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D.Sc. / Please refer to full text to view abstract

In an effect to develop for more selective neuronal nicotinic acetylcholine receptor analgesics that have less toxicity and adverse side effects relative to epibatidine, three new classes of epibatidine analogues were synthesized and evaluated in vitro as potential potent selective nAChR ligands. Specifically, three analogues of epibatidine were synthesized to explore the structure-activity relationships of epibatidine relative to neuromuscular blocking activity as well as nAChRs. Both quaternary epibatidine analogues 2 and bis-epibatidine derivative 3 exhibited high binding affinity relative to nicotine. In addition, a new series of 2-(hydroxyalkylpyridyl)-7-azabicyclo[2.2.1]heptane derivatives were synthesized and evaluated as potential ligands for nicotinic acetylcholine receptors. Moreover, two rigid 2-acetoxy-7-azabicyclo[2.2.1]heptane analogues have been prepared to study the binding conformation of acetylcholine at the active sites of the nicotinic acetylcholine receptors.

Submitted in partial fulfillment for the Degree of Master of Applied Sciences in Biotechnology, Durban University of Technology, Durban, South Africa, 2016. / Pharmacological research is essential for the advancement of treatment therapies to combat diseases that plague mankind. Pyrimidines have been a subject under investigation by medicinal chemists for many years due to their interesting pharmacological properties. In previous studies, pyrimidines and their derivatives have been reported to have antimicrobial, anti-inflammatory, antimalarial, analgesic, and antitumour activities amongst other biological activities. Although there has been a significant amount of research carried out on these heterocycles, there will always be a continuous need for the discovery of novel synthetic drugs which have a higher degree of potency and fewer side effects. Hence, this study was undertaken to determine the pharmacological activities of eight novel 1, 4 dihydropyrimidine analogues (DHPM 1 – 8), that have been synthesized in our laboratory. The dihydropyrimidines were synthesized and characterized and thereafter evaluated for in vitro antimicrobial, antioxidant, anti-inflammatory, cytotoxicity and apoptotic activities. The compounds also underwent a safety study. Antimicrobial activity was evaluated using the disk diffusion assay; compounds displaying superior activity were subjected to further analysis to establish the minimum inhibitory concentration. Overall compounds DHPM 7 and 8 showed the best antibacterial activity against Gram positive bacteria. The minimum inhibitory concentration (MIC) for DHPM 7 against the Gram positive organisms (B.cereus, S.aureus and B.coagulans) was 0.75 µg/mL; however DHPM 7 had a MIC of 0.37 µg/mL against M. luteus. DHPM 8 displayed an MIC of 0.75 µg/mL against B.cereus, S.aureus, M.luteus, S.faecalis and B.coagulans. Antioxidant activity was assessed using the DPPH method. DHPM 2 showed outstanding free radical scavenging capacity of 90.63% at a concentration of 1 mg/mL. The DHPM 1 - 8 were analysed for their lipoxygenase inhibitory activity. Excellent inhibition ranging from 59.37 ± 0.6 to 81.19 ± 0.94% was demonstrated. The inhibitory activity was elucidated by a molecular docking study against the lipoxygenase enzyme (PDB code = 3V99) using the MOE 2013.08 and Leadit 2.1.2 software and high affinities were demonstrated. DHPM 1 - 8 were tested for cytotoxic activity against two human cancer cell lines, MCF-7 and UACC-62 by means of the MTT assay. It was observed for the MCF-7 cell line, DHPM 1, 4, 6, 7 and 8 displayed cytotoxicity above 89% at 50 µg/mL. The DHPMs at 50 µg/mL were noted to be very effective against the Melanoma cell line with DHPM 2 having a cytotoxicity value of 82.62% and DHPM 1, 4, 5, 6, 7 and 8 exhibiting cytotoxicity greater than 96%. Only slight inhibition of the proliferation of PBMC’s was noted. IC50 values of DHPM 1-8 were determined and the best activity overall was displayed by DHPM 8. The IC50 of DHPM 8 was 0.92 ± 0.09 and 1.97 ± 0.08 µM against MCF - 7 and UACC - 62 cell lines, respectively. The compounds that displayed toxicity towards the UACC - 62 cell line were investigated for their apoptotic inducing potential. The apoptotic studies were performed by flow cytometry using the following assays; Annexin V, JC-1 and Caspase -3 assays. The effect of these compounds was compared to a known anti-cancer drug, Camptothecin. On evaluation of the mechanism of action of the compounds, it was found that most compounds are using apoptotic pathways for cell death. Our studies have identified antimicrobial activity (DHPM 1-8) against Gram positive organisms, high antioxidant activity (DHPM 2), anti-inflammatory activity (DHPM 1-8) and anticancer activity (DHPM 1-8) against UACC-62 and MCF-7 cells. DHPM 1-8 were found to have no toxicity at 100 µg/mL in the brine shrimp assay and hence are probably safe as therapeutic agents. Furthermore molecular docking studies confirmed the activity of DHPM 1-8 as potential lipoxygenase inhibitors. DHPM 1-8 are novel compounds with great potential to be developed into chemotherapeutic agents. / M

