This thesis is concerned with phytoestrogenic isoflavones, which are a group of plant-derived compounds that can be consumed in the diet or as over-the-counter preparations for self-medication, and have been associated with a wide range of health benefits. However, unlike the extract of St John's wort and grapefruit juice, little is known about the potential for phytoestrogenic isoflavones to be involved in pharmacokinetic interactions. This thesis describes a series of experiments that investigate that potential by assessing the effects of the isoflavones on intestinal P-glycoprotein-mediated transport, hepatic metabolism, and hepatic cell membrane transport of conventional drugs.

This thesis is concerned with phytoestrogenic isoflavones, which are a group of plant-derived compounds that can be consumed in the diet or as over-the-counter preparations for self-medication, and have been associated with a wide range of health benefits. However, unlike the extract of St John's wort and grapefruit juice, little is known about the potential for phytoestrogenic isoflavones to be involved in pharmacokinetic interactions. This thesis describes a series of experiments that investigate that potential by assessing the effects of the isoflavones on intestinal P-glycoprotein-mediated transport, hepatic metabolism, and hepatic cell membrane transport of conventional drugs.

The role of metals in biological processes has been discussed with particular emphasis on the importance of chelation. Furst has suggested that many anticancer drugs may owe their activity to their chelating properties. A number of new amidoximes and hydroxylamine have been made from the appropriate imidoyl chloride and a hydroxylaqine. The spectral and chelating properties of these compounds are discussed. All the compounds have been submitted to the anticancer screening programme of the National Cancer Institute. The results available so far are presented and indicate that the compounds are toxic but inactive against experimental tumours. Sodium sulphide reduces a-phenyl-o-nitro-cinnamonitrile (106) to 2-amino-3-phenylquinoline-1-oxide (107) in good yield. Extension of the reduction to other o-nitrocinnamonitriles gives very poor results. The spectral properties, configurations and conformations of the o-nitrocinnamonitriles are discussed. The 12-aminoquinoline-1-oxide group is shown to form solid metal complexes. That from 2-amino-3-phenylquinoline-1-oxide (107) with nickel has been prepared. Antitumour screening results are presented for several 2-aminoquinoline derivatives. None of these compounds appears to be active.

The role of metals in biological processes has been discussed with particular emphasis on the importance of chelation. Furst has suggested that many anticancer drugs may owe their activity to their chelating properties. A number of new amidoximes and hydroxylamine have been made from the appropriate imidoyl chloride and a hydroxylaqine. The spectral and chelating properties of these compounds are discussed. All the compounds have been submitted to the anticancer screening programme of the National Cancer Institute. The results available so far are presented and indicate that the compounds are toxic but inactive against experimental tumours. Sodium sulphide reduces a-phenyl-o-nitro-cinnamonitrile (106) to 2-amino-3-phenylquinoline-1-oxide (107) in good yield. Extension of the reduction to other o-nitrocinnamonitriles gives very poor results. The spectral properties, configurations and conformations of the o-nitrocinnamonitriles are discussed. The 12-aminoquinoline-1-oxide group is shown to form solid metal complexes. That from 2-amino-3-phenylquinoline-1-oxide (107) with nickel has been prepared. Antitumour screening results are presented for several 2-aminoquinoline derivatives. None of these compounds appears to be active.

