The chemistry of Algoa Bay ascidians
- Authors: Bromley, Candice Leigh
- Date: 2016
- Subjects: Sea squirts -- South Africa -- Algoa Bay , Marine metabolites , Chemistry, Analytic , Liquid chromatography , Inductively coupled plasma mass spectrometry , Metal ions , Nucleosides , Vanadium
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4560 , http://hdl.handle.net/10962/d1020606
- Description: This thesis investigates the chemistry of 25 ascidian species collected from Algoa Bay, South Africa with a concerted focus on metal accumulation by these ascidians and the possible interaction of these metals with ascidian metabolites. Chapter 2 details the screening techniques employed to establish the presence of nitrogenous metabolites (1H- 15N HMBC), hyper-accumulated metal ions (ICP-MS) and potential metal ion/ ascidian metabolite complexes (LC-ICP-MS/ESI-MS). Unfortunately, exhaustive attempts to detect intact metal ion/ascidian metabolite complexes through the use of liquid chromatography with parallel inductively coupled plasma mass spectrometry/electrospray mass spectrometry (LC-ICPMS/ ESI-MS) were unsuccessful. However, the LC-ICP-MS/ESI-MS data obtained for the crude organic extracts of six of the Algoa Bay ascidian species, Distaplia skoogi, Aplidium monile, Aplidium sp., Didemnum sp., Leptoclindines sp. and Polycitor sp. enabled identification of a number of ten halogenated metabolites, namely the indoles 2.28-2.30, and the tyramine and tyrosine derivatives (2.31-2.33, 2.41, 2.43, 2.44 and 2.46), within the ascidian extracts. This study confirmed that LC-ICP-MS/ESI-MS is a powerful tool for the dereplication of halogenated metabolites in complex mixtures especially where these compounds are present in very small amounts. This study is also the first report of these compounds (eight of which are known) in African ascidians. Compounds 2.32 and 2.46 have not been reported before from a marine source. Compounds 2.28-2.30 and 2.33 were present in sufficient amounts in the respective ascidian extracts to allow their isolation and structure elucidation using standard spectroscopic techniques Chapter 3 explores the ability of ascidians to accumulate a wide range of metal ions at concentrations which are often orders of magnitude higher than those of the surrounding sea water. Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the total ion concentrations of 24 metals in 25 Algoa Bay ascidian species. To the best of our knowledge this is the largest and most extensive investigation of metal concentrations in a group of different ascidians occurring in the same area. Hypotheisizing that the metal ion concentrations for each ascidian specimen screened may represent a unique fingerprint for each specimen principal component analysis (PCA) was used in an attempt to establish whether there were spatial, temporal or phylogenetic relationships associated with the metal concentration fingerprints of the ascidians that formed part of this study. The PCA results showed that there were no statistically significant relationships between ascidian metal ion concentrations and either the collection year or the collection site of the ascidians. However, species from the family Didemnidae provided the clearest statistical evidence supporting a phylogenetic relationship between these ascidians and their hyperaccumulated metal ion profiles. Furthermore, these results suggested that ascidian species are indeed actively concentrating metal ions from the surrounding sea water and are not simply sinks for passively accumulated metal ions. Interestingly, the concentration of vanadium in the set of ascidians studied did not appear to correlate with any of the other metals accumulated by these ascidians suggesting that there is possibly a unique method employed for the accumulation of vanadium by ascidians. Chapter 4 investigated this possibility further after the nucleosides 4.10, 4.11, 4.13, 4.15, 4.17 and 4.40 were isolated from the vanadium accumulating ascidian Aplidium monile. Studies into the interactions between nucleosides and vanadyl are unfortunately rare and usually qualitative in nature with limited information provided about the stability or structures of the complexes formed. The vanadyl accumulating aplousobranch ascidians e.g. Aplidium monile dominated our study of Algoa Bay ascidians therefore providing us with the rationale to investigate the relatively little studied binding ability and stability of vandyl-nucleoside complexes. Potentiometric studies were conducted to determine the stability constants of complexes formed between the oxovanadium ion vanadyl (VO2+) and the commercially available nucleosides 4.10-4.14. The data afforded by this analysis clearly confirmed the complexity of the vanadyl/nucleoside complexation and suggested that guanosine (4.12) formed the most stable complex with oxovanadium ions. We were also able to establish a third protonation constant for the hydroxyl moiety in 4.12 with a logK 8.87 which has not been previously reported. Finally, Chapter 5 revisited the cytoxicity two Algoa Bay ascidians, Clavelina sp. and Atriolum marinense the extracts from which produced promising bioactivity results in previous studies against oesophageal cancer cells. The HP-20 fractionated extracts of Clavelina sp. and Atriolum marinense proved to be similalrly cytotoxic to breast cancer cells. With the exception for the 100% acetone(aq)fractions the NMR data for both species suggested that most active non polar fractions were dominated by what appeared to be structurally unremarkable fatty acid glycerides and as such were not pursued further. Purification of the 100% acetone(aq)fraction of A. marinense resulted in the isolation of a styrene trimer, 5.1, common to both ascidian extracts. The NMR simulation software WIN-DAISY was employed to confirm the structure of 5.1. Attempts to establish if 5.1 was an isolation artefact or a product of marine pollution were inconclusive
- Full Text:
- Date Issued: 2016
- Authors: Bromley, Candice Leigh
- Date: 2016
- Subjects: Sea squirts -- South Africa -- Algoa Bay , Marine metabolites , Chemistry, Analytic , Liquid chromatography , Inductively coupled plasma mass spectrometry , Metal ions , Nucleosides , Vanadium
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4560 , http://hdl.handle.net/10962/d1020606
- Description: This thesis investigates the chemistry of 25 ascidian species collected from Algoa Bay, South Africa with a concerted focus on metal accumulation by these ascidians and the possible interaction of these metals with ascidian metabolites. Chapter 2 details the screening techniques employed to establish the presence of nitrogenous metabolites (1H- 15N HMBC), hyper-accumulated metal ions (ICP-MS) and potential metal ion/ ascidian metabolite complexes (LC-ICP-MS/ESI-MS). Unfortunately, exhaustive attempts to detect intact metal ion/ascidian metabolite complexes through the use of liquid chromatography with parallel inductively coupled plasma mass spectrometry/electrospray mass spectrometry (LC-ICPMS/ ESI-MS) were unsuccessful. However, the LC-ICP-MS/ESI-MS data obtained for the crude organic extracts of six of the Algoa Bay ascidian species, Distaplia skoogi, Aplidium monile, Aplidium sp., Didemnum sp., Leptoclindines sp. and Polycitor sp. enabled identification of a number of ten halogenated metabolites, namely the indoles 2.28-2.30, and the tyramine and tyrosine derivatives (2.31-2.33, 2.41, 2.43, 2.44 and 2.46), within the ascidian extracts. This study confirmed that LC-ICP-MS/ESI-MS is a powerful tool for the dereplication of halogenated metabolites in complex mixtures especially where these compounds are present in very small amounts. This study is also the first report of these compounds (eight of which are known) in African ascidians. Compounds 2.32 and 2.46 have not been reported before from a marine source. Compounds 2.28-2.30 and 2.33 were present in sufficient amounts in the respective ascidian extracts to allow their isolation and structure elucidation using standard spectroscopic techniques Chapter 3 explores the ability of ascidians to accumulate a wide range of metal ions at concentrations which are often orders of magnitude higher than those of the surrounding sea water. Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the total ion concentrations of 24 metals in 25 Algoa Bay ascidian species. To the best of our knowledge this is the largest and most extensive investigation of metal concentrations in a group of different ascidians occurring in the same area. Hypotheisizing that the metal ion concentrations for each ascidian specimen screened may represent a unique fingerprint for each specimen principal component analysis (PCA) was used in an attempt to establish whether there were spatial, temporal or phylogenetic relationships associated with the metal concentration fingerprints of the ascidians that formed part of this study. The PCA results showed that there were no statistically significant relationships between ascidian metal ion concentrations and either the collection year or the collection site of the ascidians. However, species from the family Didemnidae provided the clearest statistical evidence supporting a phylogenetic relationship between these ascidians and their hyperaccumulated metal ion profiles. Furthermore, these results suggested that ascidian species are indeed actively concentrating metal ions from the surrounding sea water and are not simply sinks for passively accumulated metal ions. Interestingly, the concentration of vanadium in the set of ascidians studied did not appear to correlate with any of the other metals accumulated by these ascidians suggesting that there is possibly a unique method employed for the accumulation of vanadium by ascidians. Chapter 4 investigated this possibility further after the nucleosides 4.10, 4.11, 4.13, 4.15, 4.17 and 4.40 were isolated from the vanadium accumulating ascidian Aplidium monile. Studies into the interactions between nucleosides and vanadyl are unfortunately rare and usually qualitative in nature with limited information provided about the stability or structures of the complexes formed. The vanadyl accumulating aplousobranch ascidians e.g. Aplidium monile dominated our study of Algoa Bay ascidians therefore providing us with the rationale to investigate the relatively little studied binding ability and stability of vandyl-nucleoside complexes. Potentiometric studies were conducted to determine the stability constants of complexes formed between the oxovanadium ion vanadyl (VO2+) and the commercially available nucleosides 4.10-4.14. The data afforded by this analysis clearly confirmed the complexity of the vanadyl/nucleoside complexation and suggested that guanosine (4.12) formed the most stable complex with oxovanadium ions. We were also able to establish a third protonation constant for the hydroxyl moiety in 4.12 with a logK 8.87 which has not been previously reported. Finally, Chapter 5 revisited the cytoxicity two Algoa Bay ascidians, Clavelina sp. and Atriolum marinense the extracts from which produced promising bioactivity results in previous studies against oesophageal cancer cells. The HP-20 fractionated extracts of Clavelina sp. and Atriolum marinense proved to be similalrly cytotoxic to breast cancer cells. With the exception for the 100% acetone(aq)fractions the NMR data for both species suggested that most active non polar fractions were dominated by what appeared to be structurally unremarkable fatty acid glycerides and as such were not pursued further. Purification of the 100% acetone(aq)fraction of A. marinense resulted in the isolation of a styrene trimer, 5.1, common to both ascidian extracts. The NMR simulation software WIN-DAISY was employed to confirm the structure of 5.1. Attempts to establish if 5.1 was an isolation artefact or a product of marine pollution were inconclusive
- Full Text:
- Date Issued: 2016
The anodic oxidation of calcium lactate : an estimation of the products of electrolysis and an investigation into some of the problems involved
- Authors: Impey, Norman Robert Murray
- Date: 1949
- Subjects: Electrolytic oxidation
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4480 , http://hdl.handle.net/10962/d1012556 , Electrolytic oxidation
- Description: The subject of this thesis was chosen originally as a result of a suggestion made by a manufacturer of lactic acid. Lactic acid is made by a fermentation process from molasses and the acid is extracted from the fermentation liquors as calcium lactate. The conversion of the calcium lactate back to lactic acid is a tedious process from an industrial point of view. It was therefore suggested that the conversion may be more easily accomplished by electrolysis. The first experimental work was conducted with this object in view, but it soon became apparent that it was unlikely that lactic acid could be produced in suitable quantities for industrial purposes by this means. There was no reference in the literature to the electrolysis of calcium lactate, and little reference to the electrolysis of lactates in general, and what there was appeared to be conflicting, so it was decided to continue the investigation into the subject in order to determine what are the products of the anodic oxidation of calcium lactate. Intro., p.1.