Thesis advisor: Udayan Mohanty / Solar fuel synthesis via photoelectrochemistry represents a promising strategy to achieve solar energy conversion and storage. The improvement of photoelectrochemical water splitting performance lies in choosing suitable photoelectrode materials, followed by strategic optimization of their properties. Among those properties, the interface between the semiconductors and electrolyte is of paramount importance, yet it is still not well understood. In my dissertation, I will mainly focus on understanding and controlling those interfaces, with two study platforms. The first study platform is tantalum nitride (Ta3N5), which is an attractive photoanode material with good optoelectronic properties. However, it suffers from low photovoltage despite of the high theoretical expectation and rapid performance decay when it is used for water oxidation. With the help of various characterization methods, it was found that water or hydroxyl group adsorption on the surface as well as the self-limited surface oxidation during water oxidation led to the positive shift of band edge positions and Fermi level, accompanied with increase of charge transfer resistance on the surface. In consequence, decrease of photovoltage and photocurrent was observed. Two different strategies were developed. The first was to fully isolate Ta3N5 from water with the deposition of uniform protection layer through atomic layer deposition. The second strategy utilized the reaction between Ta¬3N5 and co-catalyst instead of water, which led to the formation of a photo-induced interface that favored the desired chemistry instead of side reactions. The second study platform is a Si buried junction protected by GaN. By tuning the loading amount of Pt nanoparticles on GaN surface, both the photocurrent density and photovoltage of the photocathode was improved. With detailed spectroscopic study, it was implied that both charge transfer kinetics and interfacial energetics could be influenced by the loading of Pt on the surface. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

A thesis submitted to the Faculty of Science, University of the Witwatersrand, in fulfillment of the requirements for the degree, Doctor of philosophy Degree (PhD) in chemistry Johannesburg, 2013. / Nitrogen doped carbon nanotubes (N-CNTs) were synthesised using thermal-Chemical Vapour Deposition (CVD). The obtained material was purified, characterised and used as a support for ruthenium nanoparticles. The catalytic performance of the Ru/N-CNTs was investigated in different chemical reactions. Thus, this thesis is divided into two sections. The synthesis of the nanomaterials, the catalyst performance of nanomaterials in the oxygen reaction reduction (ORR) and activity in the oxidation of styrene and benzyl alcohol. In the first section N-CNTs were synthesised using a thermal-CVD method in a horizontal split-tube furnace. The reactions were carried out in a tubular quartz reactor. Cyclohexanol was used as carbon source, aniline as a nitrogen source and ferrocene as catalyst. A mixture of cyclohexanol-aniline-ferrocene was placed in a quartz boat that was directly introduced in the centre of the first furnace and vaporised at 280 °C. The resultant vapours were transferred to the second furnace where the N-CNTs were grown at a temperature of 900°C under the carrier gas flow (nitrogen or 5% H2 balanced in argon gas). The N-CNTs formed had a fairly crystalline structure, constituted by a periodical bamboo like structure with tubes diameters of 35 - 100 nm and nitrogen content up to 1.3 at. %.The N-CNTs with 0.8 at.% were selected to be used becaused of the quality and the amount of CNTs produced. N-CNTs were then used to support ruthenium (Ru) nanoparticles using a microwave assisted reduction technique. The synthesised nanostructured materials were characterised by TEM, SEM, TGA, and XRD. The TEM images of the Ru catalysts supported on N-CNTs revealed homogenous dispersion of Ru nanoparticles with a narrow sizes distribution and small particle size with an average diameter of 2.5 nm when 500 W power was used. In the second section, part A; four catalysts with different Ru wt. % supported on N-CNTs were prepared: the amount of Ru deposited on the N-CNTs was varied between 0 –10 wt. %. The activity of the prepared nanocatalysts towards the oxygen reduction reaction (ORR) was characterised using the rotating disk electrode and voltammetry techniques. The ORR activity was higher at lower concentrations of Ru on N-CNTs. The 4e- pathway of ORR was more favourable on 2 and 5 % Ru loaded N-CNTs than as 10 % Ru loaded N-CNTs. In Part B; prepared Ru/CNT and Ru/N-CNT catalysts were calcined and used for the liquid-phase oxidation reaction of styrene and benzyl alcohol. The influence of