Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: The creation of nanometer-scale (nanoscale) materials has fascinated and inspired the scientific community for more than a quarter of a century because of the wide range of applications of these materials, e.g. applications in drug delivery, medicine, tissue engineering, memory storage, display and audio devices, semiconductors, etc. π-Conjugated dendrimers have a proposed flat packing arrangement. An alternating phenyl isoxazole dendrimer system was developed to investigate this phenomenon. The synthesis of this dendritic system was attempted by divergent and convergent approaches. Preparation of the second generation failed because some functional groups inhibited the monomers to react to the first generation. Other examples of nano materials that have attracted a vast amount of interest are the so-called discotic amphiphiles. Discotic amphiphilic molecules have the potential to self-assemble into helical architectures. Discotic systems bearing chiral polar side chains (one and three respectively) were developed. Their self-assembly was investigated in variable concentration and variable solvent composition experiments. These systems did show signs of aggregation in UV-vis and CD spectroscopy experiments. Thread-like helical structures were observed with transmission electron microscopy. / AFRIKAANSE OPSOMMING: Nanometer-skaal materiale inspireer en fassineer wetenskaplikes al vir meer as 25 jaar as gevolg van hulle wye verskeidenheid toepassings bv.: die vervoer van geneesmiddels, weefsel ontwerp, geheue stoorspasie, digitale skerms, klank toerusting, geleiers, ens. π-Gekonjugeerde dendrimere het 'n plat drie dimmensionele rangskikking. 'n Afwisselende feniel isoxazole dendrimer stelsel was ontwikkel om hierdie verskynsel te ondersoek. Die sintese van hierdie dendritiese stelsel is aangepak deur divergerende en konvergerende benaderings. Sintese van die tweede generasie het misluk omdat sommige funksionele groepe die monomere geïnhibeer het om te reageer met die eerste generasie. Ander interessante voorbeelde van nano materiale, is die sogenaamde skyfvormige amphiphiles. Skyfvormige amphiphiles het die potensiaal om spontaan te versamel in heliese strukture. Skyfvormige molekules met chirale polêre sykettings (een en drie onderskeidelik) is ontwikkel. Hulle potensiaal om spontaan te versamel is ondersoek met wisselende konsentrasie en wisselende oplosmiddel samestelling eksperimente. Hierdie stelsels het tekens van versameling gewys in UV-vis en CD-spektroskopiese eksperimente. Staaf-vormige heliese strukture is waargeneem met transmissie-elektronmikroskopie.

Thesis (MSc)--Stellenbosch University, 2013. / Aminoquinolines are important class of drugs that have been used for malaria chemotherapy for centuries. However, long-term exposure to these drugs leads to extensive spread of drug resistance. As such, modified chloroquinoline derivatives are being studied as alternative antimalarial agents with the possibility to overcome drug resistance associated with chloroquine analogues. In this study, 15 aminoquinoline derivatives that are linked by a 1,4-disubstituted 1,2,3-triazole ring to an ethyl and propyl carbon spacer with a distal amine motif were designed and synthesized as novel antimalarial agents using the Cu(I)-promoted Huisgen reaction. The compounds have been synthesized from the 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine alkyne precursor and the azides of ethyl and propyl amino moieties using a 1,3-dipolar cycloadditioncoupling in the presence of CuI catalyst to obtain moderate to good yields (53 – 85%). These compounds have been characterized by the combination of NMR, ESI+ HRMS and IR spectroscopic methods. The antiplasmodial activity of the compounds was investigated in vitro against P. falciparum strain NF54 using chloroquine as a reference drug together with a standard antimalarial drug artesunate. Of the 15 novel chloroquinoline derivatives, 11 have demonstrated to possess promising potency by way of the inhibition concentrations less than 250 nM with the lowest being 28 nM. The observed activities have been ascribed to the overall modifications such as the introduction of a triazole linker and changing of carbon chain length as these were the variables. The compounds are accordingly under further biological investigations and only the chloroquine sensitive results are reported in this work.

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: In this thesis the synthesis of a range of model and siloxane functionalized salicylaldimine ligands and [N-(n-propyl)-(2-pyridyl)] diimine ligands are described. The functionalized ligands were obtained by the reaction of salicylaldehyde and 2-pyridinecarboxaldehyde with 3-aminopropyltriethyoxysilane. All ligands were characterized by FT-IR and 1H NMR spectroscopy. The salicylaldimine ligands were reacted with either Cu(II) or Pd(II) salts to form both the model and functionalized Cu(II) and Pd(II) complexes. The Cu(II) complexes were characterized using FT-IR, EPR and UV-VIS spectroscopy while the Pd(II) complexes were characterized using FT-IR, 1H NMR and 13C{1H} NMR spectroscopy. The diimine ligands were reacted with Cu(II) salts to form functionalized pyridinyl complexes which were characterized used FT-IR spectroscopy. Two mesoporous silica supports, MCM-41 and SBA-15 were synthesized. The siloxane functionalized salicylaldimine Cu(II) and Pd(II) complexes were immobilized onto these supports to produce heterogenized catalysts. These catalysts were characterized using a range of solid-state techniques: BET nitrogen adsorption/desorption, scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), ICP-AES, and powder X-ray diffraction (XRD) analysis. The powder XRD and SEM analysis showed that the structural integrity of the catalyst supports was kept intact during the immobilization process. BET analysis and ICP-AES showed that the complexes had been attached to the silica supports. Both the model complexes and heterogenized catalyst systems were tested in the oxidation of benzyl alcohol to benzaldehyde. The model copper catalyst showed high activity in this reaction with molecular oxygen used as oxidant and the (2,2,6,6-tetramethylpiperidin-1-yl)oxyl radical as co-oxidant. The immobilized copper complexes showed low activity in the same reaction. This was attributed to steric hindrance around the active site dye to its entrapment with the silica matrix thus hindering the formation of a key intermediate in the oxidation cycle due to steric hindrance. The palladium complexes were