- Full Text:
- Date Issued: 1949
- Authors: Impey, Norman Robert Murray
- Date: 1949
- Subjects: Electrolytic oxidation
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4480 , http://hdl.handle.net/10962/d1012556 , Electrolytic oxidation
- Description: The subject of this thesis was chosen originally as a result of a suggestion made by a manufacturer of lactic acid. Lactic acid is made by a fermentation process from molasses and the acid is extracted from the fermentation liquors as calcium lactate. The conversion of the calcium lactate back to lactic acid is a tedious process from an industrial point of view. It was therefore suggested that the conversion may be more easily accomplished by electrolysis. The first experimental work was conducted with this object in view, but it soon became apparent that it was unlikely that lactic acid could be produced in suitable quantities for industrial purposes by this means. There was no reference in the literature to the electrolysis of calcium lactate, and little reference to the electrolysis of lactates in general, and what there was appeared to be conflicting, so it was decided to continue the investigation into the subject in order to determine what are the products of the anodic oxidation of calcium lactate. Intro., p.1.
- Full Text:
- Date Issued: 1949
The adsorption of chelating reagents on oxide minerals
- Bryson, Michael Andrew Walker
- Authors: Bryson, Michael Andrew Walker
- Date: 1986
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:20969 , http://hdl.handle.net/10962/5729
- Description: This work constitutes a fundamental study of the interaction between chelating reagents and oxide minerals . The adsorption mechanisms have been elucidated for most of the systems generated by the oxides of copper(II) or iron(III) and chelating reagents octyl hydroxamate, N-phenylbenzohydroxamate, salicylaldoxime, 5-nitrosalicylaldoxime or 8-hydroxyquinoline. The results of the preliminary work on one of the systems, viz. the oxide-hydroxamate system, indicated that the classical type adsorption process, in which the reagent forms a uniform layer of chelate over the oxide surface was not applicable. Rather, the adsorption occurred via the formation of a discrete metal-chelate precipitate at the oxide surface. In order to better understand the associated with copper (II) oxide, adsorption process the oxide was recrystallized to produce a coarser material with a more uniform surface. This allowed the oxide surface to be viewed under the scanning electron microscope and also enabled the relative concentration of "surface" and "bulk" chelate to be assessed. A detailed investigation of the effect of the system variables; pH, conditioning period, concentration, temperature, surface area and dispersing reagent on the rate of precipitation of the copper chelate species of general form, Cu(chel)2' was made. In addition the chemical nature of the adsorbed species and the structural form of the precipitates were determined with the aid of infra-red spectroscopy and the scanning electron microscope. On the basis of these results a model has been formulated for the adsorption processes. In this model the adsorption dissolution, is considered to occur in stages: 1. Oxide dissolution, 2. metal complex formation, 3. Metal chelate precipitation at the oxide surface and 4. “bulk” chelate formation by post-precipitation processes. The precipitation process was examined in more detail by the study of the adsorption of chelate on copper metal. The results of this study showed that it was possible to relate the structural type of precipitate formed, ie. fibrous or platelike, to the degree of supersaturation of the metal complex in solution. Furthermore, it was found that the precipitate structure determined whether it remained attached to the surface or detached. Contact angle measurements of air bubbles on copper metal conditioned with chelate were related to the adsorption results in an attempt to isolate the optimum conditions for flotation of oxide minerals.
- Full Text:
- Date Issued: 1986
- Authors: Bryson, Michael Andrew Walker
- Date: 1986
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:20969 , http://hdl.handle.net/10962/5729
- Description: This work constitutes a fundamental study of the interaction between chelating reagents and oxide minerals . The adsorption mechanisms have been elucidated for most of the systems generated by the oxides of copper(II) or iron(III) and chelating reagents octyl hydroxamate, N-phenylbenzohydroxamate, salicylaldoxime, 5-nitrosalicylaldoxime or 8-hydroxyquinoline. The results of the preliminary work on one of the systems, viz. the oxide-hydroxamate system, indicated that the classical type adsorption process, in which the reagent forms a uniform layer of chelate over the oxide surface was not applicable. Rather, the adsorption occurred via the formation of a discrete metal-chelate precipitate at the oxide surface. In order to better understand the associated with copper (II) oxide, adsorption process the oxide was recrystallized to produce a coarser material with a more uniform surface. This allowed the oxide surface to be viewed under the scanning electron microscope and also enabled the relative concentration of "surface" and "bulk" chelate to be assessed. A detailed investigation of the effect of the system variables; pH, conditioning period, concentration, temperature, surface area and dispersing reagent on the rate of precipitation of the copper chelate species of general form, Cu(chel)2' was made. In addition the chemical nature of the adsorbed species and the structural form of the precipitates were determined with the aid of infra-red spectroscopy and the scanning electron microscope. On the basis of these results a model has been formulated for the adsorption processes. In this model the adsorption dissolution, is considered to occur in stages: 1. Oxide dissolution, 2. metal complex formation, 3. Metal chelate precipitation at the oxide surface and 4. “bulk” chelate formation by post-precipitation processes. The precipitation process was examined in more detail by the study of the adsorption of chelate on copper metal. The results of this study showed that it was possible to relate the structural type of precipitate formed, ie. fibrous or platelike, to the degree of supersaturation of the metal complex in solution. Furthermore, it was found that the precipitate structure determined whether it remained attached to the surface or detached. Contact angle measurements of air bubbles on copper metal conditioned with chelate were related to the adsorption results in an attempt to isolate the optimum conditions for flotation of oxide minerals.
- Full Text:
- Date Issued: 1986
Tetra 4-(propargyloxy)phenoxy phthalocyanines: synthesis, spectroscopic, nonlinear optical and electrocatalytic properties
- Authors: Mwanza, Daniel
- Date: 2017
- Subjects: Phthalocyanines , Nonlinear optics , Electrocatalysis , Spectrum analysis , Thermogravimetry , Phthalocyanines Spectra
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/65144 , vital:28695
- Description: This study presents the synthesis, spectroscopic, photophysical and theoretical characterisation of metal-free (H2TPrOPhOPc), cobalt (CoTPrOPhOPc) and manganese (MnTPrOPhOPc) tetra 4-(4-propargyloxy) phenoxy phthalocyanines. Thermal analysis using thermogravimetric analysis (TGA) confirmed the excellent thermal stability of synthesized tetra 4-(4- propargyloxy) phenoxy phthalocyanines. The metal complexes, CoTPrOPhOPc and MnTPrOPhOPc, exhibited better thermal stability when compared to H2TPrOPhOPc. The residual percentage weight remaining was approximately 70% for CoTPrOPhOPc and MnTPrOPhOPc and 45% for H2TPrOPhOPc after 600°C, clearly confirming the stability of the metal complexes. The MTPrOPhOPcs (where M = H2, Co and Mn) complexes exhibited excellent nonlinear optical properties with strong reverse saturable absorption (RSA), especially when 560 nm excitation laser was used. Their nonlinear optical properties followed this trend: H2TPrOPhOPc > CoTPrOPhOPc > MnTPrOPhOPc. According to the trend observed, the H2TPrOPhOPc was an excellent nonlinear optical limiter when compared to the CoTPrOPhOPc and MnTPrOPhOPc. All the investigated complexes exhibited optical limiting properties comparable to the phthalocyanine complexes reported in the literature. The MTPrOPhOPc complexes were further studied for their electrocatalytic and electroanalytical properties towards the detection of hydrogen peroxide. For the electrocatalytic studies, the synthesized complexes were immobilized onto gold electrode surfaces pre-functionalized with phenylazide (Au-PAz) monolayer. Copper (I) catalyzed alkynyl-azide cycloaddition reaction was used to covalently immobilize the MTPrOPhOPcs onto the gold electrode surfaces to form Au-PAz-MTPrOPhOPc. The MTPrOPhOPcs modified gold surfaces (Au-PAz-MTPrOPhOPc) exhibited good reproducibility and stability in various electrolyte conditions. Electrochemical and surface characterisation of the functionalised gold electrode surfaces confirmed the presence of the MTPrOPhOPcs and their electroanalysis was excellent towards electrocatalytic reduction of H2O2, with the limit of detection (LoD) and limit of quantification (LoQ) in the ^M range. The electrocatalytic reduction peaks for H2O2 were observed at -0.37 V for Au-PAz-MnTPrOPhOPc and -0.31 V for Au-PAz-CoTPrOPhOPc when Ag|AgCl pseudo-reference electrode was used. The Au-PAz-MnTPrOPhOPc and Au- PAz-CoTPrOPhOPc gold electrode surfaces showed good sensitivity and reproducibility towards the electrocatalytic reduction of hydrogen peroxide in pH 7.4 phosphate buffer solution. , Thesis (MSc) -- Faculty of Science, Chemistry, 2017
- Full Text:
- Date Issued: 2017
- Authors: Mwanza, Daniel
- Date: 2017
- Subjects: Phthalocyanines , Nonlinear optics , Electrocatalysis , Spectrum analysis , Thermogravimetry , Phthalocyanines Spectra
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/65144 , vital:28695
- Description: This study presents the synthesis, spectroscopic, photophysical and theoretical characterisation of metal-free (H2TPrOPhOPc), cobalt (CoTPrOPhOPc) and manganese (MnTPrOPhOPc) tetra 4-(4-propargyloxy) phenoxy phthalocyanines. Thermal analysis using thermogravimetric analysis (TGA) confirmed the excellent thermal stability of synthesized tetra 4-(4- propargyloxy) phenoxy phthalocyanines. The metal complexes, CoTPrOPhOPc and MnTPrOPhOPc, exhibited better thermal stability when compared to H2TPrOPhOPc. The residual percentage weight remaining was approximately 70% for CoTPrOPhOPc and MnTPrOPhOPc and 45% for H2TPrOPhOPc after 600°C, clearly confirming the stability of the metal complexes. The MTPrOPhOPcs (where M = H2, Co and Mn) complexes exhibited excellent nonlinear optical properties with strong reverse saturable absorption (RSA), especially when 560 nm excitation laser was used. Their nonlinear optical properties followed this trend: H2TPrOPhOPc > CoTPrOPhOPc > MnTPrOPhOPc. According to the trend observed, the H2TPrOPhOPc was an excellent nonlinear optical limiter when compared to the CoTPrOPhOPc and MnTPrOPhOPc. All the investigated complexes exhibited optical limiting properties comparable to the phthalocyanine complexes reported in the literature. The MTPrOPhOPc complexes were further studied for their electrocatalytic and electroanalytical properties towards the detection of hydrogen peroxide. For the electrocatalytic studies, the synthesized complexes were immobilized onto gold electrode surfaces pre-functionalized with phenylazide (Au-PAz) monolayer. Copper (I) catalyzed alkynyl-azide cycloaddition reaction was used to covalently immobilize the MTPrOPhOPcs onto the gold electrode surfaces to form Au-PAz-MTPrOPhOPc. The MTPrOPhOPcs modified gold surfaces (Au-PAz-MTPrOPhOPc) exhibited good reproducibility and stability in various electrolyte conditions. Electrochemical and surface characterisation of the functionalised gold electrode surfaces confirmed the presence of the MTPrOPhOPcs and their electroanalysis was excellent towards electrocatalytic reduction of H2O2, with the limit of detection (LoD) and limit of quantification (LoQ) in the ^M range. The electrocatalytic reduction peaks for H2O2 were observed at -0.37 V for Au-PAz-MnTPrOPhOPc and -0.31 V for Au-PAz-CoTPrOPhOPc when Ag|AgCl pseudo-reference electrode was used. The Au-PAz-MnTPrOPhOPc and Au- PAz-CoTPrOPhOPc gold electrode surfaces showed good sensitivity and reproducibility towards the electrocatalytic reduction of hydrogen peroxide in pH 7.4 phosphate buffer solution. , Thesis (MSc) -- Faculty of Science, Chemistry, 2017
- Full Text:
- Date Issued: 2017
Synthetic, spectrometric and computer modelling studies of novel ATP analogues
- Gxoyiya, Babalwa Siliziwe Blossom
- Authors: Gxoyiya, Babalwa Siliziwe Blossom
- Date: 2008
- Subjects: Spectrum analysis Tuberculosis -- Treatment Chemotherapy Adenosine triphosphate Adenosine triphosphate -- Synthesis Adenosine triphosphate -- Computer simulation Adenosine triphosphate -- Spectrometric imaging Glutamine synthetase Tuberculosis -- Chemotherapy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4386 , http://hdl.handle.net/10962/d1005051
- Description: This study has been concerned with the design and synthesis of A TP analogues with the potential to act as inhibitors of glutamine synthetase - a novel target for therapeutic intervention in the treatment of tuberculosis. Using a structural -analogy approach, various 3-indolylalkanoic acid, benzimidazole and pyrazolo[3,4-dJpyrimidine derivatives have been prepared and characterized. Alkylation of the heterocyclic bases using 4-(bromomethyl)-2,2-dimethyl-1 ,3-d ioxolane, 2-(bromomethoxy)ethyl acetate and 2-(chloroethoxy)ethanol in the presence of either NaH or BulOK afforded the corresponding N-alkylated derivatives of benzimidazole and 4-aminopyrazolo[3,4-dJpyrimidine (4-APP). Similar reactions with 3-indo lylalkanoic esters resulted in O-alkyl cleavage with the formation of new esters. Alkylation of benzimidazole with allyl bromide, 4-bromobutene and 2-methylbut-2-ene has also been shown to afford the corresponding l-alkenylbenzimidazoles in moderate to excellent yield (43-96%). Subsequent oxidation of these products using CTAP, gave the dihydroxy derivatives in poor to good yields (26-77%). Phosphorylation of various hydroxy derivatives of benzimidazole and 4-APP has been achieved using diethyl chlorophosphate to afford the corresponding monophosphate and 1,2-diphosphate esters. Glycosylation of each of the heterocyclic bases has been successfully achieved using 1,2,3,4,6-penta-O-acetyl-D-glucopyranose and SnCl4 in acetonitri le, while methanolysis of the resulting tetraacetates, using methanolic NaOMe, afforded the hydroxy derivatives in good yield (50-70%). Various 1- and 2-dimensional NMR spectroscopic methods (e.g., IH, 13C, lip, COSY, HSQC and HMBC) have been used to confirm the structures of the synthesized A IP analogues. The application of NMR prediction programmes has been explored, permitting assessment of their agreement with the experimental data and confirmation of assigned structures. High-resolution electron impact (EI) mass spectrometric data have been used to explore the mass fragmentation pathways exhibited by selected derivatives, and certain common fragmentations have been identified. Molecular modelling of selected products as potential glutamine synthetase ligands has been performed on the Accelrys Cerius2 platform, and interactive receptor-ligand docking studies have been conducted using the Ligand-Fit module. These studies have revealed possible hydrogen-boding interactions between the selected analogues and various amino acid residues in the glutamine synthetase active site.