Content removed due to copyright restrictions: E I-Sherbiny, I.M., Lins, R.l , Abdel-Bary, E.M., Harding, D.R.K. Preparation, characterization, swelling and in vitro drug release behaviour of poly[Nacryloylglycine- chitosan] interpolymeric pH and thermally-responsive hydrogels. Eur. Polym. J. 41 (2005) 2584. E I-Sherbiny, I.M., Abdel-Bary, E.M., Harding, D. R.K. Preparation and swelling study of a pH-dependent interpolymeric hydrogel based on chitosan for controlled drug release. Inl. J. Polym. Mater. 55 (2006) 789. El-Sherbiny, I.M., Abdel-Bary, E.M., Harding, D. R. K. Swelling characteristics and in-vitro drug release study with pH and thermo-sensitive hydro gels based on modified chitosan. J. Appl. Polym. Sci. 102 (2006) 977. Abdelaal, M.Y., Abdel-Razik, E . A , Abdel-Bary, E.M., El-Sherbiny, I.M. Study on chitosan-poly(vinyl alcohol) interpolymeric pH-responsive hydrogel films for controlled drug delivery. J. Appl. Polym. Sci. (2006) in press. El-Sherbiny, I. M., Abdel-Bary, E.M., Harding, D. R. K. In-vitro investigation of new biodegradable pH-responsive hydrogel beads for oral delivery of protein drugs in the small intestine. New Zealand Institute of Chemistry Conference (NZIC), (2006) Rotorua, New Zealand, 2-6 December. / Controlled drug release enhances the safety, efficacy and reliability of drug therapy. Regulation of the drug release rate results in a reduction in the frequency of drug administration and should encourage patients to comply with dosing instructions. Hydrogels are crosslinked, three-dimensional hydrophilic polymers, which swell without dissolving when brought into contact with water or other biological fluids. The number of polymers suitable for the controlled release of viable therapeutics is quite limited because of inherent toxicity or lack of certain properties such as biodegradability. In this thesis, chitosan was chosen as the base polymer for the development of new hydrogels that can be tailored for use in the site-specific delivery of drugs to the gastrointestinal tract. Chitosan is a non-toxic and biodegradable polymer obtained through the alkaline deacetylation of natural chitin. The interesting characteristics of chitosan make it an ideal candidate for use in controlled drug release formulations. However, chitosan exhibits some shortcomings such as hydrophobicity and a high pH-dependency for its physical properties. Hence, it is very difficult to control drug release with chitosan itself because of the various pH values of the internal organs of the human body. This may negatively affect the human body because of drug under- or over-release. In a structured programme, some new chitosan-based hydrogels have been prepared for controlled drug release investigations by applying three main approaches to overcome the shortcomings of chitosan. The first approach was the incorporation of chitosan into interpenetrating polymer network hydrogels with either a hydrophilic polymer or with hydrophilic monomers treated to bring about in situ copolymerization in the presence of chitosan and a suitable crosslinking agent. The second approach was the chemical modification of chitosan by grafting of a suitable vinyl macromer such as poly(ethylene glycol)-diacrylate, then crosslinking this modified chitosan. The equilibrium swelling studies were carried out for the hydrogels prepared using these two approaches at 37 °C at pH 2.1 (simulated gastric fluid, SGF) and at pH 7.4 (simulated intestinal fluid, SIF). The swelling results showed a pH-responsive nature of these hydrogels. They attained higher swelling values in SGF than in SIF. 5-Fluorouracil (5-FU), an anti cancer drug, was entrapped as a model drug in all the hydrogels prepared using these two approaches. The in-vitro drug release studies were carried out at 37 °C in SGF and SIF. From the preliminary investigations of the prepared hydrogels, they may be customized and used to expand the utilization of these systems in drug delivery applications. In the third approach, chitosan was modified in such a fashion that the hydrogels produced were also pH-responsive but attained limited swelling in SGF and higher swelling in SIF. Hence, the resulting hydrogels could be tailored for utilization for intestine-targeted delivery of peptide and protein drugs with a potential protection of the drugs from the harsh acidity of the stomach. In this third approach the ionotropic gelation was used for the preparation of the hydrogels based on the modified chitosan with another natural polymer (sodium alginate) in the presence of a divalent ion. Bovine serum albumin (BSA) was entrapped as a model protein drug and the in-vitro drug release profiles were established at 37 °C in SGF and SIF. The results showed promising release profiles of BSA. However, this hydrogel study requires more effort to limit the swelling and consequently the loss of drug in the SGF, to act as an excellent candidate for intestine-specific delivery of peptide and protein drugs.