not active in the oxidation reaction when molecular oxygen was used as oxidant, but showed slight activity when hydrogen peroxide was used. / AFRIKAANSE OPSOMMING: In hierdie tesis word die sintese van ‘n reeks model sowel as gefunksioneerde salisielaldemien ligande en [N-(n-propiel)-(2-piridiel)] di-imien ligande beskryf. Die gefunksioneerde ligande is verkry deur die reaksie van salisielaldehied en en 2-piridienaldehied met 3-aminopropieltriëtoksiesilaan. Al die ligande is gekarakteriseer deur FT-IR en 1H-KMR spektroskopie. Die salisielaldimien ligande is met óf Cu(II) óf Pd(II) soute reageer om beide die model en gefunksioneerde Cu(II) en Pd(II) komplekse te vorm. Die Cu(II) komplekse is gekarakteriseer deur FT-IR, EPR en UV-Vis spektroskopie terwyl die Pd(II) komplekse deur FT-IR, 1H-KMR en 13C{1H}-KMR spektroskopie gekarakteriseer is. Die di-imien ligande is met Cu(II) soute reageer om gefunksioneerde piridinielkompekse te vorm wat deur FT-IR spektroskopie gekarakteriseer is. Twee mesoporeuse silika draers, MCM-41 en SBA-15 is gesintetiseer. Die siloksaan-gefunksioneerde salisielaldemien Cu(II) en Pd(II) komplekse is op hierdie draers geimobiliseer om geheterogeniseerde katalisatore te vorm. Hierdie katalisatore is gekarakteriseer deur van ‘n wye reeks vaste toestand tegnieke gebruik te maak: BET stikstof adsorpsie/desorpsie, skandeer elektron mikroskopie (SEM), termiese gravimetriese analise (TGA), ICP-AES en poeier-XRD analise. Die poeier-XRD en SEM analisies het aangetoon dat die strukturele integriteit van die katalisator draers behoue gebly het tydens die immobiliseringsproses. BET analise en ICP-AES het aangetoon dat die komplekse aan die silika draers geheg is. Beide die model komplekse en geimobiliseerde katalisators is getoets in die oksidasie van bensielalkohol na bensaldehied. Die model Cu(II) katalisator het hoë aktiwiteit in hierdie reaksie getoon met molekulêre suurstof as oksideermiddel en die (2,2,6,6-tetrametielpipiridien-1-iel)oksiel radikaal as ko-oksideermiddel. Die geimobiliseerde Cu(II) komplekse het lae aktiwiteit in dieselfde reaksie getoon. Dit is toegeskryf aan steriese hindernis rondom die aktiewe sentrum as gevolg van die verstrikking binne die silika matrys, wat die vorming van ‘n belangrike tussentoestand in die oksidasie-siklus verhinder. Die Pd(II) komplekse was nie aktief in die oksidasie-reaksie in die geval waar molekulêre suurstof as oksideermiddel gebruik is nie, maar het effense aktiwiteit getoon waneer waterstofperoksied gebruik is. / Sasol

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Calixarenes are large cyclic molecules that have a distinctive bowl-shaped geometry. The nonplanar nature of these molecules means that, by selectively functionalizing the calixarene on one side of the symmetry plane, one introduces inherent chirality. As with other varieties of chirality, this asymmetry can be utilised to impart stereoselectivity to the formation of new bonds through asymmetric catalysis. The evaluation of inherently chiral calixarenes has been hindered thus far by the difficulty in obtaining enantiomerically pure samples. Using a recently developed stereoselective methodology, incorporating chiral oxazoline directed ortholithiation, the synthesis of a series of upper-rim meta-substituted inherently chiral calixarenes is described. With the use of this methodology, the desired calixarene ligands are synthesised in high diastereoselectivity (from 75% de to >99% de). The inherently chiral meta-substituted bidentate thioether-oxazoline calixarenes synthesised were subsequently investigated as asymmetric ligands for palladium catalysed allylic alkylation. The debutylated series of calixarenes showed good catalytic efficiency, achieving high levels of conversion (>90% isolated yield). A rate enhancement relative to a planar model system was observed. Moderate levels of enantioselectivity (31% ee to 89% ee) were achieved. The influence of the central chirality of the chiral oxazoline was determined to be the predominant stereoselective effect. Increasing the steric bulk on this chiral carbon resulted in a significant increase in the stereoselectivity. Inherent chirality was found to have a subtle but significant effect. Increasing the steric bulk on the calixarene bowl, through the use of analogous tert-butylated calixarene, had an adverse effect on the catalytic efficiency. These ligands formed unstable complexes that decomposed before any appreciable yield of the desired product could be formed. / AFRIKAANSE OPSOMMING: Calixarene is groot sikliese molekule met 'n kenmerkende bak-vormige meetkunde. Die nie-planêre aard van hierdie molekules beteken dat selektiewe functionaliseering van die calixareen op een kant van die simmetrievlak vorm 'n inherente chirale molekuul. Soos met ander soorte van chiraliteit, hierdie asymmetrie kan gebruik word om stereoselektiwiteit aan die vorming van nuwe bindings aan te dra, deur middel van asimmetriese katalise. Die evaluering van inherente chirale calixarene dusver is verhinder deur probleme in die verkryging van enantiomeerisesuiwer monsters. Met behulp van 'n onlangse ontwikkelde stereoselektief metodologie, waarin ‘n chirale oksasolien gerig ortolitiëring, die sintese van 'n reeks van boonste rand meta-gefunksionaliseerde inherent chirale calixarene word beskryf. Met die gebruik van hierdie metodologie, word die verlangde calixareen ligande gesintetiseer in hoë diastereoselektiwiteit (van 75% to t 99% do). Die inherente chirale meta-gefunktionaliseerde tio-eter oksasolien calixarene gesintetiseer is daarna as asimmetriese ligande vir palladium-gekataliseerde allyliese alkilering ondersoek. Die gedebutieleerde reeks van calixarene het goeie katalitiese effektiwiteit getoon, met die bereiking van hoë vlakke van omsetting (> 90% geïsoleerde opbrengs). ‘n Tempoverbetering relatief tot 'n planêre modelstelsel is waargeneem. Gematige vlakke van enantioselektiwiteit (31% eo tot 89% eo) is behaal. Die invloed van die sentrale chiraliteit van die chirale oksasolien is bepaal as die oorheersende stereoselektiewe effek. Die verhoging van die steriese massa op hierdie chirale koolstof het gelei tot 'n beduidende toename in die stereoselektiwiteit. Inherente chiraliteit is gevind om 'n subtiele, maar betekenisvolle uitwerking te hê. Die verhoging van die steriese grootmaat op die calixarene bak, deur die gebruik van analoog tert-butieleerde calixarene, het 'n nadelige uitwerking op die katalitiese effektiwiteit. Hierdie ligande vorm onstabiel komplekse dat ontbind voordat enige aansienlike opbrengs van die verlangde produk kan gevorm word.