- Full Text:
- Date Issued: 2008
- Authors: Gxoyiya, Babalwa Siliziwe Blossom
- Date: 2008
- Subjects: Spectrum analysis Tuberculosis -- Treatment Chemotherapy Adenosine triphosphate Adenosine triphosphate -- Synthesis Adenosine triphosphate -- Computer simulation Adenosine triphosphate -- Spectrometric imaging Glutamine synthetase Tuberculosis -- Chemotherapy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4386 , http://hdl.handle.net/10962/d1005051
- Description: This study has been concerned with the design and synthesis of A TP analogues with the potential to act as inhibitors of glutamine synthetase - a novel target for therapeutic intervention in the treatment of tuberculosis. Using a structural -analogy approach, various 3-indolylalkanoic acid, benzimidazole and pyrazolo[3,4-dJpyrimidine derivatives have been prepared and characterized. Alkylation of the heterocyclic bases using 4-(bromomethyl)-2,2-dimethyl-1 ,3-d ioxolane, 2-(bromomethoxy)ethyl acetate and 2-(chloroethoxy)ethanol in the presence of either NaH or BulOK afforded the corresponding N-alkylated derivatives of benzimidazole and 4-aminopyrazolo[3,4-dJpyrimidine (4-APP). Similar reactions with 3-indo lylalkanoic esters resulted in O-alkyl cleavage with the formation of new esters. Alkylation of benzimidazole with allyl bromide, 4-bromobutene and 2-methylbut-2-ene has also been shown to afford the corresponding l-alkenylbenzimidazoles in moderate to excellent yield (43-96%). Subsequent oxidation of these products using CTAP, gave the dihydroxy derivatives in poor to good yields (26-77%). Phosphorylation of various hydroxy derivatives of benzimidazole and 4-APP has been achieved using diethyl chlorophosphate to afford the corresponding monophosphate and 1,2-diphosphate esters. Glycosylation of each of the heterocyclic bases has been successfully achieved using 1,2,3,4,6-penta-O-acetyl-D-glucopyranose and SnCl4 in acetonitri le, while methanolysis of the resulting tetraacetates, using methanolic NaOMe, afforded the hydroxy derivatives in good yield (50-70%). Various 1- and 2-dimensional NMR spectroscopic methods (e.g., IH, 13C, lip, COSY, HSQC and HMBC) have been used to confirm the structures of the synthesized A IP analogues. The application of NMR prediction programmes has been explored, permitting assessment of their agreement with the experimental data and confirmation of assigned structures. High-resolution electron impact (EI) mass spectrometric data have been used to explore the mass fragmentation pathways exhibited by selected derivatives, and certain common fragmentations have been identified. Molecular modelling of selected products as potential glutamine synthetase ligands has been performed on the Accelrys Cerius2 platform, and interactive receptor-ligand docking studies have been conducted using the Ligand-Fit module. These studies have revealed possible hydrogen-boding interactions between the selected analogues and various amino acid residues in the glutamine synthetase active site.
- Full Text:
- Date Issued: 2008
Synthetic studies of swazinecic acid dilactone
- Authors: Liddell, James Richard
- Date: 1989
- Subjects: Phrrolizidines Alkaloids -- Synthesis
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4298 , http://hdl.handle.net/10962/d1004668
- Description: The occurrence and syntheses of the pyrrolizidine alkaloids from 1976 to March 1988 is reviewed, and a stereoselective total synthesis of swazinecic acid dilactone was attempted. One approach involved an asymmetric synthesis of the allylic α-hydroxy acid 2-hydroxy-2,3-dimethyl-3-butenoic acid employing oxazolines as chiral auxilaries. The oxazoline, (4S,5S)-2-(1-bromoethyl)-4-methoxymethyl-5-phenyl-2-oxazoline, was obtained by direct halogenation of the 2-ethyl oxazoline analogue. This was condensed with acetone in a Darzens type reaction and the resultant epoxy oxazoline rearranged to an allylic α-hydroxy oxazoline which was then hydrolysed to the chiral hydroxy acid in low enantiomeric excess. The hydroxy acid, as the O-silylated ethyl ester, was elaborated by allylic diethyl malonate to bromination and condensation with diethyl 5-carboethoxy-2-methyl-3- methylene-2-0-tert-butyldimethylsilylhexanedioate. Removal of the silyl protecting group and epoxidation provided an epoxy triester, which on hydrolysis provided a mixture of acids of uncertain structures.
- Full Text:
- Date Issued: 1989
- Authors: Liddell, James Richard
- Date: 1989
- Subjects: Phrrolizidines Alkaloids -- Synthesis
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4298 , http://hdl.handle.net/10962/d1004668
- Description: The occurrence and syntheses of the pyrrolizidine alkaloids from 1976 to March 1988 is reviewed, and a stereoselective total synthesis of swazinecic acid dilactone was attempted. One approach involved an asymmetric synthesis of the allylic α-hydroxy acid 2-hydroxy-2,3-dimethyl-3-butenoic acid employing oxazolines as chiral auxilaries. The oxazoline, (4S,5S)-2-(1-bromoethyl)-4-methoxymethyl-5-phenyl-2-oxazoline, was obtained by direct halogenation of the 2-ethyl oxazoline analogue. This was condensed with acetone in a Darzens type reaction and the resultant epoxy oxazoline rearranged to an allylic α-hydroxy oxazoline which was then hydrolysed to the chiral hydroxy acid in low enantiomeric excess. The hydroxy acid, as the O-silylated ethyl ester, was elaborated by allylic diethyl malonate to bromination and condensation with diethyl 5-carboethoxy-2-methyl-3- methylene-2-0-tert-butyldimethylsilylhexanedioate. Removal of the silyl protecting group and epoxidation provided an epoxy triester, which on hydrolysis provided a mixture of acids of uncertain structures.
