tetrameric and dimeric clusters. Synthetic details, IR, 1H and 31P NMR spectroscopy and elemental analyses are reported for all new complexes. Further, single crystal X-ray structures of MoO2Cl2Ph2P(O)CH2COOH, MoO2Cl2Ph2P(O)C6H4tBuS(O), [Mo4(µ3-O)4(µ-O2PR2)4O4], (PR2 = PPh2, PMe2), [(CH3O)2(O)W(µ-O)( µ-O2PPh2)2W(O)(CH3O)2] and [Mo2O2(acac)2(µ-O)(µ-OC2H5)(µ-O2CR)] (R = C6H5, (o-OH)C6H4) are also presented.