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: The high-resolution 195Pt NMR signals (128.8 MHz) of most of the octahedral mixed-ligand Pt(IV) complexes in the series [PtCl6-n(OH)n]2-, n = 0-6, have been recorded in aqueous solutions at 293 K. These signals show characteristic 35/37Cl isotope-induced fine structure that results from the presence of several isotopologues in samples with a natural chlorine isotope distribution; each 37Cl isotope incorporated into the Pt coordination sphere of one of these complexes affords a fixed upfield (low frequency) isotope shift of between 0.17 and 0.22 ppm, depending on the particular complex. This assignment is confirmed by the excellent agreement between the natural abundances of the various isotopologues and the relative contributions of the corresponding signals to the overall area of the experimental spectrum of the particular isotoplogue set, obtained by a non-linear least-squares line fitting procedure. These results confirm that the 195Pt magnetic shielding in isotopomers differing only in the combination of the two chlorine isotopes coordinated in sites trans to hydroxido-ligands are indistinguishable under these experimental conditions, unlike those of similar isotopomers in the related series of aqua-complexes [PtCln(H2O)6-n]4-n, n = 3-5, as reported by Koch and co-workers. Moreover, the order of 195Pt shielding for the members of all stereoisomer pairs in the series of hydroxido-complexes is the reverse of that reported for the corresponding pairs in the aqua-series. These and other observations are interpreted qualitatively in terms of the relative strengths of the trans-influences of aqua-, hydroxido- and chlorido-ligands and the effect of these on bond displacements in these complexes. The 195Pt NMR spectra of especially the complexes cis-[PtCl2(OH)4]2- and [PtCl(OH)5]2- show remarkable fine structure in a ca. 45 % 18O-enriched aqueous solution; apart from additional signals resulting from 18O-containing isotopologues, the resonance signals of isotopomers differing in the combination of 16/18O isotopes in sites trans to chlorido-ligands are partially resolved. The effect of temperature on the 35/37Cl isotope-induced fine structure in the 195Pt signals of [PtCl6]2- and [PtCl(OH)5]2- was investigated in the range 283-308 K; some interesting differences are observed. 195Pt relaxation time measurements for [PtCl6]2- in this temperature range reveal that line-broadening is at least partially responsible for the loss of resolution between the signals of isotopologues of this complex as the temperature is increased, possibly due to the spin-rotation relaxation mechanism. The temperature coefficient of 195Pt shielding and the magnitude of isotope shifts in the spectra of the complexes in this series show interesting correlations with the 195Pt shielding itself; an interpretation of these observations is presented. / AFRIKAANSE OPSOMMING: Die hoëresolusie 195Pt NMR seine (128.8 MHz) van die oktaëdriese gemengde-ligand Pt(IV) komplekse in die reeks [PtCl6-n(OH)n]2- is waargeneem in waterige oplossing by ʼn temperatuur van 293 K. Hierdie seine toon ʼn karakteristieke 35/37Cl isotoop-geïnduseerde fynstruktuur as gevolg van die teenwoordigheid van verskeie isotopoloë in monsters met ʼn natuurlike chloor isotoopverspreiding. Die verplasing van ʼn 35Cl isotoop deur ʼn 37Cl isotoop in die Pt koördinasiesfeer van hierdie komplekse lei tot ʼn laefrekwensie isotoopverskuiwing van die 195Pt resonansiesein van tussen 0.17 en 0.22 ppm, afhangend van die spesifieke kompleks. Die toekenning van resonansieseine in hierdie spektra word ondersteun deur die goeie ooreenstemming tussen die berekende natuurlike verspreiding van isotopoloë en die persentasie area bydrae van die ooreenstemmende pieke tot die area van volledige stel seine van die chemiese spesie, soos bepaal deur ʼn nie-linieêre kleinste-kwadrate passingsmetode. Hierdie resultate bevestig dat vir isotopomere waarvan slegs die kombinasie van chloorisotope wat in posisies trans tot hidroksido-ligande gekoördineer is ʼn ononderskeibare 195Pt magnetiese skerming waargeneem word, m.a.w. ʼn enkele resonansiesein word vir hierdie isotopomere gemeet, anders as gerapporteer deur Koch en medewerkers vir die verwante aqua-komplekse [PtCln(H2O)6-n]4-n waar n = 3-5. Verder is die order van 195Pt magnetiese skerming vir stereoisomere in hierdie hidroksido-komplekse in elke stereoisomer paar die teenoorgestelde van dit waargeneem vir die ooreenstemmende aqua-komplekse. Hierdie waarnemings word kwalitatief geïnterpreteer in terme van die verskillende trans-invloede van die chlorido-, aqua- en hidroksido-ligande en die effekte daarvan op bindingslengtes in die komplekse. In ʼn ongeveer 45 % 18O-verrykte monster toon die 195Pt seine van veral die komplekse cis-[PtCl2(OH)4]2- en [PtCl(OH)5]2- uitsonderlike fynstruktuur vanweë die addisionele seine van 18O-bevattende isotopoloë en die parsiële resolusie van die seine van isotopomere wat verskil in die kombinasie van 16/18O isotope wat trans tot chlorido-ligande gekoördineer is. ʼn Studie is gemaak van die uitwerking van temperatuur op die 35/37Cl isotoop-geïnduseerde fynstruktuur in die 195Pt seine van die komplekse [PtCl6]2- en [PtCl(OH)5]2- in die gebied 283-308 K; interessante verskille is waargeneem. 195Pt magnetiese relaksasietyd metings vir die kompleks [PtCl6]2- in waterige oplossing in hierdie temperatuurgebied toon dat verbreeding van resonansieseine ten minste gedeeltelik verantwoordelik is vir die waargenome verlies aan resolusie tussen die seine van isotopoloë namate die temperatuur styg; die verbreeding van seine kan waarskynlik aan die spin-rotasie relaksasiemeganisme toegeskryf word. Die temperatuurkoëffisiënt van 195Pt magnetiese skerming en die grootheid van isotoopverskuiwings in die spektra van die hidroksido-komplekse in hierdie reeks toon interessante korrelasies tot die 195Pt magnetiese skerming; ʼn interpretasie van hierdie waarnemings word voorgestel.