- Full Text:
- Date Issued: 1989
Synthetic ion exchange resins, incorporating asymmetric groups, as resolving agents
- Authors: O'Sullivan, Diarmid John
- Date: 1958
- Subjects: Ion exchange resins -- Synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4485 , http://hdl.handle.net/10962/d1012991
- Description: The object of this research is to further investigate the possiblitiy of resolving racemic bases on an optically active cation exchange resin. Any success in this direction would help to explain the reason for Bunnett and Mark's failure, since the general assumption that selective adsorption of one enantimorph of a racemic compound on an active exchanger should occur has been verified by Grubhofer and Schleith. The work can be conveniently divided into two sections. a) The preparation of optically active cation exchange resins and, b) the use of these as resolving agents. P. 8
- Full Text:
- Date Issued: 1958
- Authors: O'Sullivan, Diarmid John
- Date: 1958
- Subjects: Ion exchange resins -- Synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4485 , http://hdl.handle.net/10962/d1012991
- Description: The object of this research is to further investigate the possiblitiy of resolving racemic bases on an optically active cation exchange resin. Any success in this direction would help to explain the reason for Bunnett and Mark's failure, since the general assumption that selective adsorption of one enantimorph of a racemic compound on an active exchanger should occur has been verified by Grubhofer and Schleith. The work can be conveniently divided into two sections. a) The preparation of optically active cation exchange resins and, b) the use of these as resolving agents. P. 8
- Full Text:
- Date Issued: 1958
Synthetic approaches to marine labdane diterpenes
- Authors: Wisch, Gregory Albert
- Date: 2002 , 2013-05-10
- Subjects: Diterpenes
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4289 , http://hdl.handle.net/10962/d1003131 , Diterpenes
- Description: The work presented in this thesis describes the synthesis of labd-13-en-8ß, 15-diol (46) a stable reduced derivative of an unstable marine natural product aldehyde [8ß-hydroxylabd-13E-en-15-al (6)] isolated by Cimino, et al. from the skin of a Notaspidean mollusc Pleurobranchaea meckelii. The rationale for the synthesis was to provide sufficient 46 for eventual mild oxidation to 6 and investigation of the biological activity of this latter compound. (-)-Sclareol (32), a common diterpene synthetic precursor, was the starting point for the ten step synthesis of 46 described in this thesis. A search of the literature revealed that only one non stereospecific synthesis of 46 had been previously reported. To provide the necessary background to the synthetic component of this thesis, both the occurrence of labdane and ent-labdane in the marine environment and the use of sclareol in the synthesis of marine natural products, was reviewed. The initial step in the synthesis of 46 was the potassium permanganate oxidation of sclareol to give a bisnorlabdane ketone. Reduction of this ketone with lithium aluminium hydride produced a mixture of diols which, through t-butyldimethysilyl triflate protection, afforded a quantitative route to protecting the C-13 ketone in an effort to prevent unwanted intramolecular cyclization reactions. Dehydration of the tertiary alcohol moiety at C-8 with phosphorous oxychloride yielded the Δ⁸·¹⁵ exocyclic alkene required for the next oxidation step. Ozonolysis succeeded in producing the desired C-8 ketone after much deliberation and research into alternative oxidation strategies. Methyl lithium methylation quantitatively afforded the desired a-methyl substitution at C-8, identified at the onset as the key step in the synthesis. Tetra-butylarnmonium fluoride deprotection yielded the 8ß,13-dihydoxylated product, which was in turn subjected to a Swern oxidition to give the desired 8ß-hydroxy-bisnorlabda-13-one. A modified Horner-Wadsworth-Emmons reaction allowed for elaboration at C-13 to yield a to Δ¹³ olefin with a terminal C-15 ethyl ester. Diisobutylaluminium hydride reduction of the ester produced the desired labd-13-en-8ß, 15-diol (46) in a low overall yield of 3.4%. Although opportunities for optimization of at least three steps in the synthesis exist, time constraints prevented both optimization of these steps and an investigation of the oxidation of 46 to 6. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2002
- Authors: Wisch, Gregory Albert
- Date: 2002 , 2013-05-10
- Subjects: Diterpenes
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4289 , http://hdl.handle.net/10962/d1003131 , Diterpenes
- Description: The work presented in this thesis describes the synthesis of labd-13-en-8ß, 15-diol (46) a stable reduced derivative of an unstable marine natural product aldehyde [8ß-hydroxylabd-13E-en-15-al (6)] isolated by Cimino, et al. from the skin of a Notaspidean mollusc Pleurobranchaea meckelii. The rationale for the synthesis was to provide sufficient 46 for eventual mild oxidation to 6 and investigation of the biological activity of this latter compound. (-)-Sclareol (32), a common diterpene synthetic precursor, was the starting point for the ten step synthesis of 46 described in this thesis. A search of the literature revealed that only one non stereospecific synthesis of 46 had been previously reported. To provide the necessary background to the synthetic component of this thesis, both the occurrence of labdane and ent-labdane in the marine environment and the use of sclareol in the synthesis of marine natural products, was reviewed. The initial step in the synthesis of 46 was the potassium permanganate oxidation of sclareol to give a bisnorlabdane ketone. Reduction of this ketone with lithium aluminium hydride produced a mixture of diols which, through t-butyldimethysilyl triflate protection, afforded a quantitative route to protecting the C-13 ketone in an effort to prevent unwanted intramolecular cyclization reactions. Dehydration of the tertiary alcohol moiety at C-8 with phosphorous oxychloride yielded the Δ⁸·¹⁵ exocyclic alkene required for the next oxidation step. Ozonolysis succeeded in producing the desired C-8 ketone after much deliberation and research into alternative oxidation strategies. Methyl lithium methylation quantitatively afforded the desired a-methyl substitution at C-8, identified at the onset as the key step in the synthesis. Tetra-butylarnmonium fluoride deprotection yielded the 8ß,13-dihydoxylated product, which was in turn subjected to a Swern oxidition to give the desired 8ß-hydroxy-bisnorlabda-13-one. A modified Horner-Wadsworth-Emmons reaction allowed for elaboration at C-13 to yield a to Δ¹³ olefin with a terminal C-15 ethyl ester. Diisobutylaluminium hydride reduction of the ester produced the desired labd-13-en-8ß, 15-diol (46) in a low overall yield of 3.4%. Although opportunities for optimization of at least three steps in the synthesis exist, time constraints prevented both optimization of these steps and an investigation of the oxidation of 46 to 6. , KMBT_363 , Adobe Acrobat 9.54 Paper Capture Plug-in
- Full Text:
- Date Issued: 2002
Synthetic and spectroscopic studies of indolizine derivatives
- Authors: Bode, Moira Leanne
- Date: 1994
- Subjects: Indole alkaloids -- Derivatives Spectrum analysis Chemistry, Organic DNA -- Synthesis
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4385 , http://hdl.handle.net/10962/d1005050
- Description: The crystalline compound resulting from thermal cyclization of the Baylis-Hillman product, methyl 3-hydroxy-2-methylene-3-(2-pyridyl)propanoate, has been identified as the indolizine derivative, methyl indolizine-2-carboxylate, and this approach involving the reaction of pyridine-2-carboxaldehydes and acrylate analogues has been established as a general route to 2-substituted indolizines. The ease of cyclization the Baylis-Hillman products to indolizines has been shown to increase by converting the hydroxy group to an acetoxy group, and a range of acetylated Baylis-Hillman products were prepared and cyc1ized to the corresponding 2-substituted indolizines, generally in good overall yield. In the reaction of pyridine-2-carboxaldehyde and methyl vinyl ketone, the intermediate cyclized readily and directly to the corresponding indolizine. One- and two-dimensional ¹H and ¹³C NMR analysis of the 2-substituted indolizine products has permitted complete assignment of all ¹H and ¹³C NMR signals, as well as the measurement of all coupling constants for these compounds. A kinetic and mechanistic study has been conducted on the Baylis-Hillman reaction using ¹H NMR spectroscopy. A range of substrates has been examined and the reaction has been found to be third-order overall. A mechanism involving an addition - elimination sequence is proposed, which fits the kinetic data and accounts for observed substituent effects. Reaction of N,N-dimethylacrylamide with pyridine-2-carboxaldehyde in the presence of the tertiary amine catalyst, DABCO, in chloroform, yielded an unexpected product which has been identified by single crystal X-ray diffraction analysis as 1-(2,2,2-trichloro-1-hydroxyethyl)pyridine. Attempted extension of the general indolizine route to the preparation of chromene systems by reacting salicylaldehyde with methyl acrylate in the presence of DABCO, also led to an unexpected, crystalline material, identified by single crystal X-ray diffraction analysis as the coumarin derivative, 3-[(2-formylphenoxy)methyl]coumarin.A series of chloroquine analogues have been prepared from indolizine-2-carboxylic acid, pyrrolo[I,2-a]quinoline-2-carboxylic acid and imidazo[I,2-a]pyridine-2-carboxylic acid by reaction with suitable amines in the presence of the coupling reagent 1, I' -carbonyldiimidazole. This route has been shown to be a vast improvement on earlier procedures and has provided access to both secondary and tertiary indolizine-2-carboxamides. A range of N,N-dialkylindolizine-2-carboxamides have been prepared by this route, and the influence of substituents on their N-CO rotational energy barriers has been determined using variable temperature ¹H and ¹³C NMR techniques. Intercalation with natural DNA by both chloroquine and the synthesized chloroquine analogues has been examined using UV spectrophotometry, and ¹H and ³¹P NMR spectroscopy. The pyrrolo[I,2-a]quinolines have been shown to be DNA intercalators with binding affinities similar to that of the known antimalarial intercalator, chloroquine. In a preliminary study the synthesis of a short oligonucleotide has been undertaken and changes have been observed in the ¹H and ³¹P NMR spectra of the oligonucleotide on addition of the intercalator, chloroquine.
- Full Text:
- Date Issued: 1994
- Authors: Bode, Moira Leanne
- Date: 1994
- Subjects: Indole alkaloids -- Derivatives Spectrum analysis Chemistry, Organic DNA -- Synthesis
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4385 , http://hdl.handle.net/10962/d1005050
- Description: The crystalline compound resulting from thermal cyclization of the Baylis-Hillman product, methyl 3-hydroxy-2-methylene-3-(2-pyridyl)propanoate, has been identified as the indolizine derivative, methyl indolizine-2-carboxylate, and this approach involving the reaction of pyridine-2-carboxaldehydes and acrylate analogues has been established as a general route to 2-substituted indolizines. The ease of cyclization the Baylis-Hillman products to indolizines has been shown to increase by converting the hydroxy group to an acetoxy group, and a range of acetylated Baylis-Hillman products were prepared and cyc1ized to the corresponding 2-substituted indolizines, generally in good overall yield. In the reaction of pyridine-2-carboxaldehyde and methyl vinyl ketone, the intermediate cyclized readily and directly to the corresponding indolizine. One- and two-dimensional ¹H and ¹³C NMR analysis of the 2-substituted indolizine products has permitted complete assignment of all ¹H and ¹³C NMR signals, as well as the measurement of all coupling constants for these compounds. A kinetic and mechanistic study has been conducted on the Baylis-Hillman reaction using ¹H NMR spectroscopy. A range of substrates has been examined and the reaction has been found to be third-order overall. A mechanism involving an addition - elimination sequence is proposed, which fits the kinetic data and accounts for observed substituent effects. Reaction of N,N-dimethylacrylamide with pyridine-2-carboxaldehyde in the presence of the tertiary amine catalyst, DABCO, in chloroform, yielded an unexpected product which has been identified by single crystal X-ray diffraction analysis as 1-(2,2,2-trichloro-1-hydroxyethyl)pyridine. Attempted extension of the general indolizine route to the preparation of chromene systems by reacting salicylaldehyde with methyl acrylate in the presence of DABCO, also led to an unexpected, crystalline material, identified by single crystal X-ray diffraction analysis as the coumarin derivative, 3-[(2-formylphenoxy)methyl]coumarin.A series of chloroquine analogues have been prepared from indolizine-2-carboxylic acid, pyrrolo[I,2-a]quinoline-2-carboxylic acid and imidazo[I,2-a]pyridine-2-carboxylic acid by reaction with suitable amines in the presence of the coupling reagent 1, I' -carbonyldiimidazole. This route has been shown to be a vast improvement on earlier procedures and has provided access to both secondary and tertiary indolizine-2-carboxamides. A range of N,N-dialkylindolizine-2-carboxamides have been prepared by this route, and the influence of substituents on their N-CO rotational energy barriers has been determined using variable temperature ¹H and ¹³C NMR techniques. Intercalation with natural DNA by both chloroquine and the synthesized chloroquine analogues has been examined using UV spectrophotometry, and ¹H and ³¹P NMR spectroscopy. The pyrrolo[I,2-a]quinolines have been shown to be DNA intercalators with binding affinities similar to that of the known antimalarial intercalator, chloroquine. In a preliminary study the synthesis of a short oligonucleotide has been undertaken and changes have been observed in the ¹H and ³¹P NMR spectra of the oligonucleotide on addition of the intercalator, chloroquine.
