Studies on the synthesis, cyclodextrin inclusion and biological activity of ajoene analogues as potentially novel anti-cancer agents

Includes bibliographical references (leaves 107-111).The first part of the thesis describes synthesis of 10-( 4-methoxyphenyl)-4,5,9-trithia-deca- 1 ,6-diene (25) as an ajoene mimic and as a mixture of EIZ-geometrical isomers using new synthetic methodology. 4,5,9-trithia-dodeca-1,6-diene 9-oxide (43), 4,5,9-trithia-dodeca-,6- ene 9-oxide (44) and 2,3,7-trithia-deca-4-ene 7-oxide (45) were also successfully synthesized as a mixture of EIZ- separable geometrical isomers using the same synthetic methodology. The synthesis involved a radical addition and a chemoselective oxidation as key steps. Characterisation was carried out by [1]H NMR, [13]C NMR, IR and HRMS spectroscopies

UC781: BETA-CYCLODEXTRIN COMPLEXATION AND FORMULATION AS AN ANTI-HIV MICROBICIDE

ABSTRACTBackground: UC781, a tight-binding non-nucleotide reverse transcriptase inhibitor (NNRTI) of HIV-1, is a thiocarboxanilide that has been identified as a potential microbicide agent. UC781 prevents HIV-1 infection by potently inhibiting HIV-1 replication (EC50„l8nM) with a broad therapeutic index (>62,000). However, its extremely poor water solubility leads to a great challenge for its formulation development. A beta-cyclodextrin (beta-CD) based drug delivery system was developed for UC781 to overcome this issue.Method: The complex of UC781: beta-CD was assessed with UV, FTIR, DSC, and NMR. An HPLC method was used to investigate the thermodynamic behavior of the UC781 complex. Complexation of UC781 with either hydroxypropyl -beta-Cyclodextrin (HP-beta-CD) or methyl-beta-cyclodextrin (M-beta-CD) was optimized by evaluation of four processing methods (autoclave, lyophilization, shaking, and kneading), incorporation of four water-soluble polymers (HPMC, HEC, PVA, and PVP K30), and utilization of three buffering systems (pH 7.0, 9.0 and 11.0). Finally, three formulations¡Xmethylcellulose (MC) gel, hydroxyethylcellulose (HEC) gel, and polyvinyl alcohol (PVA) film¡Xwere developed for UC781. The physical properties, toxicity, and anti-HIV activity of UC781 containing formulations were evaluated with in vitro and ex vivo models. Results: Complexation of UC781 with beta-CDs was confirmed and characterized with UV, FTIR, DSC, and NMR. UC781¡¦s complexation was found to be an enthalpy driven process. The solubility of UC781 was increased from almost none to 35 ug/ml in 15% HP-beta- CD and 180 ug/ml in 15% M-beta- CD solutions after optimization.Complexation technique significantly improved the release of UC781 from all three formulations. The complexation of UC781 with HP-beta- CD or M-beta- CD greatly increased the osmolality and decreased the viscosity of MC and HEC gel; shortened the disintegration time of PVA film; and reduced IC50 for UC781 in all three formulations. No observed toxicity was found in all complexed UC781 containing formulations.Conclusion:beta-CD complexation technique provided an effective method to overcome the aqueous solubility challenge for UC781. UC781 complexation can be used as a safe and effective drug delivery system for UC781. Of the formulations tested, PVA film with complexed UC781 provided the most promising option for microbicide product development

The design and synthesis of novel chiral ionic liquids for testing as chiral selecting agents in GC stationary phases

