Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.

No description available.

No description available.

Organic-inorganic hybrid materials of divalent transition metal halides and simple organic molecules are known to exhibit interesting properties, with both the organic and the inorganic metal halide components contributing to the overall properties of the material (Aakeroy, Champness and Janaik, 2010) (Alexandre et al., 2007) (Aruta et al., 2004) (Criado et al., 1999) (Chondroudis and Mitzi, 1999) (Mitzi, Chondroudis and Kagan, 2001) (Robin and Fromm, 2006). The benzamide molecule was chosen as the primary organic component in this study, due to its potential to form aromatic interactions, and the fact that it possesses two potential sites for hydrogen bonding or protonation or coordination, via the amide group. In addition, the 4-aminobenzamide molecule was investigated due to its similarity to the benzamide molecule, except for an additional functional group on the opposite side of the amide group. A range of inorganic, divalent transition metal chlorides and bromides were selected as inorganic components, including CuX2, CdX2, CoX2, MnX2, HgX2 and ZnX2, where X = Cl or Br. Both ionic and neutral coordination type materials can be formed through the combination of the organic components and inorganic components described above, and the outcome of the reaction is controlled by the presence or absence of acid in the reaction medium. In acidic medium protonation of the organic component results in the formation of an ionic material, and in the absence of an acid a neutral coordination material results from the coordination of the organic component to the metal atom of the metal halide component. The stoichiometry and concentration of the acid will also have an influence on the structure as some of the organic ligand may remain unprotonated. In this study seven novel neutral coordination type structures and one ionic material were characterised by single crystal X-ray diffraction. Four isostructural, neutral, one-dimensional coordination polymer structures were observed for the combination of benzamide with CuCl2, CuBr2, CdCl2 and CdBr2 respectively. In this isostructural series the metal ions adopt an octahedral geometry in the case of the Cd analogues, and a tetragonal geometry, due to Jahn-Teller distorsion, for the Cu members of the series. The combination of ZnCl2 with benzamide yielded an isolated, zero-dimensional, neutral coordination compound in which the zinc(II) ion displays a tetrahedral geometry. An octahedral, paddle wheel-type, isolated, zero-dimensional coordination molecule formed from the combination of MnBr2 and benzamide. In all the coordination compounds of benzamide, coordination was found to occur through the oxygen atom of the amide group, while the NH2 group participates in intra- and intermolecular hydrogen bonding interactions. Due to the poor basicity of benzamide, only one ionic compound of this organic component was characterised structurally. In this compound, formed in combination with HgBr2, half of the benzamide molecules are protonated, and a unique, novel, one-dimensional perhalometallate anion was observed in this structure. The combination of 4-aminobenzamide with CoBr2 yielded an isolated, zero-dimensional, neutral coordination structure, in which the cobalt(II) ion adopts an octahedral geometry. The neutral, coordination compound formed between 4-aminobenzamide and CuBr2 has a trigonal bipyramidal geometry, and in addition to the organic and halogeno ligands, aqua ligands are also coordinated to the metal ion in both of the 4-aminobenzamide-containing molecules. Hydrogen bonding and aromatic interactions occur in all of the structures, and these interaction geometries were analysed in detail. It was found that these interactions play an important role in the cohesion of the units in the structure, with exception of the ionic compound of benzamide, which displays strong hydrogen bonding interactions but long aromatic centroid-to-centroid distances. Diffuse reflectance spectroscopy (DRS) was employed to measure the band gaps of the series of isostructural, one-dimensional coordination polymers. These measurements indicated that the Cd analogues in this series have band gaps that place them in the category of electronic insulators. The Cu members of this series were found to be two-band gap materials, with the lower of the two band gaps falling within the conductor range, while the higher band gap falls in the semi-conductor range for the structure containing CuBr2 and benzamide and the structure containing CuCl2 and benzamide. The suitability of Density Functional Theory (DFT) calculations to theoretically calculate the electronic structures and band gap values of the isostructural series of one-dimensional coordination polymers was tested in this study. The plane-wave cut off energy and k-point grid were optimised for the structures, and a range of functionals were tested. The best performing functional was used to calculate the band gap energies, the band structures and the density of states for the four isostructural materials. DFT calculations are known to underestimate band gap energies, and even though the calculated band gaps differ from the experimentally measured band gaps, this difference is smaller than expected. In addition, the DFT calculations were successful in predicting and providing insight into the electronic characteristics of the materials. Copyright / Dissertation (MSc)--University of Pretoria, 2012. / Chemistry / unrestricted