Content removed due to copyright restrictions: E I-Sherbiny, I.M., Lins, R.l , Abdel-Bary, E.M., Harding, D.R.K. Preparation, characterization, swelling and in vitro drug release behaviour of poly[Nacryloylglycine- chitosan] interpolymeric pH and thermally-responsive hydrogels. Eur. Polym. J. 41 (2005) 2584. E I-Sherbiny, I.M., Abdel-Bary, E.M., Harding, D. R.K. Preparation and swelling study of a pH-dependent interpolymeric hydrogel based on chitosan for controlled drug release. Inl. J. Polym. Mater. 55 (2006) 789. El-Sherbiny, I.M., Abdel-Bary, E.M., Harding, D. R. K. Swelling characteristics and in-vitro drug release study with pH and thermo-sensitive hydro gels based on modified chitosan. J. Appl. Polym. Sci. 102 (2006) 977. Abdelaal, M.Y., Abdel-Razik, E . A , Abdel-Bary, E.M., El-Sherbiny, I.M. Study on chitosan-poly(vinyl alcohol) interpolymeric pH-responsive hydrogel films for controlled drug delivery. J. Appl. Polym. Sci. (2006) in press. El-Sherbiny, I. M., Abdel-Bary, E.M., Harding, D. R. K. In-vitro investigation of new biodegradable pH-responsive hydrogel beads for oral delivery of protein drugs in the small intestine. New Zealand Institute of Chemistry Conference (NZIC), (2006) Rotorua, New Zealand, 2-6 December. / Controlled drug release enhances the safety, efficacy and reliability of drug therapy. Regulation of the drug release rate results in a reduction in the frequency of drug administration and should encourage patients to comply with dosing instructions. Hydrogels are crosslinked, three-dimensional hydrophilic polymers, which swell without dissolving when brought into contact with water or other biological fluids. The number of polymers suitable for the controlled release of viable therapeutics is quite limited because of inherent toxicity or lack of certain properties such as biodegradability. In this thesis, chitosan was chosen as the base polymer for the development of new hydrogels that can be tailored for use in the site-specific delivery of drugs to the gastrointestinal tract. Chitosan is a non-toxic and biodegradable polymer obtained through the alkaline deacetylation of natural chitin. The interesting characteristics of chitosan make it an ideal candidate for use in controlled drug release formulations. However, chitosan exhibits some shortcomings such as hydrophobicity and a high pH-dependency for its physical properties. Hence, it is very difficult to control drug release with chitosan itself because of the various pH values of the internal organs of the human body. This may negatively affect the human body because of drug under- or over-release. In a structured programme, some new chitosan-based hydrogels have been prepared for controlled drug release investigations by applying three main approaches to overcome the shortcomings of chitosan. The first approach was the incorporation of chitosan into interpenetrating polymer network hydrogels with either a hydrophilic polymer or with hydrophilic monomers treated to bring about in situ copolymerization in the presence of chitosan and a suitable crosslinking agent. The second approach was the chemical modification of chitosan by grafting of a suitable vinyl macromer such as poly(ethylene glycol)-diacrylate, then crosslinking this modified chitosan. The equilibrium swelling studies were carried out for the hydrogels prepared using these two approaches at 37 °C at pH 2.1 (simulated gastric fluid, SGF) and at pH 7.4 (simulated intestinal fluid, SIF). The swelling results showed a pH-responsive nature of these hydrogels. They attained higher swelling values in SGF than in SIF. 5-Fluorouracil (5-FU), an anti cancer drug, was entrapped as a model drug in all the hydrogels prepared using these two approaches. The in-vitro drug release studies were carried out at 37 °C in SGF and SIF. From the preliminary investigations of the prepared hydrogels, they may be customized and used to expand the utilization of these systems in drug delivery applications. In the third approach, chitosan was modified in such a fashion that the hydrogels produced were also pH-responsive but attained limited swelling in SGF and higher swelling in SIF. Hence, the resulting hydrogels could be tailored for utilization for intestine-targeted delivery of peptide and protein drugs with a potential protection of the drugs from the harsh acidity of the stomach. In this third approach the ionotropic gelation was used for the preparation of the hydrogels based on the modified chitosan with another natural polymer (sodium alginate) in the presence of a divalent ion. Bovine serum albumin (BSA) was entrapped as a model protein drug and the in-vitro drug release profiles were established at 37 °C in SGF and SIF. The results showed promising release profiles of BSA. However, this hydrogel study requires more effort to limit the swelling and consequently the loss of drug in the SGF, to act as an excellent candidate for intestine-specific delivery of peptide and protein drugs.

The role of metals in biological processes has been discussed with particular emphasis on the importance of chelation. Furst has suggested that many anticancer drugs may owe their activity to their chelating properties. A number of new amidoximes and hydroxylamine have been made from the appropriate imidoyl chloride and a hydroxylaqine. The spectral and chelating properties of these compounds are discussed. All the compounds have been submitted to the anticancer screening programme of the National Cancer Institute. The results available so far are presented and indicate that the compounds are toxic but inactive against experimental tumours. Sodium sulphide reduces a-phenyl-o-nitro-cinnamonitrile (106) to 2-amino-3-phenylquinoline-1-oxide (107) in good yield. Extension of the reduction to other o-nitrocinnamonitriles gives very poor results. The spectral properties, configurations and conformations of the o-nitrocinnamonitriles are discussed. The 12-aminoquinoline-1-oxide group is shown to form solid metal complexes. That from 2-amino-3-phenylquinoline-1-oxide (107) with nickel has been prepared. Antitumour screening results are presented for several 2-aminoquinoline derivatives. None of these compounds appears to be active.

The role of metals in biological processes has been discussed with particular emphasis on the importance of chelation. Furst has suggested that many anticancer drugs may owe their activity to their chelating properties. A number of new amidoximes and hydroxylamine have been made from the appropriate imidoyl chloride and a hydroxylaqine. The spectral and chelating properties of these compounds are discussed. All the compounds have been submitted to the anticancer screening programme of the National Cancer Institute. The results available so far are presented and indicate that the compounds are toxic but inactive against experimental tumours. Sodium sulphide reduces a-phenyl-o-nitro-cinnamonitrile (106) to 2-amino-3-phenylquinoline-1-oxide (107) in good yield. Extension of the reduction to other o-nitrocinnamonitriles gives very poor results. The spectral properties, configurations and conformations of the o-nitrocinnamonitriles are discussed. The 12-aminoquinoline-1-oxide group is shown to form solid metal complexes. That from 2-amino-3-phenylquinoline-1-oxide (107) with nickel has been prepared. Antitumour screening results are presented for several 2-aminoquinoline derivatives. None of these compounds appears to be active.