various reaction parameters such as reaction time, catalyst mass, solvent nature and reaction temperature were evaluated. It is interesting to note that the RuO2 on carbon material catalyst was more active for styrene oxidation than for benzyl alcohol oxidation reaction. The conversion of styrene was 41 % and the selectivity to benzaldehyde was 85 % when 5 % RuO2/CNTs catalyst was used with 1,4-dioxane as a solvent at 80 °C in 4 h. The highest conversion of benzyl alcohol was 11 % also with 85 % benzaldehyde selectivity. The benzyl alcohol oxidation was performed at 110 °C for 5 h. Ru/N-CNTs were shown to exhibit better activity for a styrene oxidation reaction. Therefore further investigations on the activity of nitrogen doped carbon nanotubes (N-CNTs*) prepared by reaction of acetylene (C2H2) and acetonitrile (CH3CN) at 700 °C over a 10 % Fe-Co supported on calcium carbonate (CaCO3) catalyst was investigated for styrene oxidation. In this case the nitrogen doped carbon nanotubes (N-CNTs*) with 2.2 at. % nitrogen content was used. A 5 % Ru/N-CNT* catalyst was highly selective as compared to the previous N-CNT supports used in the styrene oxidation reaction. Comparing the support it was deduced that the nitrogen present in the support is playing a major role. With the increase in the nitrogen content in the matrix of the CNTs the conversion of styrene decreased but with an increase in the selectivity. The selectivity towards benzaldehyde was 96 % after 4 h when N-CNTs* were used as support for the styrene conversion reaction. In comparison for the RuO2 on CNTs and N-CNTs the styrene conversions were 85 and 87 % respectively.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. July, 2017 / Eukaryotic protein synthesis occurs in three phases: initiation, elongation and termination. The elongation phase is mediated by elongation factors. Elongation factors are divided into elongation factor 1 (eEF1) and elongation factor 2 (eEF2). Elongation factor 1 complex are proteins that mediates the extension of growing polypeptide chains by adding one amino acid residue at a time. The eEF-1 complex comprises of four subunits, eEF1α, eEF1β, eEF1γ and eEF1δ. The β-subunit of elongation factor 1 complex (eEF1) plays a central role in the elongation step of eukaryotic protein biosynthesis, which essentially involves interaction with the α-subunits (eEF1α) and γ-subunits (eEF1γ). To biophysically characterise heEF1β, three E. coli expression vector systems was constructed for recombinant expression of the full length (FL-heEF1β), amino terminus (NT-heEF1β) and the carboxyl terminus (CT-heEF1β) regions of the protein. NT-heEF1β was created from the FL-heEF1β by site-directed mutagenesis using mutagenic forward and reverse primers. The results suggest that heEF1β is predominantly alpha-helical and possesses an accessible hydrophobic cavity in the CT-heEF1β. Both FL-heEF1β and NT-heEF1β forms dimers of size 62 kDa and 30 kDa, respectively, but the CT-heEF1β is monomeric. FL-heEF1β interacts with the N-terminus GST-like domain of heEF1γ (NT-heEF1γ) to form a 195 kDa complex, or a 230 kDa complex in the presence of oxidised glutathione. On the other hand, NT-heEF1β forms a 170 kDa complex with NT-heEF1γ and a high molecular weight aggregate of size greater than 670 kDa. This study affirms that the interaction between heEF1β and heEF1γ subunits occurs at the N-terminus regions of both proteins, also the N-terminus region of heEF1β is responsible for its dimerisation and the C-terminus region of heEF1β controls the formation of an ordered eEF1β-γ oligomer, a structure that may be essential in the elongation step of eukaryotic protein biosynthesis. / MT 2018

Thesis advisor: James P. Morken / Described herein is the exploration of a novel methodology whereby boronate-ester bearing cyclopentanes are produced by reaction between an unactivated olefin and what is described as a boron alkylidene. The mechanism is evaluated and concluded to proceed through a boracyclic intermediate that is achieved by a closed-shell, carbanion addition to the olefin. This mechanistic conclusion is arrived upon by considering two likely alternative routes (an open-shell, radical cyclization and a [2+2] concerted process) and providing evidence to refute them. A reaction scope is established as well as the utility of the methodology through the racemic synthesis of a natural sesquiterpene: aphanamal. Finally, the future of the reaction development will be considered by providing a single example of a 6-endo cyclization. / Thesis (MS) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Part A: N-Heterocyclic Carbenes Catalyzed Enantioselective Boryl Conjugate Additions to α,β-Unsaturated Ketones, Esters, Weinreb Amides and Aldehydes. The first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls are reported. Transformations are promoted by 5.0 mol % of a chiral Lewis basic N-heterocyclic carbene. The distinctive feature of the reactions in chemoselectivity of the method compared to the Cu-catalyzed