Ce travail a eu pour objectif l’étude d’une nouvelle méthodologie de fonctionnalisation aromatique basée sur la déprotonation par les bases magnésiates (alkyl- et/ou amidomagnésiates de lithium) à température ambiante encore très peu étudiée et l’examen de la réactivité nucléophile et dans le couplage croisé catalysé par un métal de transition des complexes (hétéro)arylmagnésiates générés. La première partie a été centrée sur la déprotonation des hétérocycles à 5 chaînons (furane, thiophène, benzoxazole et oxazole) qui a été réalisée avec succès en utilisant essentiellement la base Bu3MgLi. Les complexes hétéroarylmagnésiates dont les formes ouvertes issues de la déprotonation de l’oxazole et du benzoxazole ont révélé d’une part une bonne réactivité nucléophile vis à vis d’agents de deutération, d’halogénation, de sylilation et des aldéhydes aromatiques pour conduire aux hétérocycles substitués avec de bons rendements. D’autre part les complexes magnésiates ont été engagés avec succès dans le couplage croisé avec des partenaires bromo(hétéro)aromatiques catalysé par PdCl2(dppf). La seconde partie a été consacrée à l’étude de l’ortho-fonctionnalisation des dérivés benzéniques. Les conditions d’ortho-magnésiation par les bases tri(tétra)alkylmagnésiates de (di)lithium des oxazolyl-, carboxamido-, pivaloylamino-, et alkoxybenzènes ainsi que du benzène sulfoxyde ont été mises au point. Les complexes arylmagnésiates générés ont révélé d’une part une bonne réactivité nucléophile vis à vis d’agent de deutération, d’halogénation, de sylilation et du méthyloxirane. Seule la réactivité vis-à-vis des aldéhydes s’est révélée moindre mettant à jour deux réactions compétitives, l’addition d’un groupement butyle et la réduction concurrente de la fonction carbonyle. D’autre part, les nouveaux complexes arymagnésiates à l’exception de ceux issus de la déprotonation du benzène sulfoxyde ont été couplés avec succès avec des dérivés (hétéro)aromatiques bromés. De façon plus générale, la méthodologie de fonctionnalisation par déprotonation par les bases magnésiates s’est révélée efficace et apporte de nouveaux avantages par rapport aux méthodes classiques tels que d’une part la déprotonation au voisinage de la température ambiante pour les applications industrielles et d’autre part l’utilisation d’une nouvelle classe de réactifs organométalliques utilisables aussi bien pour le piégeage électrophile que pour le couplage croisé catalysé par un métal de transition. / This present work reports the development of a novel versatile aromatic functionnalization methodology based upon deprotonation with magnesiate bases (lithium alkyl- and /or amidomagnesiates) at room temperature, currently poorly studied and the use of the novel arylmagnesiates complexes formed as nucleophilic agents and organometallic partners in the cross-coupling reaction. The deprotonation of the five-membered heterocycles (furan, thiophene, benzoxazole and oxazole) was first successfully accomplished using mainly Bu3MgLi as base. The arylmagnesiates thus obtained, including the expected ring-opened magnesiate complexes obtained from deprotonation of benzoxazole and oxazole, proved to be effective in several reactions as deuteration, halogenation, silylation and nucleophilic addition on aromatic aldehydes leading to the corresponding substituted heterocycles. Futhermore the heteroarylmagnesiates complexes revealed to be efficient in cross-coupling reaction with bromo(hetero)aromatics catalyzed by PdCl2(dppf). In a second part, works were directed toward the study of the ortho-functionnalization of benzene derivatives. Thus, the deprotonation of oxazolyl-, carboxamido-, pivaloylamino- and methoxybenzenes as well as benzene sulfoxyde was achieved using mainly (di)lithium tri(tetra)magnesiate bases. The arylmagnesiates complexes showed a good nucleophilic reactivity toward deuterative, halogenative and silylative agents and methyloxirane whereas reactions with aromatic aldehydes occurred in more moderate yields due to two side processes, addition of a butyle group and reduction of the aldehyde function. The arylmagnesiates excepted from benzene sulfoxyde could be coupled with bromo(hetero)aromatics under PdCl2(dppf)-catalysis. In summary, the novel aromatic functionnalization based upon the use of magnesiate bases proved to be particularly efficient and represents many advantages compared to classical methods such as metalation at room temperature for direct industrial application as well as the use of a new class of organometallic reagents possessing a good nucleophilic reactivity and directly valuable in the transition metal-catalyzed cross-coupling reaction.