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: This study focused on the development of an analytical method whereby creatinine, creatine and caffeine could be determined quantitatively. Urine is the preferred body fluid for the analysis of metabolites that the body excretes after administration of medicinal and illicit drugs. The detection of these metabolites depends on the volume of water the patient has drunk or, in criminal cases, the amount of water the suspect may deliberately add to their urine to dilute it. Creatinine, whose concentration in urine has been found to correlate with muscle mass, is chosen as an endogenous control substance against which the metabolite concentration is compared. While high performance liquid chromatography with ultraviolet detection (HPLC–UV) is commonly selected for the analysis, the quality of chromatography is affected by the fact that creatinine, being highly polar, is not retained in the reversed-phase columns. Furthermore, urine contains many polar substances that elute with the solvent front along with creatinine, thereby grossly affecting HPLC measurements. Hydrophilic interaction chromatography (HILIC) is a good alternative, although these methods generally require extensive sample preparation. Direct infusion electrospray ionization mass spectrometry (DI–ESI–MS) is ideally suited to highly polar compounds and was selected for this work. Pneumatically assisted ESI is preferred above the standard ionization method of atmospheric pressure chemical ionization (APCI) since pneumatically assisted ESI disperses the solution into ion-containing aerosol droplets which do not promote online conversion of creatinine to creatine. The objective of this study was to develop a simple and sensitive DI–ESI–MS method for the determination of various compounds in urine with creatinine as analytical reference compound and internal standard (IS). The analytical method development includes addition of 1-methyl-3-phenylpropylamine as a primary IS to standard solutions as well as to urine samples, followed by direct infusion of the sample into a mass spectrometer to determine the absolute concentrations of creatinine, creatine and caffeine. After appropriate instrument conditions were established, linear graphs of analyte-IS signal intensity ratios were obtained. The ratio of the concentration of the analyte (drug or metabolite) to that of creatinine (as IS) may be used to determine analyte concentration in artificial samples and/or urine. This method is not affected by change in fluid volume or adulteration of urine samples because the analyte-to-creatinine ratio remains unchanged. As part of this study, the developed DI–ESI–MS method was compared with an LC–UV–MS method developed for this purpose. / AFRIKAANSE OPSOMMING: Hierdie studie fokus op die ontwikkeling van ‘n analitiese metode waardeur kreatinien, kreatien en kaffeïen kwantitatief bepaal kan word. Uriene is die voorkeur liggaamsvloeistof vir die analise van metaboliete wat deur die liggaam, na administrasie van mediese en onwettige middels, uitgeskei word. Die deteksie van hierdie metaboliete hang van die volume water af wat die pasiënt gedrink het, of in strafbare gevalle, die hoeveelheid water wat verdagtes met opset by hul uriene gevoeg het ten einde dit te verdun. Daar is bevind dat die konsentrasie van kreatinien in uriene met spiermassa korreleer, derhalwe is kreatinien as ‘n interne kontrolemiddel gekies waarmee die metaboliet-konsentrasie vergelyk kan word. Hoë-druk vloeistofchromatografie met ultravioletdeteksie (HPLC–UV) word algemeen vir die analise van kreatinien ingespan, maar die gehalte van die chromatografie word deur die hoogs polêre aard van kreatinien beïnvloed en het swak retensie in omgekeerde-fasekolomme tot gevolg. Bowendien, uriene bevat groot hoeveelhede polêre middels wat saam met kreatinien in die oplosmiddelfront elueer en sodoende HPLC-bepalings uitermatig beïnvloed. Hidrofiliese interaksiechromatografie (HILIC) is ‘n goeie alternatief, ofskoon omvangryke monster-voorbereidings algemeen vereis word. Direkte inspuitelektrosproei-ionisasiemassaspektrometrie (DI–ESI–MS) is ideaal geskik vir hoogs polêre stowwe en is vir hierdie studie gekies. Pneumatiese hulp-ESI word bo die standaard ionisasie-metode van lugdruk chemiese ionisasie (APCI) verkies weens pneumatiese hulp-ESI se vermoë om die oplosmiddel in aërosoldruppels wat ione bevat, te versprei – sonder die aanlynomskakeling van kreatinien na kreatien. Die doel van hierdie studie was om ‘n eenvoudige en sensitiewe DI–ESI–MS-metode te ontwikkel wat verskeie stowwe in uriene kan bepaal deur kreatinien as analitiese verwysingsmiddel en interne standaard (IS) vir die opstelling van ‘n IS-kalibrasiekurwe te gebruik. Die analitiese metode-ontwikkeling sluit die gebruik van 1-metiel-3-fenielpropielamien as primêre IS in. Die IS word tot standaard oplossings en urienemonsters gevoeg, gevolg deur direkte inspuiting van die monster in ‘n massaspektrometer om die absolute konsentrasies van kreatinien, kreatien en kaffeïen te bepaal. Lineêre kurwes van die seinintensiteitsverhouding van analiet tot IS is verkry na gepaste instrumentkondisies vasgestel is. Die verhouding van konsentrasie van die analiet (middel of metaboliet) tot dié van kreatinien (as IS) mag gebruik word om die analietkonsentrasie in die standaard oplossings en/of urienemonster te bepaal. Die metode word nie deur veranderinge in die vloeistofvolume of verwatering van urienemonsters beïnvloed nie, weens die analiet-tot-kreatinienverhouding wat onveranderd bly. ‘n LC–UV–MS-metode is voorts ontwikkel om die ontwikkelde DI–ESI–MS-metode se data te vergelyk.