As the production of new chiral products such as drugs continually increases, the currently available CSPs are not guarantees to provide adequate enantioseparation for new products. With the increased demand from drug regulatory agencies for drug manufacturers to provide safety data by way of enantiomeric purity, there is a need for the development of more chiral selectors for application in gas chromatography (GC) or liquid chromatography (LC) stationary phases for the analysis of chiral drug products. Given that GC is one of the preferred methods of chiral analysis recommended by drug regulatory agencies, it is important to have a range of GC stationary phases which possess diverse physical and chemical properties to allow researchers to conduct not only routine chiral analysis but provide a selection of stationary phases with the appropriate properties required to conduct specialised enantioselective analysis experiments. Ionic liquids have been identified as good candidates for application as stationary phases in GC. Their negligible vapour pressure, good thermal stability, multiple solvation interaction and their tuneable physical and chemical properties make them ideal candidates for application in the design of new stationary phases. In this work the design, synthesis, and testing of novel chiral ionic liquids (ILs), for enantioselective capability in GC stationary phases is presented. First, new chiral cis- and trans-2,4,5-triphenylimidazolinium ILs are synthesised as well as their achiral 2,4,5-triphenylimidazolium IL counter parts. Following which the asymmetrical N-derivatisation of trans-2,4,5-triphenylimidazoline with various amino acids is described, which upon alkylation with an alkylhalide served as precursors for the synthesis of novel chiral ILs. We also describe the synthesis of new asymmetrical chiral imidazolinium ILs with various side groups from simple amino acids, permitting the incorporation of various functional groups at positions 2, 3, 4, and 5 on the imidazoline moiety, allowing for the production of a wide range of imidazolinium ILs with tunable physical and chemical properties. New ionic cyclodextrins (CD) were also synthesised from per-6-iodo-2,3-hydroxy-β-CD, per-6-iodo-2,3-O-acetyl-β-CD, per-6-iodo-2,3-O-acetyl-γ-CD to afford variousper-6-imidazolium-2,3-hydroxy-β-CD iodide, per-6- imidazolium-2,3-O-acetyl-β-CD iodide, and per-6-imidazolium-2,3-O-acetyl-γ-CD iodide as well as their pyridium ionic CD counterparts. A selection of chiral ILs incorporated into capillary columns as chiral selectors diluted in OV-1701, and their phase polarities and their enantioselective capabilities evaluated. The resultant mixed phases remained relatively non-polar while displaying markedly altered retention behaviours for various analytes. A good example of the need for a wider selection of chiral stationary phases that possess a variety of chemical properties for specialized applications was illustrated. In the study we conducted with chiral oximes undergoing dynamic molecular interconversion between their E & Z isomeric forms during the chromatographicelution process on wax stationary phases. The study was conducted on wax column coupled to a chiral column to allow the sequential examination of the interconversion process and chiral resolution. Ideally the interconversion process and enantiomer resolution should be examined simultaneously, however, stationary phases with such capabilities are currently not available on the market, illustrating the need for the development of new chiral stationary phases (CSPs) for routine and specialised enantioselective analysis

Dynamic behaviour of volatile organic compounds in air treatment systems applied to animal house emissions

The attention for air quality has increased in recent decades through both the scientific and social debate, and is therefore a hot topic as it is often associated with human health, environmental and climate problems. An increasing world population and activity have both a baleful influence on air quality. For example, the gaseous emissions from animal sites cause odour nuisance in neighbouring areas and the current end-of-pipe techniques are insufficiently capable of controlling these emissions. The aim of this doctoral research was to gradually gain insight into the behaviour of odour compounds in air purification systems, mainly air scrubbers and biofilters. Fundamental knowledge was obtained about how the removal of odour compounds depends on its physical-chemical properties. In addition, it was investigated to what extent the behaviour of odour compounds can be changed by specifically changing the liquid phase of the air purification systems. This work is a combination of fundamental knowledge, which was later applied on a pilot scale and eventually validated on a practical scal

Two new, single-isomer, sulfated β-cyclodextrins for use as chiral resolving agents for enantiomer separations in capillary electrophoresis