The role of metals in biological processes has been discussed with particular emphasis on the importance of chelation. Furst has suggested that many anticancer drugs may owe their activity to their chelating properties. A number of new amidoximes and hydroxylamine have been made from the appropriate imidoyl chloride and a hydroxylaqine. The spectral and chelating properties of these compounds are discussed. All the compounds have been submitted to the anticancer screening programme of the National Cancer Institute. The results available so far are presented and indicate that the compounds are toxic but inactive against experimental tumours. Sodium sulphide reduces a-phenyl-o-nitro-cinnamonitrile (106) to 2-amino-3-phenylquinoline-1-oxide (107) in good yield. Extension of the reduction to other o-nitrocinnamonitriles gives very poor results. The spectral properties, configurations and conformations of the o-nitrocinnamonitriles are discussed. The 12-aminoquinoline-1-oxide group is shown to form solid metal complexes. That from 2-amino-3-phenylquinoline-1-oxide (107) with nickel has been prepared. Antitumour screening results are presented for several 2-aminoquinoline derivatives. None of these compounds appears to be active.

Les glycosyltransférases sont responsables de la biosynthèse d’oligosaccharides, de polysaccharides et de glycoconjugués. Etant donné le nombre croissant de processus biologiques reliés aux saccharides, il existe un grand intérêt pour la compréhension des rôles biologiques des ces saccharides et étudier leurs applications thérapeutiques potentielles. Ce projet concerne la conception, la synthèse, l’évaluationbiologique et l’analyse structurale de deux nouveaux types d’inhibiteurs de glycosyltransférases analogues du substrat donneur naturel. L’analogie repose sur l’incorporation d’une unité pyridine ou amino-acide neutre comme mime du motif pyrophosphate afin de fournir des substrats capables de pénétrer les cellules pour des applications potentielles in cellulo ou in vivo. Les synthèses d’inhibiteurs neutres de GTs ont été réalisées en utilisant une combinaison de réactions de conjugaison créant une liaison O-glycosidique, amide ou triazole. Au total, 26 inhibiteurs neutres de GTs ont ainsi été synthétisés. L’évaluation de l’inhibition pour cinq galactosyltransférases et une GlcNAc-transférase(OGT) a révélé des inhibitions modestes de l’ordre du micromolaire. La co-cristallisation des meilleurs inhibiteurs avec l’une de ces galactosyltransférases a démontré que le motif pyridine neutre chélate le cation manganèse impliqué dans le site catalytique de l’enzyme. Cependant, le motif galactose est orienté vers l’extérieur du site catalytique et loin de la position initiale du substart naturel (UDP-Gal) etindique donc un nouveau mode de liaison. Le concept d’inhibiteur neutre a aussi été examiné sur un système modèle de membrane pour leur perméation membranaire. / Glycosyltransferase is an important class of enzyme in living organisms responsible for the biosynthesis of oligosaccharides, polysaccharides and glycoconjugates. As more and more carbohydrate related biological processes are elucidated, there is great interest to define the biological roles of a given carbohydrate and examine its potential therapeutic applications. The present study reports the design, synthesis, biological evaluation and structural analysis of two novel types of glycosyltransferase donor substrate analogues. The design rationale is to make analogues of sugar nucleotide diphosphate substrates, but incorporating a ‘neutral’ pyridine or amino-acid moiety as thepyrophosphate surrogate in order to provide cell permeable substrates for potential in cellulo or in vivo applications. The syntheses of “neutral” GTs inhibitors were performed using a combination of conjugations through O-glycoside bond, amide bond or triazole functionalities. A total number of 26 “neutral” GT inhibitors were prepared. The evaluation of inhibition towards five galactosyltransferasesand one GlcNAc-transferase (OGT) revealed moderate inhibitions in the micromolar range. More interestingly, co-crystallyzation could be achieved for the most potent compounds in complex with a glycosyltransferase. The designed ‘neutral’ pyridine linker could chelate the manganese cation involved in the enzyme catalytic site. Whereas the sugar head-group was oriented away from the position found inthe related complex with natural substrate (UDP-Gal) indicating a new binding mode. The concept of ‘neutral’ inhibitor was examined by an artificial cell membrane penetration test.