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: In this thesis we describe various attempts at incorporating macrocycles into dendritic architectures to form macrocycle-dendrimer conjugates with the aim of preparing materials that would exhibit properties that are more than the sum of the constituent parts, in this case macrocycles and dendrimers. A further aim was the synthesis and characterization of metallodendrimers based on such scaffolds and to test these as catalyst precursors in the catalytic oxidation of alcohols. The synthesis of two different types of conjugate systems was attempted; viz. dendrimers functionalized with macrocycles on the peripheries and dendrimers with macrocyclic cores. The synthesis of conjugate systems based on cyclam as the macrocycle was attempted. This required the mono functionalization of cyclam with a linker molecule capable of further reaction with the functional groups at the periphery of commercially available N,N,N,N-tetrakis(3-aminopropyl)-1,4-butanediamine dendrimer. Several approaches were taken in trying to make such conjugate systems but they were not entirely successful. One of the major issues was the final deprotection step, of the Boc-protected cyclam units which proved difficult in our hands. Another approach to prepare the target conjugates involved the use of click chemistry in order to synthesize a dendrimer with an aromatic core and cyclam peripheries. A dendrimer with Boc-protected cyclam peripheries that are bonded through triazole groups to the aromatic core was synthesized. However, subsequent attempts at de-protection of the cyclam functionalities of this conjugate failed to yield the pure de-protected dendrimer. Greater success was achieved with the preparation of a dendrimer with a macrocyclic core. A cyclam cored dendrimer with salicylaldimine peripheries was successfully synthesized and characterized. This dendritic ligand was complexed to Cu(II), Ni(II) and Zn(II) metal ions respectively to form a series of new metallodendrimers. These metallodendrimers were fully characterized using a range of analytical techniques including FT-IR spectroscopy, mass spectrometry, elemental analysis, thermogravimetric analysis, magnetic susceptibility measurements and NMR spectroscopy where appropriate. The Cu(II) and Ni(II) metallodendrimers were tested as catalyst precursors in the catalytic oxidation of benzyl alcohol to benzaldehyde. The catalytic system consisted of the appropriate metallodendrimer, the free radical, 2,2,6,6-tetramethylpiperidinyl- 1-oxyl (TEMPO) and O2 as the oxidant. The reaction parameters, namely the nature of the solvent, catalyst loading, substrate concentration and reaction temperature were sequentially optimized to achieve the best catalytic efficiency. The Cu(II) catalyst precursor exhibited relatively high catalytic activity and achieved TOF’s between 40 and 30 when operating under the optimized conditions, while the Ni(II) catalytic system showed very poor catalytic activity. / AFRIKAANSE OPSOMMING: In hierdie tesis beskryf ons pogings om makroringe in die dendritiese argitektuur te inkorporeer om makroring-dendrimeer gekonjugeerdes te vorm met die hoop dat sulke molekules eienskappe sal toon wat meer is as die somtotaal van die afsonderlike eenhede. ‘n Verdere doel was die sintese en karakterisering van metallodendrimere gebaseer op sulke draers sowel as die toetsing van hierdie molekules as pre-katalisore in die katalitiese oksidasie van alkohole. Pogings tot die sintese van twee verskillende tipes makroring-dendrimeer gekonjugeerdes word beskryf naamlik, dendritiese ligande met makroringe by die buiterand sowel as dendritiese ligande met ‘n makroring as kern word bespreek. Die sintese van makroring-dendrimeer gekonjugeerdes gebasseer op die makroring cyclam word beskryf. Hierdie sintese vereis die gebruik van ‘n monogefunksioneerde cyclam wat ‘n gepaste koppelingsgroep besit. Hierdie koppelingsgroep kan dan verder met funksionele groepe op die oppervlak van die kommersieel beskikbare DAB-dendrimeer reageer. Verskeie pogings is aangewend om sulke gekonjugeerde stelsels te sintetiseer maar hierdie pogings was nie volkome suksesvol nie. ‘n Groot uitdaging was die gebruik en gevolglike latere verwydering van beskermende groepe soos Boc. ‘n Ander benadering het gebruik gemaak van “click” chemie met die doel om ‘n dendrimeer bestaande uit ‘n aromatiese kern en cyclam periferie te vorm. ‘n Dendrimeer met Boc beskermde cyclam eenhede op die buiterand geheg aan ‘n aromatiese kern deur triasool groepe is gesintetiseer. Die verwydering van die beskermende groepe geheg aan die cyclam eenhede was egter weereens ‘n probleem en hierdie metode kon nie die suiwer dendrimeer lewer nie. Groter sukses is behaal met die sintese van ‘n dendrimeer met ‘n cyclam kern en salisielaldimien periferieë. Die dendritiese ligand is vervolgens met metaalsoute van Cu(II), Ni(II) en Zn(II) gereageer om verskeie multikern metaalkomplekse te vorm. Die metaalkomplekse is volledig gekarakteriseer deur verskeie analitiese tegnieke insluitende infrarooi spektroskopie, massa spektrometrie, termografiese analiese, mikroanaliese asook KMR spektroskopie waar moontlik. Die Cu(II) en Ni(II) metaalkomplekse is geëvalueer as pre-katalisatore in die katalitiese oksidasie van alkohole. Hierdie katalitiese sisteem bestaan uit die metaalkompleks, die radikaal TEMPO en molekulêre suurstof. Die invloed van verskeie reaksie- parameters soos die tipe oplosmiddel, die hoeveelheid katalisator, die konsentrasie van die alkohol asook die temperatuur is ondersoek. Gevolglik is die optimale kondisies bepaal om die hoogste opbrengs van bensaldehied te lewer. Die Cu(II) kompleks het ‘n relatief hoë omset van bensielalkohol na bensaldehied getoon met omset frekwensie waardes tussen 30 en 40 onder die optimale kondisies. Die Ni(II) kompleks het egter swak aktiwiteit getoon vir hierdie transformasie.