variants has been illustrated. Part B: Enantioselective Synthesis of Boron-Substituted Quaternary Carbon Stereogenic Centers through N-Heterocyclic Carbenes Catalyzed Boryl Conjugate Additions to Cyclic and Acyclic Enones The first examples of Lewis base catalyzed enantioselective boryl conjugate additions that afford products containing boron-substituted quaternary carbon stereogenic centers are presented. The carbon–boron bond forming reactions are promoted by 1.0–5.0 mol % of a chiral N–hererocyclic carbene. Cyclic or linear α,β–unsaturated ketones can be used as suitable substrates and the desired products are obtained in 63–95% yield and 91:9 to >99:1 enantiomeric ratio. The utility of the Lewis base-catalyzed approach is demonstrated in the context of an enantioselective formal synthesis of antifungal natural product crassinervic acid. Chapter 2. Enantioselectivity Fluctuations in Phosphine–Cu-Catalyzed Enantioselective Boron-Allyl Addition to Aryl-Substituted Olefins. Catalytic enantioselective multicomponent processes involving B2(pin)2, aryl or heteroaryl monosubstituted olefins, and allylic phosphates or carbonates are disclosed. Transformations promoted by a chiral Cu–phosphine complex afford products that contain a primary C–B(pin) bond and an allyl-substituted tertiary carbon stereogenic center in up to 84% yield and 98:2 enantiomeric ratio. The utility of the approach is showcased in the enantioselective formal synthesis of biologically active heliespirones A and C. Based on mechanistic and computational studies, we show that enantioselectivities variations can depend on electronic and/or steric factors of the alkene substrate and the allyl electrophile as well as their concentration. In most cases, selectivity loss can be minimized and that the resulting insights are also applicable to reactions involving Cu–H species. Chapter 3. Synthesis of Vicinal Diboronate Compounds through Practical Phosphine–Copper Catalyzed Three-Component Processes. The phosphine–Cu-catalyzed multicomponent processes have been developed for a practical and direct synthesis of vicinal diboronate compounds. Reactions of alkenyl–boronates, allylic phosphates, and diboron reagents are promoted by 2.5–10 mol % of a Cy3P–Cu complex affording a wide range of desirable vicinal diboronate products. The ability for easy access to either regioisomers of the products with a C–B(pin) and an adjacent C–B(dan) bond that can be site-selectively functionalized is a noteworthy feature of the method. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

In this dissertation, we discuss the development of a synthetic method to functionalize various α-haloglycine esters, as key precursors to a large variety of non-proteinogenic α-amino acids (Xaas). At first, we discovered a very practical and high yielding acetyl chloride-mediated cascade reaction to synthesize α-arylated amino esters in one-pot. In this multicomponent reaction (MCR), a primary carbamate was condensed with a glyoxylate, followed by an in situ halogenation which proved essential to trigger the final Friedel−Crafts functionalization. After careful reaction optimization, a plethora of arene nucleophiles were reacted with high regioselectively in CHCl3 at low temperatures (Method A) while less activated arenes reacted more cleanly in CH3CN and at higher temperatures (Method B). To broaden the scope of this reaction to acid sensitive nucleophiles, a one-pot reaction was designed via evaporation of all acid by-products at the α-haloglycine stage. The anion-binding Schreiner’s thiourea catalyst proved to be extremely efficient to promote this complementary approach (Method C) which relies on the chloride leaving group activation by the catalyst to assist the functionalization stage and deliver the α-amino ester product. In the second chapter, some highly practical and efficient preparations of α-haloglycine esters in one-pot have been developed to generate useful precursors of non-proteinogenic α-amino esters. Also, a mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation/deoxy halogenation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. Friedel–Crafts reaction between α-chloroglycine and N-methylindole have been studied in details to understand the mechanistic intricacy of this reaction. Our findings through the initial kinetic profiling support that the arylation likely proceeds via a SN1-like (or SN2C+) mechanism. In third chapter, we discuss the development of the most challenging α,α-disubstituted amino esters in a multicomponent fashion. Our results highlight that the MCR proceeds via the formation of an enamide intermediate, which is further tautomerized to corresponding iminium to produce the desired product. In collaboration with Eli Lilly at the Automated Synthesis Laboratory (ASL), we have developed silver (I) salts mediated Friedel–Crafts reaction for synthesis of α-trifluoromethylated α-amino esters on a fully automatized robot. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection