Opioid receptors are central to the development of tools that can be used to manage and fight against the opioid crisis that is prevalent in North America. They are part of a large protein family called G-protein-Coupled Receptors (GPCRs), which are the most therapeutically targeted receptors within the human body. Once activated, the receptors lead to the activation of multiple different signaling pathways such the -arrestin and G-protein signaling pathways. The -Arrestin pathway is usually associated with the side effects of opioid analgesics. An allosteric site that binds to sodium was identified within the delta-opioid receptor (DOR). Previous studies have found that the sodium cavity can regulate the activation of different signaling pathways and thus act at the functional selectivity level. Our lab has identified a subset of small molecules targeting this cavity. This finding supports the druggability of this site and thus opens the door for the development of a novel pharmacological entity to control opioid receptor activities. This thesis focuses on the characterization of the sodium cavity by performing structure activity relationship (SAR) studies on the delta opioid receptor with three allosteric modulators: MIA, HMA and zoniporide. We report that, through site-directed mutagenesis and functional studies, mutations in the allosteric sodium site has an impact on the receptor functionalities including ligand recognition, efficacy and also allosterism by small molecules; however, the mutations do not prevent the binding of the allosteric modulators to the receptor. We also report the development of a novel biomedical tool that can be used to study the recruitment of the G-protein subtypes as well as the arrestin subtypes. Our data suggest it is possible to design drugs that will target the sodium pocket and this site has a major role within DOR and could be used to design novel modulators with unique pharmacological properties. My work will serve as a platform to study other members of the opioid receptor family and for the future rational design of novel modulators.

Includes bibliographical references. / X-ray crystallographic studies have been used to elucidate the structures of two new Werner clathrates. ... The chloroform molecule is disordered, lying on a two-fold axis. Stoicheiometric characterization of the clathrates was determined using various chemical techniques, including mass spectroscopy, proton nuclear magnetic resonance and complex iometric titration. The clathrating phase of the second clathrate was investigated by guest-loss studies on a McBain balance followed by X-ray powder photography. Host-quest non-bonded interactions of both clathrate compounds were studied using atom-pair potentials.

<p>Tetraazamacrocycles, such as cyclam (1,4,8,11-tetraazacyclotetradecane), are useful ancillary ligands in the formation of organometallic complexes. Coordination of a 3d metal can lead to the formation of square planar complexes, such as with Ni^II and Cu^II, or octahedral complexes upon coordination of additional ligands, such as with Co^II/III and Cr^II/III. Notably with Cr, a mixture of <i>cis-</i> and <i>trans-</i>octahedral complexes are formed, and the isomerism can be influenced through <i>C</i>-substitution of the cyclam macrocycle. Herein, Cr^III complexes featuring <i>C</i>-substituted cyclam derivatives and either redox-active ligands or alkynyl ligands are reported.</p> <p>Chapter 1 features an introduction to the photophysical processes of Cr(III), an overview of cyclam and its derivatives, and a brief review of Cr^III(cyclam/cyclam’) bis-alkynyl complexes for various applications. Chapter 2 discusses the structural, optical, electronic, and magnetic characterizations of <i>cis</i>-[Cr(HMC)catecholate]⁺ and <i>cis</i>-[Cr(HMC)semiquinonate]²⁺ complexes, which feature redox-active catecholate and semiquinonate ligands. Chapter 3 highlights a series of <i>trans</i>-[Cr(HMC)(C₂Ar)Cl]⁺ complexes, which expands upon prior research on bis-alkynyl complexes. Chapter 4 discusses how a different <i>C</i>-substituted cyclam derivative, MPC, is used to produce <i>trans</i>-[Cr(MPC)Cl₂]⁺ starting material in higher quantity than the HMC derivative. This allows for higher amounts of <i>trans</i>-[Cr(MPC)(C₂Ar)₂]⁺ complexes to be synthesized, making it a more practical macrocycle for the future pursuit of dissymmetric bis-alkynyl complexes.</p>