- Full Text:
- Date Issued: 1994
Synthetic and spectroscopic studies of 1,4-benzodiazepine analogues
- Authors: Mphahlele, Malose Jack
- Date: 1994
- Subjects: Benzodiazepines Tranquilizing drugs
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4384 , http://hdl.handle.net/10962/d1005049
- Description: In this project, an extensive range of benzodiazepine analogues have been synthesised via Schmidt reaction of specially prepared flavanone, 4-quinolone and l-thioflavanone precursors; nitrogen insertion being effected by use of trimethylsilyl azide in trifluoroacetic acid. In some cases, several of the benzodiazepine analogues have also been prepared by alternative cyclisation routes. A detailed kinetic-mechanistic study of the Schmidt reaction of flavanones has been carried out using 'H NMR spectroscopy to explain the observed regiochemistry of nitrogen insertion. The reaction rates, for the formation of both amide and tetrazolo derivatives have been found to be influenced by the electronic effects of the A- and B-ring substituents. A series of benzodiazepine analogues have been shown to undergo regioselective A-ring chlorination with t-butylhypochlorite; the products being characterised by 'H NMR, IR and mass spectroscopy. The mass spectrometric fragmentation patterns of series of 2-aryl-4-quinolones, and 2-aryl-l ,4-benzodiazepinones and their tetrazolo[l ,5-dl analogues have been elucidated using a combination of low-resolution, high-resolution and metastable-peak analyses. The binding affinities of various benzodiazepine analogues for rat brain benzodiazepine receptors have been evaluated using a radioreceptor assay technique. Structure-activity relationships were investigated to establish the effects of various A-, B- and Coring substituents on binding affinity. The conformational preferences of selected systems have been studied using a combination of multi-pulse 'H NMR spectroscopy, X-ray crystallography and computer modelling techniques with a view to establishing the influence of conformation on binding affinity.
- Full Text:
- Date Issued: 1994
- Authors: Mphahlele, Malose Jack
- Date: 1994
- Subjects: Benzodiazepines Tranquilizing drugs
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4384 , http://hdl.handle.net/10962/d1005049
- Description: In this project, an extensive range of benzodiazepine analogues have been synthesised via Schmidt reaction of specially prepared flavanone, 4-quinolone and l-thioflavanone precursors; nitrogen insertion being effected by use of trimethylsilyl azide in trifluoroacetic acid. In some cases, several of the benzodiazepine analogues have also been prepared by alternative cyclisation routes. A detailed kinetic-mechanistic study of the Schmidt reaction of flavanones has been carried out using 'H NMR spectroscopy to explain the observed regiochemistry of nitrogen insertion. The reaction rates, for the formation of both amide and tetrazolo derivatives have been found to be influenced by the electronic effects of the A- and B-ring substituents. A series of benzodiazepine analogues have been shown to undergo regioselective A-ring chlorination with t-butylhypochlorite; the products being characterised by 'H NMR, IR and mass spectroscopy. The mass spectrometric fragmentation patterns of series of 2-aryl-4-quinolones, and 2-aryl-l ,4-benzodiazepinones and their tetrazolo[l ,5-dl analogues have been elucidated using a combination of low-resolution, high-resolution and metastable-peak analyses. The binding affinities of various benzodiazepine analogues for rat brain benzodiazepine receptors have been evaluated using a radioreceptor assay technique. Structure-activity relationships were investigated to establish the effects of various A-, B- and Coring substituents on binding affinity. The conformational preferences of selected systems have been studied using a combination of multi-pulse 'H NMR spectroscopy, X-ray crystallography and computer modelling techniques with a view to establishing the influence of conformation on binding affinity.
- Full Text:
- Date Issued: 1994
Synthetic and spectrometric studies of benzodioxepinone derivatives
- Authors: Gelebe, Aifheli Carlson
- Date: 1995
- Subjects: Benzodiazepines -- Research Flavonoids -- Research
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4382 , http://hdl.handle.net/10962/d1005047
- Description: An extensive range of oxygen and sulphur substituted benzodiazepine analogues has been synthesised via Baeyer-Villiger and Schmidt reactions of specially prepared flavanone and N-acetyl-4-quinolone precursors. Alternative, cyclisation routes have also been used to prepare some of these compounds. Ring-opening reactions of 1,5-benzodioxepinones have been investigated and a detailed kinetic-mechanistic study of the Baeyer-Villiger reaction of flavanones has been carried out using 1 H NMR spectroscopy to explain the observed regiochemistry of oxygen insertion. The electron-impact mass spectrometric fragmentation patterns of series of 4-aryl-l ,5-benzoxathiepinones, 3-aryl-4, I-benzoxathiepinones and 3-aryl-4,1-benzoxathiepines have been studied using a combination of low-resolution, highresolution and metastable-peak analyses. The 170 NMR spectroscopic properties of various oxygenated analogues have also been studied. The binding affinities of selected benzodiazepine analogues for rat brain benzodiazepine receptors have been evaluated using a radioreceptor assay technique; at certain concentrations, some of test compounds exhibited remarkable potentiation of diazepam binding, others the ability to displace diazepam from benzodiazepine receptors. A conformational analysis of the 7-membered ring systems has been undertaken, using lH NMR spectroscopic, computer modelling and x-ray crystallographic techniques, and certain conformational preferences have been identified.
- Full Text:
- Date Issued: 1995
- Authors: Gelebe, Aifheli Carlson
- Date: 1995
- Subjects: Benzodiazepines -- Research Flavonoids -- Research
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4382 , http://hdl.handle.net/10962/d1005047
- Description: An extensive range of oxygen and sulphur substituted benzodiazepine analogues has been synthesised via Baeyer-Villiger and Schmidt reactions of specially prepared flavanone and N-acetyl-4-quinolone precursors. Alternative, cyclisation routes have also been used to prepare some of these compounds. Ring-opening reactions of 1,5-benzodioxepinones have been investigated and a detailed kinetic-mechanistic study of the Baeyer-Villiger reaction of flavanones has been carried out using 1 H NMR spectroscopy to explain the observed regiochemistry of oxygen insertion. The electron-impact mass spectrometric fragmentation patterns of series of 4-aryl-l ,5-benzoxathiepinones, 3-aryl-4, I-benzoxathiepinones and 3-aryl-4,1-benzoxathiepines have been studied using a combination of low-resolution, highresolution and metastable-peak analyses. The 170 NMR spectroscopic properties of various oxygenated analogues have also been studied. The binding affinities of selected benzodiazepine analogues for rat brain benzodiazepine receptors have been evaluated using a radioreceptor assay technique; at certain concentrations, some of test compounds exhibited remarkable potentiation of diazepam binding, others the ability to displace diazepam from benzodiazepine receptors. A conformational analysis of the 7-membered ring systems has been undertaken, using lH NMR spectroscopic, computer modelling and x-ray crystallographic techniques, and certain conformational preferences have been identified.
- Full Text:
- Date Issued: 1995
Synthetic and spectrometric investigation of 1,4-benzoxazepines
- Authors: Whittal, R D
- Date: 1990
- Subjects: Spectrum analysis , Benzodiazepines
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4381 , http://hdl.handle.net/10962/d1005046
- Description: Flavanone (2,3-dihydro-2-phenyl-4H-benzopyran-4-one) and a series of 4'- and 7-halogeno derivatives were prepared from the corresponding 2'-hydroxychalcones [1-(2-hydroxyphenyl)-3-phenyl-2-propen-l-ones], which, in turn, were synthesized by aldol condensation of substituted 2'-hydroxacetophenones with various benzaldehydes. A series of 2,3-dihydro-2-phenyl-l,4-benzoxazepin-5(4H)-ones were prepared by ring expansion of the corresponding flavanones, via the Schmidt reaction, using trimethylsilylazide and trifluoroacetic acid. A series of tetrazoles {2,3-dihydro-2-phenyl-tetrazolo[1,5-d]-1,4-benzoxazepines} were also isolated as by-products of the Schmidt reaction. Flavanone oxime was synthesized for use in Beckmann reactions, and its molecular structure was determined by x-ray crystallography. Attempts to prepare 1,4-benzoxazepinone or its 1,5-analogue via Beckmann rearrangement of flavanone oxime, with polyphosphoric acid or phosphorus pentachloride catalysts, however, were unsuccessful. Several methods for introducing Δ²-unsaturation into the benzoxazepinone system were also examined. High resolution ¹H n.m.r., computer modelling, and molecular mechanics techniques were used to determine the conformations of the heterocycles of the benzoxazepinones and tetrazoles and results are compared with earlier studies in this field. Certain trends in the fragmentation patterns were observed in the low resolution mass spectra of the benzoxazepinones and tetrazoles, and high resolution mass spectrometric data were used to explore the major fragmentation patterns of these compounds.
- Full Text:
- Date Issued: 1990
- Authors: Whittal, R D
- Date: 1990
- Subjects: Spectrum analysis , Benzodiazepines
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4381 , http://hdl.handle.net/10962/d1005046
- Description: Flavanone (2,3-dihydro-2-phenyl-4H-benzopyran-4-one) and a series of 4'- and 7-halogeno derivatives were prepared from the corresponding 2'-hydroxychalcones [1-(2-hydroxyphenyl)-3-phenyl-2-propen-l-ones], which, in turn, were synthesized by aldol condensation of substituted 2'-hydroxacetophenones with various benzaldehydes. A series of 2,3-dihydro-2-phenyl-l,4-benzoxazepin-5(4H)-ones were prepared by ring expansion of the corresponding flavanones, via the Schmidt reaction, using trimethylsilylazide and trifluoroacetic acid. A series of tetrazoles {2,3-dihydro-2-phenyl-tetrazolo[1,5-d]-1,4-benzoxazepines} were also isolated as by-products of the Schmidt reaction. Flavanone oxime was synthesized for use in Beckmann reactions, and its molecular structure was determined by x-ray crystallography. Attempts to prepare 1,4-benzoxazepinone or its 1,5-analogue via Beckmann rearrangement of flavanone oxime, with polyphosphoric acid or phosphorus pentachloride catalysts, however, were unsuccessful. Several methods for introducing Δ²-unsaturation into the benzoxazepinone system were also examined. High resolution ¹H n.m.r., computer modelling, and molecular mechanics techniques were used to determine the conformations of the heterocycles of the benzoxazepinones and tetrazoles and results are compared with earlier studies in this field. Certain trends in the fragmentation patterns were observed in the low resolution mass spectra of the benzoxazepinones and tetrazoles, and high resolution mass spectrometric data were used to explore the major fragmentation patterns of these compounds.
- Full Text:
- Date Issued: 1990
Synthetic and physical organic studies of chromone derivatives
- Ramaite, Ipfani David Isaiah
- Authors: Ramaite, Ipfani David Isaiah
- Date: 1997
- Subjects: Benzopyrans Heterocyclic compounds -- Derivatives Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4380 , http://hdl.handle.net/10962/d1005045
- Description: A range of chromone-2-carboxylic acids has been prepared by condensing suitably substituted 2-hydroxyacetophenones with diethyl oxalate. pK₂ Studies of these acids revealed that 6- or 7-methoxy substituents decreased acidity while the 6-nitro group enhanced acidity; the strongest acid was the 3-chloro derivative, the increase in acidity being attributed to steric inhibition of acid-weakening delocalisation between the carboxyl group and the chromone system. Various chromone-2-carboxamides, derived from acid chloride precursors, were converted to polysubstituted acrylamides by nucleophilic ring-opening with selected amine nucleophiles. The main fragmentation patterns exhibited by these acrylamides were elucidated using a combination of low resolution, high resolution and meta-stable peak analysis, while the effect of substituents on the simultaneous internal rotation involving the carboxamide and enamine moieties were studied using dynamic NMR spectroscopy. Rotational barriers of ca. 67.1 kJmol ̄¹ and ca. 102 kJmol ̄¹ were found for the enamine and amide rotors, respectively. Several synthetic pathways were followed to prepare a series of 2-(N,N-dialkylamino)chromones which were subjected to detailed mass spectral analysis. In addition to substituent-specific fragmentations , the 2-aminochromones appear to fragment via 3 major pathways. The effect of substituents on the internal rotation of the amino moeity was investigated by variable temperature ¹H NMR spectroscopy and the resulting DNMR data was used to calculate the rotational barriers. Examination of the data reveals that the electron-releasing 6- and 7- substituents reduce the C-NMe₂ rotational barrier to ca. 43.5 kJmol ̄¹ , while the nitro analogue has the largest rotational barrier (ca. 46.1 kJmol ̄¹) because of the electron-withdrawing effect of this substituent.