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: With a cure for HIV and AIDS still absent, non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a major role in the current antiretroviral treatments used, which have shown to improve and prolong the lives of HIV patients significantly. However, with rapid mutations of the HI virus, the use of these drugs is becoming limited, thereby highlighting the need for the development of new NNRTIs. Previous work by our research team has led to the development of a cyclopropyl-containing indole-based compound with an inhibition activity (IC50 value) of 0.1 μM, as determined in an in vitro single-cycle, non-replicative phenotypic assay. Therefore, in this project, we focussed on enhancing the intermolecular interactions of our compound to three major areas in the NNRTI binding pocket, namely the Tyr181, the Val179, and the Lys101 binding pockets. Hereby we were able to obtain both improved and lower potencies, with our most active compound having an inhibition activity (IC50 value) of 1 nM. For the interaction to the Tyr181 binding pocket, we were thus unable to synthesise a heterocyclic ring system onto our molecule as opposed to the previously used phenyl ring. Secondly, for the interaction to the Lys101 binding pocket we were able to synthesise a tetrazole ring system and an amide functionality onto the 2-position of the indole. Lastly, in our quest to synthesise the cyclopropyl moiety onto our compound for the interaction in the Val179 binding pocket, we were able to investigate the full inhibition effect of this interaction by synthesising a similar compound with no interaction in this binding pocket. Moreover, we were able to synthesise a new compound with a methoxy moiety for this interaction with an inhibition activity (IC50 value) of 1 nM. With this compound only being submitted for efficacy evaluation as a racemic compound mixture, this opened a new door for research possibilities for our team. / AFRIKAANSE OPSOMMING: In die awesigheid van 'n geneesmiddel vir MIV en VIGS, speel nie-nukleosied omkeerbare transkripsie inhibitore ("NNRTIs")'n groot rol in die huidige antiretrovirale behandeling. Ongelukkig ondergaan die MI virus mutasies, wat dus die gebruik van hierdie antiretrovirale middels beperk. Hierdie beklemtoon dus die noodsaaklikheid vir die ontwikkeling van nuwe "NNRTIs". Vorige werk wat deur ons navorsings groep verrig is, het gelei tot die ontwikkeling van "n siklopropiel bevattende indol verbinding, met "n inhibisie aktiwiteit ("IC50" waarde) van 0.1 μM. Gevolglik, het ons in hierdie projek gefokus om die intermolekulêre interaksies van hierdie verbinding in drie hoof areas in die "NNRTI" bindings ruimte te verbeter, genaamd die Tyr181, die Val179, en die Lys101 bindings ruimtes. Hierdie projek het dus beide verbeterde en ook laer inhibisie aktiwiteits resultate gelewer, waar die mees aktiewe verbinding 'n inhibisie aktiwiteit ("IC50" waarde) van 1 nM behaal het. Vir die interaksie na die Tyr181 bindings ruimte, was ons dus onsuksesvol om 'n heteroaromatiese ring te sintetiseer as plaasvervanger vir die oorspronklike feniel ring. Tweedens, vir die interaksie na die Lys101 bindings ruimte, was ons in staat om 'n tetrazol ring en 'n amied funksionaliteit aan die 2-posisie van die indol te sintetiseer. In ons stryd om die siklopropiel ring aan ons verbinding te sintetiseer vir die interaksie in die Val179 bindings ruimte, was ons in staat om die volledige effek van hierdie interaksie te bepaal deur 'n soortgelykke verbinding te sintetiseer met geen interaksie in die Val179 bindings ruimte nie. Daarenbowe, het ons 'n verbining gesintetiseer met 'n inhibisie aktiwiet ("IC50" waarde) van 1 nM, waarvan die aktiwitiet van slegs die rasemiese mengsel van die verbinding bepaal is. Hierdie vinding het dus 'n nuwe navorsings deur vir ons groep geopen.

Thesis (MSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Two series of amphiphilic, organic-inorganic graft copolymers of poly(methyl methacrylate) and poly(dimethylsiloxane) (PMMA-graft-PDMS), as well as poly(acrylonitrile) and poly(dimethylsiloxane) (PAN-graft-PDMS), were synthesized via conventional free radical copolymerization using the ―grafting through‖ technique. In both series the PDMS macromonomer content varied from 5 wt.% - 25 wt.% and different graft lengths of 1000 g/mol and 5000 g/mol were used. A gradient elution profile was developed to monitor the removal of the unreacted PDMS macromonomer using hexane extraction. In the case of the PAN copolymer series, the gradient profile showed that as the PDMS content in the feed increased, more PAN-graft-PDMS molecules formed relative to homopolymer PAN. In the case of the PMMA copolymer series, mostly PMMA-graft-PDMS molecules were formed as the PDMS content in the feed increased. In the case of the PAN-graft-PDMS series, the PDMS content affected the crystallization behaviour of the PAN segments and lead to a decrease in crystallinity across the composition range as the PDMS content increased. It is shown that the synthesized graft copolymers can be electrospun to produce continuous nanofibers. The effects of polymer solution concentration, copolymer composition and tip-to-collector distance on the fiber morphology are discussed. The rapid stretching of the polymer jet, as well as the