This study investigates the use of derivatives by firms listed on the Johannesburg Stock Exchange (JSE) during 2005 to 2017, and the disclosure of derivative financial instruments on the financial statements of these entities. The study can be broadly divided into two parts: the first part investigates the determinants of corporate hedging practices by JSE-listed firms, while the second part analyses the value relevance of derivatives disclosures. The first part of the study thus answers the question ‘Why do companies use derivatives?’ with reference to JSE-listed companies for the period 2005 to 2017. The second part of the study answers the question ‘Does the disclosure of derivatives in the financial statements have an impact on firm value?’ for the same companies and period. Binomial logistic regression analyses were done to assess the determinants of the corporate hedging practices employed by JSE-listed firms. Multiple linear regression analyses were used to determine the value relevance of derivatives disclosures. The results of the study suggest that firm size, growth prospects, leverage and managerial risk aversion are important determinants of JSE-listed firms’ hedging decisions. Furthermore, the findings suggest that the disclosure of firms’ use of derivatives in the financial statements is value relevant and that companies listed on the JSE are associated with a higher Tobin’s Q if they disclose a derivatives amount. This study also investigates whether the value relevance of derivatives disclosure is influenced differently under different conditions during different economic periods and whether the level of quality of the disclosure influences the value relevance of derivatives disclosure. The data show that the value relevance of risk disclosure companies depend on different economic periods, and that the level of higher quality risk disclosure has a negative impact on the value relevance of derivatives disclosures: firms are valued lower where the level of quality of derivatives disclosures is higher. / Thesis (PhD)--University of Pretoria, 2020. / Financial Management / PhD / Unrestricted

A convenient, economical, large scale synthesis of N-acetyldehydro-alanine (a-acetamidoacrylic acid) and its methyl ester was developed via a sequence of N-chlorination-dehydrochlorination. The method was extended to the synthesis of the corresponding N-benzoyl, N-phenylacetyl and N-benzyloxycarbonyl derivatives. The conversion of a-methoxy-N-acetyl alanine derivatives to the corresponding a-mercapto alanine derivatives, using zinc chloride and an appropriate mercaptan, was investigated. Methyl a-methoxy-N-acetyl-D, L-alaninate was successfully converted to the a-acetylthio derivative, in 24% yield; however, a 90% yield could be obtained by treatment of the dehydroalanine derivative with hydrogen chloride gas in neat thiolacetic acid. A facile conversion of the a-acetylthio derivative to the a-methoxy derivative, using sodium methoxide in methanol, was observed to occur. The normally facile conversion of an acetylthio group to a mercapto group, using sodium borohydride, gave mixtures of the a-mercapto derivative and alanine derivative. The reactions at the a position of a-hetero-N-acetyl-D,L-alanines and a,B-disubstituted N-acetyl-D,L-alanine derivatives seemed consistent with the formation of an acylimine intermediate under basic conditions and a carbonium ion intermediate under acidic conditions. From these studies, a facile, clean synthesis of a-halo-a-mercapto-and a-alkoxy-N-acetyl-D,L-alanine derivatives was accomplished. All attempts to synthesize a,B-dimercapto derivatives failed because the B-halogen could not be replaced with a mercapto group when the a position was a mercapto or methoxy derivative. Attempts to generate a B-mercapto-a-halo derivative also failed. A facile synthesis of the E and Z isomers of methyl B-chloro-N-acetyldehydroalaninate was developed. The ratio of Z to E isomers was found to vary with the base used for the elimination. The E and Z isomers of methyl B-chloro-N-acetyldehydroalaninate were converted to the B-mercapto derivatives by reaction with mercaptan. The reaction proceeded with retention of stereochemistry. The formation of B-substituted N-acetyldehydroalanine derivatives seemed consistent with an acylimine intermediate followed by a sequence of Michael-type addition and dehydrochlorination. A study of the conversion of the B-mercapto-N-acetyldehydroalanine derivatives to mixed dithioacetals, which would be useful in the synthesis of natural antibiotics, was undertaken. This approach to the synthesis of mixed dithioacetals was unsuccessful because an exchange of mercapto groups was observed, the addition of a second, different mercaptan failed or the yield was too low to be synthetically useful. A synthesis of B,B-dimercapto-N-aeetyldehydroalanine (mixed, unsaturated dithioacetals) derivatives was accomplished. However, because of low yields, a reduction to B,B- dimercapto-N- acetyl-D,L-alanine derivatives (mixed dithloacetals) was not investigated.

Hydroxytyrosol is one of the most powerful known antioxidants. It is a naturally occurring polyphenol, most commonly produced in Olive tree, (Olea europaea). The remarkable antioxidant and pharmacological properties of hydroxytyrosol has made it an outstanding compound in the polyphenol family and of great interest to many researchers. Hydroxytyrosol has the ability to scavenge free radicals produced during cellular oxidative stress and helps to protect the integrity of cells in living systems. Despite its numerous biological and pharmacological uses, it is found in very low concentration in olive oil, this limits its biomedical applications. A novel method for synthesizing pure hydroxytyrosol from commercially less expensive precursor catechol was successfully developed in our lab. However, it is believed that the cellular uptake of hydroxytyrosol is slow because of its high hydrophilicity. Therefore, we plan in this ongoing research to synthesize less hydrophilic derivatives of hydroxytyrosol by introducing some hydrophobic groups (such as alkyl, acyl, …) to its molecular skeleton.