Two novel, single-isomer, sulfated cyclodextrins, the sodium salts of heptakis(2- O-methyl-3-O-acetyl-6-O-sulfo)cyclomaltoheptaose (HMAS) and heptakis(2-O-methyl- 6-O-sulfo)cyclomaltoheptaose (HMS) were used as chiral resolving agents in both aqueous and non-aqueous electrophoretic separation of a set of pharmaceutically active weak base enantiomers. Enantiomers of twenty one of the twenty four weak bases were baseline resolved in one or more of the background electrolytes (BGE’s) used. An eight-step synthetic method was used to produce, on a large scale, the title compounds in greater than 97% purity. The purity of the synthetic intermediates and the final products were characterized by HPLC-ELSD and indirect UV-detection capillary electrophoresis (CE), respectively. X-ray crystallography, MALDI-TOF mass spectrometry and 1H as well as 13C NMR spectroscopy allowed for unambiguous characterization of the structure of each intermediate and the final product

SUPRAMOLECULAR BIOMATERIALS BASED ON CYCLODEXTRIN-OLIGOETHYLENIMINE STAR POLYMERS FOR DRUG AND GENE DELIVERY

Ph.DDOCTOR OF PHILOSOPH

The synthesis of water-soluble polymers with drag reducing properties

The objective of work described in this thesis was to synthesize water soluble polymers with drag reducing properties that would expand the understanding of the relationship between the molecular structure of polymers and drag reduction performance. The additional aim of this study was to identify suitable additives that would enable removal of associating polymers from the low permeability reservoirs. The copolymers of acrylamide and two hydrophobic monomers, n-decyl- and n-octadecyl acrylamide were prepared using micellar polymerisation. Polymers of N-hydroxyethyl acrylamide were also prepared via the same method. Water soluble polymers of styrene and butadiene were acquired by sulfonation of poly(styrene-block-butadiene) with acetyl sulfate. The evidence of the incorporation of hydrophobic monomers, sulfonic acid groups into copolymers and the concentration of hydrophobic moieties was studied using NMR, FT-IR and Elemental Analysis. The influence of the degree of sulfonation on the flexibility of polymers and polymer degradation temperatures were investigated by DSC, DMA and TGA. The associating properties of polymers were studied using Dynamic Light Scattering and rheology. The drag reducing properties were quantified using a standard rheometer equipped with a Couette double-gap measuring geometry, by calculating the percentage of drag reduction (% DR) based on apparent viscosity. The extent of adsorption and desorption of polymers from silica was studied by Total Organic Carbon. From the obtained results it was clear that the associating properties of polymers synthesised in this thesis were dependent on the concentration of hydrophobic moieties. In addition, the formation of hydrophobic associations and the polymer coil dimensions were found to greatly influence the drag reducing properties and shear resistance of copolymers. It was found that hydrophobically modified polyacrylamide promoted higher drag reduction in comparison to unmodified polyacrylamide. In addition, introduction of a small amount of hydrophobic moieties was found to impart drag reducing properties in poly(N-hydroxyethyl acrylamide). Moreover, water soluble sulfonated poly(styrene-block-butadiene) showed high drag reduction efficiency at extremely low molecular weights below the required lower molecular weight limit necessary to produce excellent drag reduction effect. Furthermore, the sulfonation of poly(styrene-block-butadiene) resulted in the reduced thermal stability of polymers and an increase in the degree of sulfonation resulted in the decrease in the flexibility of polymer chains. The extent of adsorption of polymers of acrylamide on silica was found to increase with molecular weight of polymers and was higher for hydrophobically modified polyacrylamide due to the formation of intermolecular associations between copolymer chains. The desorption capability of copolymers with the aid of Cyclodextrin was demonstrated and was found to depend on the type of Cyclodextrin used and on the concentration of hydrophobic moieties. Nearly 100 % of the adsorbed polymer was recovered when even small concentrations of β-Cyclodextrin were applied. Additionally, partial desorption of polyacrylamide with the aid of α and β-Cyclodextrin was also achieved