rapid solvent evaporation during the electrospinning process, resulted in highly complex nonequilibrium morphologies in the case of the electrospun PAN-graft-PDMS copolymers. The crystallization behaviour of the electrospun fibers of PAN-graft- PDMS was shown to be different from the unprocessed precursor material. Surface oxidised MWCNTs were successfully incorporated and well dispersed into the graft copolymers via the electrospinning process to produce nanocomposite nanofibers. In the case of the PAN-graft-PDMS copolymer series, the presence of MWCNTs in the nanocomposite nanofibers enhanced the overall degree of crystallinity when compared to the unfilled nanofibers. For the first time positron annihilation lifetime spectroscopy (PALS) analysis was performed on the various complex graft copolymer compositions and their electrospun fiber analogues, as well as nanocomposites, to investigate the free volume properties of the various materials. The results revealed that there are two distinct ortho-positronium (o-Ps) lifetime parameters for these complex multiphased materials. The shorter lived lifetime -3 was attributed to the o-Ps annihilation in the amorphous regions of the crystalline PAN phase in the PAN-graft-PDMS copolymer series, as well as to the o-Ps annihilation in the amorphous PMMA phase in the case of the PMMA-graft-PDMS copolymer series. The longer lived lifetime -4 was attributed to the o-Ps annihilation in the more amorphous PDMS phase. In the case of the PMMA series the relative fractional free volume was influenced by the graft lengths, where the 5000 g/mol series showed a larger increase in fractional free volume relative to the shorter 1000 g/mol series. The effects of the tip-to-collector distance during electrospinning, as well as the inclusion of MWCNTs, on the free volume properties are also discussed. It is demonstrated how positron annihilation lifetime spectroscopy can provide valuable and unique information on the internal structure and morphology of the electrospun nanofibers. / AFRIKAANSE OPSOMMING: Twee reekse amfifiliese, organies-anorganiese entkopolimere van poli(metielmetakrilaat) en poli(dimetielsiloksaan) (PMMA-ent-PDMS), asook poli(akrilonitriel) en poli(dimetielsiloksaan) (PAN-ent-PDMS), is gesintetiseer deur konvensionele vrye-radikaalkopolimerisasie. Die PDMS makromonomeerinhoud het gewissel tussen 5 wt.% - 25 wt.% in albei reekse en sykettinglengtes van 1000 g/mol en 5000 g/mol is gebruik. `n Gradient-eluasieprofiel is opgestel om die verwydering van ongereageerde PDMS makromonomeer d.m.v. heksaanekstraksie te monitor. In die PAN kopolimeer reeks het die gradient-eluasieprofiel gewys dat meer PAN-ent- PDMS molekules vorm relatief tot die PAN homopolimeer sodra meer PDMS bygevoeg word. In die PMMA kopolimeer reeks het meer PMMA-ent-PDMS molekules gevorm sodra meer PDMS toegevoeg is. In die geval van die PAN-ent- PDMS reeks, het die PDMS die kristallisasiegedrag van die PAN segmente geaffekteer en `n afname in die totale kristalliniteit veroorsaak soos die PDMS inhoud vermeerder het. Daar word bewys dat die gesintetiseerde entkopolimere geelektrospin kan word om nanovesels te vorm. Die effek van polimeeroplossingskonsentrasie, kopolimeersamestelling en punt-tot-versamelaarafstand op die nanoveselmorfologie word bespreek. Die vinnige strekking van die polimeerjet sowel as die vinnige verdamping van die oplosmiddel gedurende die elektrospinproses het gelei tot hoogs komplekse nie-ekwilibrium morfologieë in die geval van die ge-elektrospinde PAN-ent-PDMS kopolimere. Die kristallisasiegedrag van die nanovesels van PAN-ent-PDMS het verskil van die onverwerkte voorloper materiaal. Oppervlakgeoksideerde MWCNTs is suksevol geïnkorporeer en versprei in die entkopolimere d.m.v. die elektrospinproses om nanosaamgestelde nanovesels te vorm. Die teenwoordigheid van MWCNTs in die nanosaamgestelde nanovesels in die PAN-ent-PDMS kopolimeerreeks het gelei tot `n verbetering in die algehele kristalliniteit in vergelyking met die nanovesels sonder MWCNTs. Positronvernietigingsleeftyd- spektroskopie (PALS) is vir die eerste keer gebruik om die vrye volume van verskillende kompleks entkopolimeersamestellings, hul ge-elektrospinde nanovesels sowel as nanosaamgestelde nanovesels te bestudeer. Die resultate het getoon dat daar twee verskillende orto-positronium (o-Ps) leeftydparameters vir hierdie komplekse multifase materiale bestaan. Die korter leeftydparameter -3 word toegeskryf aan die o-Ps vernietiging in die amorfe areas van die kristallyne PAN fase in die PAN-ent-PDMS kopolimeerreeks, sowel as die o-Ps vernietiging in die amorfe PMMA fase in die PMMA-ent-PDMS kopolimeerreeks. Die langer leeftydparameter -4 word toegeskryf aan die o-Ps vernietiging in die amorfe PDMS fase. Die relatief fraksionele vrye volume van die PMMA reeks is deur die verskillende syketting lengtes beïnvloed. Die 5000 g/mol syketting het `n groter toename in fraksionele vrye volume veroorsaak relatief tot die korter 1000 g/mol syketting. Die effek van die punttot- versamelaar-afstand tydens die elektrospinproses op die vrye volume eienskappe, sowel as die insluiting van MWCNTs, word bespreek. Daar word aangedui hoe positron-vernietigingsleeftyd-spektroskopie waardevolle en unieke inligting kan verskaf oor die interne struktuur en morfologie van die nanovesels.