In this thesis, we present three projects. First, we investigate the numerical approximation of Hamilton-Jacobi equations with the Caputo time-fractional derivative. We introduce an explicit in time discretization of the Caputo derivative and a finite-difference scheme for the approximation of the Hamiltonian. We show that the approximation scheme so obtained is stable under an appropriate condition on the discretization parameters and converges to the unique viscosity solution of the Hamilton-Jacobi equation. Also, we study the numerical approximation of a system of PDEs which arises from an optimal control problem for the time-fractional Fokker-Planck equation with time-dependent drift. The system is composed of a backward time-fractional Hamilton-Jacobi-Bellman equation and a forward time-fractional Fokker-Planck equation. We approximate Caputo derivatives in the system by means of L1 schemes and the Hamiltonian by finite differences. The scheme for the Fokker-Planck equation is constructed in such a way that the duality structure of the PDE system is preserved on the discrete level. We prove the well-posedness of the scheme and the convergence to the solution of the continuous problem. Finally, we study a particle approximation for one-dimensional first-order Mean-Field-Games with local interactions with planning conditions. Our problem comprises a system of a Hamilton-Jacobi equation coupled with a transport equation. As we are dealing with the planning problem, we prescribe initial and terminal distributions for the transport equation. The particle approximation builds on a semi-discrete variational problem. First, we address the existence and uniqueness of the semi-discrete variational problem. Next, we show that our discretization preserves some conserved quantities. Finally, we prove that the approximation by particle systems preserves displacement convexity. We use this last property to establish uniform estimates for the discrete problem. All results for the discrete problem are illustrated with numerical examples.

<p> Nitric oxide has been implicated in a number of biological processes, the majority of them involving iron nitrosyl complexes. The urgency then is to further study and characterize these complexes to further the understanding of biological mechanisms. However, the chemical sensitivity of these species precludes the purification and isolation of these compounds which, unfortunately, has directed the trend to merely detecting the presence of these compounds rather than isolating them. To this day, a large number of Electron Paramagnetic Resonance (EPR) detectable, biological compounds have not been isolated.</p> <p> To this end, the series of biologically relevant compounds of the form Fe(NO)2(L)2 [ L = imidazole 1, 1-methylimidazole (1-MeIm) 2, 4-methylimidazole (4-MeIm) 3, benzimidazole (benzim) 4, and 5,6-dimethylbenzimidazole (56benzim) 5 ] have been synthesized by direct reaction of the appropriate imidazole ligand with Fe(NO)2(CO)2. The compounds were extremely air sensitive, both in solution and as a dry solid. This hindered attempts to purify these compounds and so, infra red (IR), nuclear magnetic resonance (NMR) and EPR spectroscopic studies were undertaken of 2:1 reaction mixtures of the appropriate imidazole ligand and Fe(NO)2(CO)2. These studies revealed that the rapid substitution of the carbonyl ligands is facilitated by a catalytic, 17-electron, electron transfer chain mechanism (ETC), where the imidazole ligand acts to oxidize the 18-electron complex into the active 17-electron Fe(NO)2(CO)2+ species.</p> <p> In the course of the EPR study of 2, crystals formed that were suitable for single-crystal, X-ray diffraction. The compound crystallizes with a monoclinic unit cell, in the C2/c space group with unit cell dimensions: a= 13.985(5) Å, b = 11.529 (5) Å, c = 15.471(4) Å, α= 90°, β= 91.72(2)°, γ = 90°, V = 2493(2) Å^3, Z = 8. During the course of study of 6, crystals suitable for single crystal X-ray diffraction were obtained. The compound crystalizes with a monoclinic unit cell, in the P2/c space group and unit cell dimensions: a= 11.707(9) Å, b = 8.1783 (5) Å, c = 17.2489 (13) Å, α= 90°, β= 106.562 (1)°, γ = 90°, V = 1583.0 (2) Å^3 A, Z = 2.</p> <p> A relatively new mass spectrometry (MS) procedure was utilized for the reaction mixtures of 1 - 5, which involved a combination of electrochemical oxidation and electrospray. The method proved very useful, yielding data that could not be obtained by other MS techniques. Oligomeric species of the form L-[(Fe(NO)2L]x (x = 2,3,4,5 or 6), were also detected by MS for each compound reaction mixture. The oligomers involved linear chains of iron dinitrosyl fragments linked via the imidazole nitrogens. However, it is believed that these oligomers are produced as a result of the conditions met by the mass spectrometer.</p> <p> A reaction of Fe(NO)2(PPh3)(CO) with 1-MeIm was also performed in hopes of producing a more stable mono-substituted complex. However, the reaction also proceeded via an Electron Transfer Chain (ETC) pathway to produce Fe(NO)2(PPh3)2 6.</p> / Thesis / Master of Science (MSc)

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