- Full Text:
- Date Issued: 1997
- Authors: Ramaite, Ipfani David Isaiah
- Date: 1997
- Subjects: Benzopyrans Heterocyclic compounds -- Derivatives Coumarins
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4380 , http://hdl.handle.net/10962/d1005045
- Description: A range of chromone-2-carboxylic acids has been prepared by condensing suitably substituted 2-hydroxyacetophenones with diethyl oxalate. pK₂ Studies of these acids revealed that 6- or 7-methoxy substituents decreased acidity while the 6-nitro group enhanced acidity; the strongest acid was the 3-chloro derivative, the increase in acidity being attributed to steric inhibition of acid-weakening delocalisation between the carboxyl group and the chromone system. Various chromone-2-carboxamides, derived from acid chloride precursors, were converted to polysubstituted acrylamides by nucleophilic ring-opening with selected amine nucleophiles. The main fragmentation patterns exhibited by these acrylamides were elucidated using a combination of low resolution, high resolution and meta-stable peak analysis, while the effect of substituents on the simultaneous internal rotation involving the carboxamide and enamine moieties were studied using dynamic NMR spectroscopy. Rotational barriers of ca. 67.1 kJmol ̄¹ and ca. 102 kJmol ̄¹ were found for the enamine and amide rotors, respectively. Several synthetic pathways were followed to prepare a series of 2-(N,N-dialkylamino)chromones which were subjected to detailed mass spectral analysis. In addition to substituent-specific fragmentations , the 2-aminochromones appear to fragment via 3 major pathways. The effect of substituents on the internal rotation of the amino moeity was investigated by variable temperature ¹H NMR spectroscopy and the resulting DNMR data was used to calculate the rotational barriers. Examination of the data reveals that the electron-releasing 6- and 7- substituents reduce the C-NMe₂ rotational barrier to ca. 43.5 kJmol ̄¹ , while the nitro analogue has the largest rotational barrier (ca. 46.1 kJmol ̄¹) because of the electron-withdrawing effect of this substituent.
- Full Text:
- Date Issued: 1997
Synthetic and mechanistic studies of heterocyclic systems
- Authors: Deane, Philip O'Grady
- Date: 1996
- Subjects: Heterocyclic chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4379 , http://hdl.handle.net/10962/d1005044 , Heterocyclic chemistry
- Description: A series of acrylate esters and selected analogues have been reacted with pyridine-2-,pyridine-3-, and pyridine-4-carboxaldehydes in the presence of diazabicyclo[2,2,2]octane (DARCO) to afford a range of Baylis-Hillman products. The pyridine-2-carboxaldehyde-derived products have been acetylated using acetic anhydride and the kinetics of the thermal cyclisation of the acetylated compounds to indolizines was investigated using proton NMR spectroscopy. The first-order kinetics of the cyclisation has been confirmed and the influence of substituents on the first-order rate constant, kₒbs has been examined. The kinetic data has been shown to be consistent with the previously proposed mechanism in which loss of the acetate group is ratedetermining. Each of the cyclisations was also monitored at three different temperatures permitting evaluation of the activation parameters. The Baylis-Hillman products and related acetylated derivatives were treated at room temperature with sodium methylthiolate; the hydroxy precursors were observed to undergo conjugate addition with a degree of diastereocontrol but the acetylated derivatives favoured an apparent SN¹ displacement of the acetate group.
- Full Text:
- Date Issued: 1996
- Authors: Deane, Philip O'Grady
- Date: 1996
- Subjects: Heterocyclic chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4379 , http://hdl.handle.net/10962/d1005044 , Heterocyclic chemistry
- Description: A series of acrylate esters and selected analogues have been reacted with pyridine-2-,pyridine-3-, and pyridine-4-carboxaldehydes in the presence of diazabicyclo[2,2,2]octane (DARCO) to afford a range of Baylis-Hillman products. The pyridine-2-carboxaldehyde-derived products have been acetylated using acetic anhydride and the kinetics of the thermal cyclisation of the acetylated compounds to indolizines was investigated using proton NMR spectroscopy. The first-order kinetics of the cyclisation has been confirmed and the influence of substituents on the first-order rate constant, kₒbs has been examined. The kinetic data has been shown to be consistent with the previously proposed mechanism in which loss of the acetate group is ratedetermining. Each of the cyclisations was also monitored at three different temperatures permitting evaluation of the activation parameters. The Baylis-Hillman products and related acetylated derivatives were treated at room temperature with sodium methylthiolate; the hydroxy precursors were observed to undergo conjugate addition with a degree of diastereocontrol but the acetylated derivatives favoured an apparent SN¹ displacement of the acetate group.
- Full Text:
- Date Issued: 1996
Synthetic and bioactivity studies of antiplasmodial and antibacterial marine natural products
- Authors: Young, Ryan Mark
- Date: 2012
- Subjects: Antibacterial agents Marine natural products Marine pharmacology Plasmodium falciparum Staphylococcus aureus Isocyanides Imidazoles
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4378 , http://hdl.handle.net/10962/d1005043
- Description: This thesis is divided into two parts, assessing marine and synthetic compounds active firstly against Plasmodium falciparum (Chapter 3 and 4) and secondly active against methicillin resistant Staphylococcus aureus (MRSA, Chapter 5). In Chapter 3 the synthesis of nine new tricyclic podocarpanes (3.203-3.207 and 3.209-3.212) from the diterpene (+)-manool is described. Initial SAR study of synthetic podocarpanes concluded that the most active compound was a C-13 phenyl substituted podocarpane (3.204, IC₅₀ 6.6 μM). By preparing analogues with varying halogenated substituents on the phenyl ring (3.209-3.212) the antiplasmodial activity was improved (IC₅₀ 1.4 μM), while simultaneously decreasing the haemolysis previously reported for this class of compounds. Inspired by the antiplasmodial activity of Wright and Wattanapiromsakul’s tricycle marine isonitriles (2.16-2.21 and 2.24-2.27) an unsuccessfully attempt was made to convert tertiary alcohol moieties to isonitrile functionalities in compounds 3.188, 3.204-3.207 and 3.209-3.212. Over a decade ago Wright et al. proposed a putative antiplasmodial mechanism of action for marine isonitriles (2.4, 2.9, 2.15, 2.19 and 2.35) and isothiocyanate (2.34) which involved interference in haem detoxification by P. falciparum thus inhibiting the growth of the parasite. In Chapter 4 we describe how we successfully managed to scale down Egan’s β-haematin inhibition assay for the analyses of small quantities of marine natural products as potential β-haematin inhibitors. Our modified assay revealed that the most active antiplasmodial marine isonitrile 2.9 (IC₅₀ 13 nM) showed total β-haematin inhibition while 2.15 (IC₅₀ 81 nM) and 2.19 (IC₅₀ 31 nM) showed partial inhibition at three equivalents relative to haem. Using contempary molecular modelling techniques the charge on the isonitrile functionality was more accurately describe and the modified charge data sets was used to explore docking of marine isonitriles to haem using AutoDock. In Chapter 5 we describe how a lead South African marine bisindole MRSA pyruvate kinase inhibitor (5.8) was discovered in collaboration with colleagues at the University of British Columbia (UBC) and how this discovery inspired us to design a synthetic route to the dibrominated bisindole, isobromotopsentin (5.20) in an attempt to increase the bioactivity displayed by 5.8. We devised a fast and high yielding synthetic route using microwave assited organic synthesis. We first tested this synthesis using simple aryl glyoxals (5.27-5.32) as precursors to synthesize biphenylimidazoles (5.21-5.26), which later allowed us to synthesize the ascidian natural product 5.111. This method was sucessfully extended to the synthesis of deoxytopsentin (5.33) from an N-Boc protected indole methyl ketone (5.89). We subsequently were able to effectively remove the carbamate protection via thermal decomposition by heating the protected bisindole imidazole (5.90) in a microwave reactor for 5 min under argon. The synthesis of 5.20 resulted in an inseparable mixture of monoprotected and totally deprotected topsentin products, and due to time constraints we were not able to optimise this synthesis. Nonetheless our synthesis of the marine natural product 5.33 which was faster and higher yielding than previously reported routes could be extended to the synthesis of other topsentin bisindoles (5.138-5.140). Work towards this goal continues in our laboratory.
- Full Text:
- Date Issued: 2012
- Authors: Young, Ryan Mark
- Date: 2012
- Subjects: Antibacterial agents Marine natural products Marine pharmacology Plasmodium falciparum Staphylococcus aureus Isocyanides Imidazoles
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4378 , http://hdl.handle.net/10962/d1005043
- Description: This thesis is divided into two parts, assessing marine and synthetic compounds active firstly against Plasmodium falciparum (Chapter 3 and 4) and secondly active against methicillin resistant Staphylococcus aureus (MRSA, Chapter 5). In Chapter 3 the synthesis of nine new tricyclic podocarpanes (3.203-3.207 and 3.209-3.212) from the diterpene (+)-manool is described. Initial SAR study of synthetic podocarpanes concluded that the most active compound was a C-13 phenyl substituted podocarpane (3.204, IC₅₀ 6.6 μM). By preparing analogues with varying halogenated substituents on the phenyl ring (3.209-3.212) the antiplasmodial activity was improved (IC₅₀ 1.4 μM), while simultaneously decreasing the haemolysis previously reported for this class of compounds. Inspired by the antiplasmodial activity of Wright and Wattanapiromsakul’s tricycle marine isonitriles (2.16-2.21 and 2.24-2.27) an unsuccessfully attempt was made to convert tertiary alcohol moieties to isonitrile functionalities in compounds 3.188, 3.204-3.207 and 3.209-3.212. Over a decade ago Wright et al. proposed a putative antiplasmodial mechanism of action for marine isonitriles (2.4, 2.9, 2.15, 2.19 and 2.35) and isothiocyanate (2.34) which involved interference in haem detoxification by P. falciparum thus inhibiting the growth of the parasite. In Chapter 4 we describe how we successfully managed to scale down Egan’s β-haematin inhibition assay for the analyses of small quantities of marine natural products as potential β-haematin inhibitors. Our modified assay revealed that the most active antiplasmodial marine isonitrile 2.9 (IC₅₀ 13 nM) showed total β-haematin inhibition while 2.15 (IC₅₀ 81 nM) and 2.19 (IC₅₀ 31 nM) showed partial inhibition at three equivalents relative to haem. Using contempary molecular modelling techniques the charge on the isonitrile functionality was more accurately describe and the modified charge data sets was used to explore docking of marine isonitriles to haem using AutoDock. In Chapter 5 we describe how a lead South African marine bisindole MRSA pyruvate kinase inhibitor (5.8) was discovered in collaboration with colleagues at the University of British Columbia (UBC) and how this discovery inspired us to design a synthetic route to the dibrominated bisindole, isobromotopsentin (5.20) in an attempt to increase the bioactivity displayed by 5.8. We devised a fast and high yielding synthetic route using microwave assited organic synthesis. We first tested this synthesis using simple aryl glyoxals (5.27-5.32) as precursors to synthesize biphenylimidazoles (5.21-5.26), which later allowed us to synthesize the ascidian natural product 5.111. This method was sucessfully extended to the synthesis of deoxytopsentin (5.33) from an N-Boc protected indole methyl ketone (5.89). We subsequently were able to effectively remove the carbamate protection via thermal decomposition by heating the protected bisindole imidazole (5.90) in a microwave reactor for 5 min under argon. The synthesis of 5.20 resulted in an inseparable mixture of monoprotected and totally deprotected topsentin products, and due to time constraints we were not able to optimise this synthesis. Nonetheless our synthesis of the marine natural product 5.33 which was faster and higher yielding than previously reported routes could be extended to the synthesis of other topsentin bisindoles (5.138-5.140). Work towards this goal continues in our laboratory.
- Full Text:
- Date Issued: 2012
Synthetic and analytical studies of biomimetic metal complexes
- Authors: Wellington, Kevin Wayne
- Date: 2000
- Subjects: Biomimetics Metal complexes Metalloenzymes Metal ions Ligands
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4377 , http://hdl.handle.net/10962/d1005042
- Description: Several series of novel diamido, diamino and diimino ligands containing different spacers and heterocyclic donors have been synthesised. The spacers include the flexible biphenyl, the rigid 1,1 O-phenanthroline and various acyclic moieties, while the heterocyclic donors comprise pyridine, imidazole or benzimidazole groups. These ligands have been designed to complex copper and act as biomimetic models of the active site of the enzyme, tyrosinase, and their complexes with copper, cobalt, nickel and platinum have been analysed using microanalytical, IR, UV-Visible and cyclic voltammetric techniques. Attempted reduction of the biphenyl-based diimino ligands resulted in an unexpected intramolecular cyclisation affording azepine derivatives, the structures of which were elucidated with the aid of single crystal X-ray analysis of cobalt and nickel complexes. Computer modelling methods have been used to explore the conformational options of the copper complexes, and to assess the accessibility of the dinuclear copper site to substrate molecules. Computer modelling has also been used, in conjunction with the available analytical data, to visualise the possible structures of selected ligands and complexes. The copper complexes, although predominantly polymeric, were evaluated as biomimetic catalysts using 3,5-di-t-butylphenol and 3,5-di-t-butylcatechol as substrates. Some of the complexes clearly displayed biomimetic potential, exhibiting both phenolase and catecholase activity.
- Full Text:
- Date Issued: 2000
- Authors: Wellington, Kevin Wayne
- Date: 2000
- Subjects: Biomimetics Metal complexes Metalloenzymes Metal ions Ligands
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4377 , http://hdl.handle.net/10962/d1005042
- Description: Several series of novel diamido, diamino and diimino ligands containing different spacers and heterocyclic donors have been synthesised. The spacers include the flexible biphenyl, the rigid 1,1 O-phenanthroline and various acyclic moieties, while the heterocyclic donors comprise pyridine, imidazole or benzimidazole groups. These ligands have been designed to complex copper and act as biomimetic models of the active site of the enzyme, tyrosinase, and their complexes with copper, cobalt, nickel and platinum have been analysed using microanalytical, IR, UV-Visible and cyclic voltammetric techniques. Attempted reduction of the biphenyl-based diimino ligands resulted in an unexpected intramolecular cyclisation affording azepine derivatives, the structures of which were elucidated with the aid of single crystal X-ray analysis of cobalt and nickel complexes. Computer modelling methods have been used to explore the conformational options of the copper complexes, and to assess the accessibility of the dinuclear copper site to substrate molecules. Computer modelling has also been used, in conjunction with the available analytical data, to visualise the possible structures of selected ligands and complexes. The copper complexes, although predominantly polymeric, were evaluated as biomimetic catalysts using 3,5-di-t-butylphenol and 3,5-di-t-butylcatechol as substrates. Some of the complexes clearly displayed biomimetic potential, exhibiting both phenolase and catecholase activity.
- Full Text:
- Date Issued: 2000
Synthetic analogues of marine bisindole alkaloids as potent selective inhibitors of MRSA pyruvate kinase
- Veale, Clinton Gareth Lancaster
- Authors: Veale, Clinton Gareth Lancaster
- Date: 2014 , 2014-04-02
- Subjects: Alkaloids , Pyruvate kinase , Staphylococcus aureus , Antibiotics , Sponges -- South Africa , Imidazoles , Biological assay , Antibacterial agents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4563 , http://hdl.handle.net/10962/d1020893
- Description: Globally, methicillin resistant Staphylococcus aureus (MRSA) has become increasingly difficult to manage in the clinic and new antibiotics are required. The structure activity relationship (SAR) study presented in this thesis forms part of an international collaborative effort to identify potent and selective inhibitors of an MRSA pyruvate kinase (PK) enzyme target. In earlier work the known marine natural product bromodeoxytopsentin (1.6), isolated from a South African marine sponge Topsentia pachastrelloides, exhibited selective and significant inhibition of MRSA PK (IC₅₀ 60 nM). Accordingly bromodeoxytopsentin provided the initial chemical scaffold around which our SAR study was developed. Following a comprehensive introduction, providing the necessary background to the research described in subsequent Chapters, this thesis has been divided into three major parts. Part one (Chapter 2) documents the synthesis of two natural imidazole containing topsentin analogues 1.40, 1.46, five new synthetic analogues 1.58—1.61, 2.104. In the process we developed a new method for the synthesis of topsentin derivatives via selenium dioxide mediated oxidation of N-Boc protected 3-acetylindoles to yield glyoxal intermediates which were subsequently cyclized and deprotected to yield the desired products. Interestingly we were able to demonstrate a delicate relationship between the relative equivalents of selenium dioxide and water used during the oxidation step, careful manipulation of which was required to prevent the uncontrolled formation of side products. Synthetic compounds 1.40, 1.46, 1.58—1.61 were found to be potent inhibitors of MRSA PK (IC₅₀ 238, 2.1, 23, 1.4, 6.3 and 3.2 nM respectively) with 1000-10000 fold selectivity for MRSA PK over four human orthologs. In the second part of this thesis (Chapter 3) we report the successful synthesis of a cohort of previously unknown thiazole containing bisindole topsentin analogues 1.62—1.68 via a Hantzsch thiazole synthesis. Bioassay results revealed that these compounds were only moderate inhibitors of MRSA PK (IC₅₀ 5.1—20 μM) which suggested that inhibitory activity was significantly reduced upon substitution of the central imidazole ring of topsentin type analogues with a thiazole type ring. In addition in Chapter 3 we describe unsuccessful attempts to regiospecifically synthesize oxazole and imidazole topsentin analogues through a similar Hantzsch method. As a consequence of our efforts in this regard we investigated three key reactions in depth, namely the synthesis of 2.2, 3.38, 3.40, 3.41 via α-bromination of 3-acetylindole and the synthesis of indolyl-3-carbonylnitriles 2.13, 3.45—3.47 and α-oxo-1H-indole-3-thioacetamides 3.48—3.51. The investigation of the latter led to the isolation and elucidation of two anomalous N,N-dimethyl-1H-indole-3-carboxamides 3.52 and 3.53. Finally the third part of this thesis (Chapter 4) deals with in silico assessment of the binding of both the imidazole and thiazole containing bisindole alkaloids to the MRSA PK protein which initially guided our SAR studies. In this chapter we reveal that there appears to be no correlation between in silico binding predictions and in vitro MRSA PK inhibitory bioassay data. Superficially it seems that binding energy as determined by the docking program used for these studies correlated with the size of the indole substituents and did not reflect IC₅₀ MRSA PK inhibitory data. Although this led us to computationally explore possible alternative binding sites no clear alternative has been identified.
- Full Text:
- Date Issued: 2014
- Authors: Veale, Clinton Gareth Lancaster
- Date: 2014 , 2014-04-02
- Subjects: Alkaloids , Pyruvate kinase , Staphylococcus aureus , Antibiotics , Sponges -- South Africa , Imidazoles , Biological assay , Antibacterial agents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:4563 , http://hdl.handle.net/10962/d1020893
- Description: Globally, methicillin resistant Staphylococcus aureus (MRSA) has become increasingly difficult to manage in the clinic and new antibiotics are required. The structure activity relationship (SAR) study presented in this thesis forms part of an international collaborative effort to identify potent and selective inhibitors of an MRSA pyruvate kinase (PK) enzyme target. In earlier work the known marine natural product bromodeoxytopsentin (1.6), isolated from a South African marine sponge Topsentia pachastrelloides, exhibited selective and significant inhibition of MRSA PK (IC₅₀ 60 nM). Accordingly bromodeoxytopsentin provided the initial chemical scaffold around which our SAR study was developed. Following a comprehensive introduction, providing the necessary background to the research described in subsequent Chapters, this thesis has been divided into three major parts. Part one (Chapter 2) documents the synthesis of two natural imidazole containing topsentin analogues 1.40, 1.46, five new synthetic analogues 1.58—1.61, 2.104. In the process we developed a new method for the synthesis of topsentin derivatives via selenium dioxide mediated oxidation of N-Boc protected 3-acetylindoles to yield glyoxal intermediates which were subsequently cyclized and deprotected to yield the desired products. Interestingly we were able to demonstrate a delicate relationship between the relative equivalents of selenium dioxide and water used during the oxidation step, careful manipulation of which was required to prevent the uncontrolled formation of side products. Synthetic compounds 1.40, 1.46, 1.58—1.61 were found to be potent inhibitors of MRSA PK (IC₅₀ 238, 2.1, 23, 1.4, 6.3 and 3.2 nM respectively) with 1000-10000 fold selectivity for MRSA PK over four human orthologs. In the second part of this thesis (Chapter 3) we report the successful synthesis of a cohort of previously unknown thiazole containing bisindole topsentin analogues 1.62—1.68 via a Hantzsch thiazole synthesis. Bioassay results revealed that these compounds were only moderate inhibitors of MRSA PK (IC₅₀ 5.1—20 μM) which suggested that inhibitory activity was significantly reduced upon substitution of the central imidazole ring of topsentin type analogues with a thiazole type ring. In addition in Chapter 3 we describe unsuccessful attempts to regiospecifically synthesize oxazole and imidazole topsentin analogues through a similar Hantzsch method. As a consequence of our efforts in this regard we investigated three key reactions in depth, namely the synthesis of 2.2, 3.38, 3.40, 3.41 via α-bromination of 3-acetylindole and the synthesis of indolyl-3-carbonylnitriles 2.13, 3.45—3.47 and α-oxo-1H-indole-3-thioacetamides 3.48—3.51. The investigation of the latter led to the isolation and elucidation of two anomalous N,N-dimethyl-1H-indole-3-carboxamides 3.52 and 3.53. Finally the third part of this thesis (Chapter 4) deals with in silico assessment of the binding of both the imidazole and thiazole containing bisindole alkaloids to the MRSA PK protein which initially guided our SAR studies. In this chapter we reveal that there appears to be no correlation between in silico binding predictions and in vitro MRSA PK inhibitory bioassay data. Superficially it seems that binding energy as determined by the docking program used for these studies correlated with the size of the indole substituents and did not reflect IC₅₀ MRSA PK inhibitory data. Although this led us to computationally explore possible alternative binding sites no clear alternative has been identified.
- Full Text:
- Date Issued: 2014
Synthesis, spectroscopic and nonlinear optical properties of metal-free and nickel β substituted binuclear phthalocyanines
- Authors: Kabwe, Kapambwe Peter
- Date: 2016
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/3013 , vital:20352
- Description: In this project, nickel and metal-free 4β-(4-tert-butylphenoxy) phthalocyanine, biphenyl bridged binuclear 4-tert-butylphenoxy phthalocyanine and naphthalene bridged binuclear 4-tert-butylphenoxy phthalocyanine have been synthesised. The Z-scan technique has been employed to comparatively study their second order nonlinear optical (NLO) properties. This work, shows that the presence of H-aggregation in binuclear Pcs of metal-free and nickel 4β-(4-tertbutylphenoxy) phthalocyanines do not have an effect on the magnitude of second order nonlinear absorption coefficient (β) as compared to monomeric Pcs. Density functional (DFT) calculations of dipolar/octupolar contributions were performed, in order to explain experimentally determined β values. Spectroscopic and photophysical properties of the synthesised compounds have been determined using a range of different spectroscopic techniques, including magnetic circular dichroism (MCD), time correlated single photon counting spectroscopy (TCSPC), UV-visible absorption spectroscopy, mass spectroscopy and IR Spectroscopy.
- Full Text:
- Date Issued: 2016
- Authors: Kabwe, Kapambwe Peter
- Date: 2016
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/3013 , vital:20352
- Description: In this project, nickel and metal-free 4β-(4-tert-butylphenoxy) phthalocyanine, biphenyl bridged binuclear 4-tert-butylphenoxy phthalocyanine and naphthalene bridged binuclear 4-tert-butylphenoxy phthalocyanine have been synthesised. The Z-scan technique has been employed to comparatively study their second order nonlinear optical (NLO) properties. This work, shows that the presence of H-aggregation in binuclear Pcs of metal-free and nickel 4β-(4-tertbutylphenoxy) phthalocyanines do not have an effect on the magnitude of second order nonlinear absorption coefficient (β) as compared to monomeric Pcs. Density functional (DFT) calculations of dipolar/octupolar contributions were performed, in order to explain experimentally determined β values. Spectroscopic and photophysical properties of the synthesised compounds have been determined using a range of different spectroscopic techniques, including magnetic circular dichroism (MCD), time correlated single photon counting spectroscopy (TCSPC), UV-visible absorption spectroscopy, mass spectroscopy and IR Spectroscopy.
- Full Text:
- Date Issued: 2016
Synthesis, spectroscopic and nonlinear optical properties of asymmetric A3B type phthalocyanine complexes
- Authors: Mugeza, Rhulani Donney
- Date: 2021
- Subjects: Spectrum analysis , Mass spectrometry , Phthalocyanines
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/171667 , vital:42108
- Description: This work reports on the synthesis of symmetrical and asymmetrical A 3 B type metal free, cobalt and zinc Phthalocyanines (Pc) .A wide range of spectroscopic techniques such as Uv - visible absorption (UV), magnetic circular dichroism (MCD), mass spectrometry, elemental analysis, IR spectroscopy and time correlated single photo n counting spectroscopy (TCSPC) have been used to study the spectroscopic properties of the phthalocyanine complexes. The Z - scan technique was used to comparatively investigate the nonlinear absorption coefficient ( 휷 ) and the nonlinear refraction index ( 풏 ퟐ ) of the synthesized complexes. The following trend was obtained for the synthesized Pc’s in terms of the 휷 values 7.25 × 10 − 10 ( 4b ) > 3.76 × 10 − 10 ( 4a ) > 3.52 × 10 − 10 ( 4c ) > 2.29 × 10 − 10 ( 3c ) > 1.68 × 10 − 10 ( 3a ) > 1.65 × 10 − 10 ( 3b ) mW - 1 . The 휷 values trend of synthesized Pc complexes show that the asymmetrical A 3 B type metal free, cobalt and zinc Pc complexes ( 4a , 4b and 4c ) have larger 휷 values as compared to the octa - substituted symmetrical metal free, cobalt and zinc Pc complexes ( 3a , 3b and 3c ) which is attributed to the low symmetry of the Pc complexes. The five - level model rate equations were used to determine the two photon absorption, excited state absorption and ground state absorption cross sections of the synthesized complexes. The z inc A 3 B type asymmetrical Pc complexes gave the largest two photon absorption and 휎 푒 / 휎 푔 ratio values. This Pc complex could be used in future work to enhance the nonlinear response further by introducing nanomaterials and converting the Pc complex to a binuclear Pc. This work also reports on the density functional theory (DFT) calculations o f dipolar/octupolar contributions in order to study the first order hyperpolarizability of the synthesized Pc complexes.
- Full Text:
- Date Issued: 2021
- Authors: Mugeza, Rhulani Donney
- Date: 2021
- Subjects: Spectrum analysis , Mass spectrometry , Phthalocyanines
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/171667 , vital:42108
- Description: This work reports on the synthesis of symmetrical and asymmetrical A 3 B type metal free, cobalt and zinc Phthalocyanines (Pc) .A wide range of spectroscopic techniques such as Uv - visible absorption (UV), magnetic circular dichroism (MCD), mass spectrometry, elemental analysis, IR spectroscopy and time correlated single photo n counting spectroscopy (TCSPC) have been used to study the spectroscopic properties of the phthalocyanine complexes. The Z - scan technique was used to comparatively investigate the nonlinear absorption coefficient ( 휷 ) and the nonlinear refraction index ( 풏 ퟐ ) of the synthesized complexes. The following trend was obtained for the synthesized Pc’s in terms of the 휷 values 7.25 × 10 − 10 ( 4b ) > 3.76 × 10 − 10 ( 4a ) > 3.52 × 10 − 10 ( 4c ) > 2.29 × 10 − 10 ( 3c ) > 1.68 × 10 − 10 ( 3a ) > 1.65 × 10 − 10 ( 3b ) mW - 1 . The 휷 values trend of synthesized Pc complexes show that the asymmetrical A 3 B type metal free, cobalt and zinc Pc complexes ( 4a , 4b and 4c ) have larger 휷 values as compared to the octa - substituted symmetrical metal free, cobalt and zinc Pc complexes ( 3a , 3b and 3c ) which is attributed to the low symmetry of the Pc complexes. The five - level model rate equations were used to determine the two photon absorption, excited state absorption and ground state absorption cross sections of the synthesized complexes. The z inc A 3 B type asymmetrical Pc complexes gave the largest two photon absorption and 휎 푒 / 휎 푔 ratio values. This Pc complex could be used in future work to enhance the nonlinear response further by introducing nanomaterials and converting the Pc complex to a binuclear Pc. This work also reports on the density functional theory (DFT) calculations o f dipolar/octupolar contributions in order to study the first order hyperpolarizability of the synthesized Pc complexes.
- Full Text:
- Date Issued: 2021
Synthesis, photophysics and electrochemical study of tin macrocycles
- Authors: Khene, Mielie Samson
- Date: 2008
- Subjects: Electrochemistry , Photochemistry , Phthalocyanines , Macrocyclic compounds , Spectrum analysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4376 , http://hdl.handle.net/10962/d1005041 , Electrochemistry , Photochemistry , Phthalocyanines , Macrocyclic compounds , Spectrum analysis
- Description: Three non-peripherally substituted tin(IV) macrocylic compounds, octahexylphthalocyaninato dichlorotin(IV) (35a), octahexyltetrabenzo-5,10,15-triazaporphyrinato dichlorotin(IV) (35b) and octadecylphthalocyaninato dichlorotin(IV) (35c) were synthesized and their photophysical and electrochemical behaviour studied. Complex (35b), containing a CH group in place of one of the aza nitrogen atom of the phthalocyanine core, shows a split Q band due to its lower symmetry. The triplet state quantum yields were found to be lower than would be expected on the basis of the heavy atom effect of tin as the central metal for phthalocyanine derivatives (35a and 35c). In contrast, (35b) shows a triplet quantum yield ΦT = 0.78. The triplet state lifetimes were solvent dependent, and were higher in THF than in toluene. Cyclic voltammetry and spectroelectrochemistry of the complexes revealed only ring based redox processes. This thesis also reports on the microwave syntheses of tetrasulphonated tin phthalocyanine and tetrasulphonated tin α,β,γ-tetrabenzcorrole. The latter was only formed at low ratios (< 1:8) of 4-sulfophthalic acid to urea. Both complexes are aggregated in aqueous media, but can be partly or fully disaggregated by the addition of Triton X-100. The SnTSTBC complex has lower triplet life times and yields, while binding constant and quenching (of bovine serum albumin) constant are lower for SnTSTBC, compared to SnTSPc. Finally Non-peripherally (α) tetra- (40) and octa-(38a) substituted dodecyl-mercapto tin(IV) phthalocyanines where synthesized and the electrochemical behavior studied. Cyclic voltammetry and spectroelectrochemistry show ring-based reductions for (38a) and (40); the former shows two ring oxidations, while the latter shows only one ring based oxidation. The adsorption kinetics of (38a) and (40) on a gold electrode have been investigated by electrochemical impedance spectroscopy (EIS). The equilibrium constant (K) for the adsorption and the Gibbs free energy ΔG(ads) of the self-assembled monolayer (SAMs) were evaluated based on the Frumkin isotherm. The interaction factor between adsorbate –adsorbate molecules is also discussed.
- Full Text:
- Date Issued: 2008
- Authors: Khene, Mielie Samson
- Date: 2008
- Subjects: Electrochemistry , Photochemistry , Phthalocyanines , Macrocyclic compounds , Spectrum analysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4376 , http://hdl.handle.net/10962/d1005041 , Electrochemistry , Photochemistry , Phthalocyanines , Macrocyclic compounds , Spectrum analysis
- Description: Three non-peripherally substituted tin(IV) macrocylic compounds, octahexylphthalocyaninato dichlorotin(IV) (35a), octahexyltetrabenzo-5,10,15-triazaporphyrinato dichlorotin(IV) (35b) and octadecylphthalocyaninato dichlorotin(IV) (35c) were synthesized and their photophysical and electrochemical behaviour studied. Complex (35b), containing a CH group in place of one of the aza nitrogen atom of the phthalocyanine core, shows a split Q band due to its lower symmetry. The triplet state quantum yields were found to be lower than would be expected on the basis of the heavy atom effect of tin as the central metal for phthalocyanine derivatives (35a and 35c). In contrast, (35b) shows a triplet quantum yield ΦT = 0.78. The triplet state lifetimes were solvent dependent, and were higher in THF than in toluene. Cyclic voltammetry and spectroelectrochemistry of the complexes revealed only ring based redox processes. This thesis also reports on the microwave syntheses of tetrasulphonated tin phthalocyanine and tetrasulphonated tin α,β,γ-tetrabenzcorrole. The latter was only formed at low ratios (< 1:8) of 4-sulfophthalic acid to urea. Both complexes are aggregated in aqueous media, but can be partly or fully disaggregated by the addition of Triton X-100. The SnTSTBC complex has lower triplet life times and yields, while binding constant and quenching (of bovine serum albumin) constant are lower for SnTSTBC, compared to SnTSPc. Finally Non-peripherally (α) tetra- (40) and octa-(38a) substituted dodecyl-mercapto tin(IV) phthalocyanines where synthesized and the electrochemical behavior studied. Cyclic voltammetry and spectroelectrochemistry show ring-based reductions for (38a) and (40); the former shows two ring oxidations, while the latter shows only one ring based oxidation. The adsorption kinetics of (38a) and (40) on a gold electrode have been investigated by electrochemical impedance spectroscopy (EIS). The equilibrium constant (K) for the adsorption and the Gibbs free energy ΔG(ads) of the self-assembled monolayer (SAMs) were evaluated based on the Frumkin isotherm. The interaction factor between adsorbate –adsorbate molecules is also discussed.
- Full Text:
- Date Issued: 2008