Thesis (MSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Cancer is the leading cause of death on the planet, killing an estimated 8.2 million people in the year of 2012.The disease is associated with two families of genes, namely oncogenes and tumour suppressor genes. The hallmarks of cancer pathogenesis include gene amplification, point mutations or chromosomal rearrangements within these genes. Kinases are responsible for the reversible phosphorylation of proteins, which plays a significant and extensive role in cellular signal transduction. Aberrant kinase activity provokes overexpression, mutations and chromosomal translocation and results in the onset of onco- and tumorogenesis, ultimately leading to cancer. Inactivation of this class of enzyme is thus critical as it would result in the suppression of these unwanted activities. For this, researchers have developed kinase inhibitors, specifically targeting these proteins and thus inhibiting signal transduction pathways and tumour growth. This has resulted in great successes, particularly in the case of the commercial inhibitor, imatinib. However, resistance to approved therapeutic agents through mutations has resulted in the search for more potent and selective inhibitors to overcome these obstacles. This project involved the synthesis of bioactive heterocycles linked to 1,2,3-triazoles using either a C-C or C-N bond forming strategy. The synthetic methodology followed included the use of Sonogashira coupling reactions between3-bromoquinoline, 7-chloro-4-iodoquinoline, 4-bromoisoquinolineand5-bromoisoquinolineand trimethylsilylacetylene (TMSA), followed by deprotection of the TMS group to yield heterocycles bearing terminal alkynes. The synthesis of both benzyl azide and 2-(azidomethyl)pyridine as azide fragments, allowed for subsequent coupling of the synthesized azide and alkyne fragments through copper-mediated click chemistry, affording a library of 1,4-substituted 1,2,3-triazole based reversible kinase inhibitors. Synthesis of a second library of o-, m- and p-substituted nitro benzyl azides, allowed for both copper- and ruthenium-mediated click reactions, between the alkynes and nitro benzyl azides synthesized, to yield 1,4- and 1,5-substituted 1,2,3-triazoles, respectively. Finally, reduction of the incorporated o-, m- and p- substituted nitro group, and acylation of the resultant amine with acryloyl chloride, resulted in the incorporation of the important Michael acceptor moiety required for irreversible inhibition. This afforded a library of both reversible and potential irreversible triazole-based kinase inhibitors through efficient copper- and ruthenium-mediated click chemistry. Biological screening and activity assays against the wildtype, and two mutated forms of the EGFR kinase, were undertaken with these synthesized compounds.A number of synthesized inhibitors showed good selectivity for the mutated forms of the EGFR kinase only.The most potent inhibitor N-{2-{[4-(isoquinolin-4-yl)-1H-1,2,3-triazol-1-yl]methyl}phenyl}acrylamide,displayed efficacy in the low μM range - comparable to that of the FDA approved drug, gefitinib. The synthetic methodology derived in this project could be applied to the use of biological space probes with further investigatory research. Furthermore, from the biological screening results obtained, and the selectivity profile shown by these inhibitors, the synthesis of a second generation library of compounds is an additional research possibility. / AFRIKAANSE OPSOMMING: Kanker is die hoof oorsaak van sterftes ter wêreld, wat verantwoordelik is vir die dood van ongeveer 8.2 miljoen mense in die jaar 2012. Die siekte word geassosieer met twee geenfamilies, naamlik onkogene en gewasonderdrukkingsgene. Die kenmerke van kanker pathiogene behels geenversterking, puntmutasies of chromosomale herrangskikking binne in die gene. Kinase is verantwoordelik vir die omkeerbare fosforilering van proteine wat 'n uiters belangrike rol in sellulere sein transduksie speel. Abnormale kinase aktiwiteit lei tot ooruitdrukking, mutasies en chromosomale translokasie wat tot die ontwikkeling van onko- en gewasgroei en wat eindelik tot kanker lei. Deaktivering van die klas van ensieme is dus krities want dit sal die ongewenste abnormale aktiwiteite onderdruk. As gevolg van die bogenoemde, het navorsers kinase inhibeerders ontwikkel wat die spesifieke protein teiken en hiermee die sein transduksie roete asook gewas groei inhibeer. Hiermee het die sukses van inhibeerders veral die kommersiele inhibeerder, imatinib, grootliks toegeneem. Oor die afgelope jare het die belangstelling in die ontwikkeling van meer selektiewe en kragtige inhibeerders toegeneem as gevolg van die weerstand wat goedgekeurde terapeutiese middels opbou. In hierdie projek is daar gebruik gemaak van 'n C-C of C-N bindingsvorming strategie om bioaktiewe heterosikliese molekules te sintetiseer wat gekoppel is aan 1,2,3-triasool funksionele groepe. Die sintetiese metode maak gebruik van Sonogashira reaksies vir die 3-bromo-kwinolien, 7-chloro-4-iodokwinolien, 4-bromoisokwinolien en 5-bromoisokwinolien met trimetielsilielasetileen (TMSA), gevolg met die ontskerming van die TMS-groep om die terminale alkyn op die heterosiklusse te ontbloot. Die asied fragmente, bensiel asied en 2-(asidometiel)piridien, was toe gesintetiseer om met die gevormde heterosiklus alkyne 'n koper ondersteunende kliek chemie te ondergaan. 'n Reeks van 1,4-digesubstitueerde 1,2,3-triasool gebaseerde omkeerbare kinase inhibitore is toe gevorm. 'n Tweede reeks met o-, m-, en p- gesubtitueerde nitro bensiel asiede was gesintetiseer om 1,4- en 1,5- digesubtitueerde 1,2,3-triasole te sintetiseer met behulp van koper- en ruthenium ondersteunende kliek chemie. Laastens was die o-, m-, en p- nitro groepe gereduseer om 'n primêre amien te vorm. Die gevormende amien het 'n asileringsreaksie met akriloïel chloried ondergaan om die kern, die Michael akseptor, te inkorporeer. Die Michael akseptor word benodig om 'n onomkeerbare inhibitoriese aktiwiteit te kan uitvoer. Die projek het dus met behulp van kliek chemie, twee 1,2,3-triasool reekse gelewer wat omkeerbare en onomkeerbare inhibitoriese aktiwiteit kan uitvoer. Die verbindings gesintetiseerd in hierdie projek het keuringstoetse ondergaan teen die wilde tipe en teen twee gemuteerde forme van die EGFR kinase ensiem. Van hierdie verbindings het goeie selektiwiteit vertoon teenoor die gemuteerde EGFR kinase ensiem. Die mees aktiewe inhibeerder, N-{2-{[4-isokwinolin-4-iel)-1H-1,2,3-triasool-1-iel]feniel}akrielamied, het aktiwiteit in die lae μM reeks vertoon. Dié inhibisie waarde is vergelykbaar met die FDA goedgekeurde medikasie, gefitinib. In hierdie projek is sintetiese metodes ontwikkel wat toegepas kan word op meer intensiewe biologiese ondersoeke en asook meer navorsing. Die resultate vekry van die biologiese aktiwiteit, asook die verbindings se selektiwiteit, gee die moontlikheid vir die ontwikkeling en sintese van 'n tweede generasie verbindings.