The drug metoclopramide was found to adsorb to the unionized and ionized silica surface. The primary objective of this research was to use potentiometric titration in order to study the specificity of the interactions of benzamide analogs with the hydroxyl groups, silanols, on the Aeroperl® silica surface. Mass titration studies showed that the acidity of surface silanols increases with dissolved metoclopramide and similar compounds. The nature of the interaction was concluded to involve a physical adsorption process. A different potentiometric titration method was devised to determine the ionization of silanols in the presence of a dissolved compound with solubility limitations. This method was found to give similar results as that described in the literature. The presence of dissolved metoclopramide was found to cause a large increase in the density of the negatively charged silanols on the silica surface. The ionization of silica was dependent on the concentration of dissolved metoclopramide at low pH but was found to be constant over a wide concentration range at pH 7.0 or higher. Adsorption studies with unionized silica indicated that specific interactions with the surface silanols occur as well as non-specific interactions driven by hydrophobic bonding with the surface siloxane groups. There was an increase in the adsorption of metoclopramide with increasing ionization of the silica surface which suggested that the negatively charged silanols constituted an additional adsorption site. The mechanism of the interaction was elucidated by potentiometric titration with various probe compounds. The titration data with lidocaine suggested that the ionization of the surface silanols is influenced by specific interactions with the adsorbed compound rather than concentration effects. The ionized site density of silica was found to be related to the relative magnitude of the aromatic π-electron density of the adsorbed benzamides. A comparison of these titration data with that of triethylamine indicated that ionic interactions between the positively charged amine groups and the negatively charged silanols are likely to be occurring. Based on the difference in chemical structure, the titration data with dissolved ephedrine indicated that the other site of interaction is likely to be between the carbonyl oxygen of the adsorbed benzamides and the unionized silanols. The pH dependence of the ionization of silanols for both adsorption sites suggested that silanols interact simultaneously with several functional groups on a single adsorbed molecule.

La surexpression des pompes d’efflux (PE) appartenant à la famille Resistance-Nodulation-Division (RND) est l’un des contributeurs majeurs de la multirésistance (MDR) et la pathogénicité des bactéries Gram-négatives. Ces transporteurs sont capables d'expulser à l’extérieur de la cellule bactérienne différentes classes d'antibiotiques, ce qui contribue de manière significative à l'échec thérapeutique du traitement des maladies infectieuses. Dans ce contexte, les PEs sont des cibles intéressantes pour la découverte de nouveaux antimicrobiens. Afin de combattre ce mécanisme de résistance, des inhibiteurs des pompes d’efflux (EPIs) sont développés comme adjuvants d'antibiotiques dans le but de restaurer ou d'améliorer leur activité. L'archétype AcrAB-TolC est particulièrement répandu chez les espèces d’Enterobacter pertinentes en clinique (pathogènes « ESKAPE »). Cette étude décrit une stratégie basée sur des analogues des fluoroquinolones pour le drug design des EPIs, contre la pompe AcrB chez E. aerogenes. Ainsi, la synthèse et l'évaluation microbiologique des dérivés de quinazoline-4(3H)-one ont été effectuées. Les propriétés structurales et moléculaires des composés testés (i.e. rigidité et flexibilité) ont également été étudiées. Pour cela, de nouveaux scaffolds ont été évaluées. Plusieurs molécules ont montré une augmentation de la sensibilité des bactéries à la norfloxacine et au chloramphénicol. Les résultats obtenus, appuyés par la modélisation moléculaire, suggèrent que la flexibilité moléculaire et la nature des fonctions chimiques des EPIs jouent un rôle essentiel dans l'amélioration de l'activité et la sélectivité vis-à-vis des fluoroquinolones. / Overexpression of Resistance-Nodulation-Division (RND) efflux pumps (EP) is a major contributor in multidrug resistance (MDR) and pathogenicity in Gram-negative bacteria. These transporters are able to expel out of the bacterial cell clinically important antibiotic classes, contributing in a significant manner to the treatment failure of infectious diseases. With the worrying levels of bacterial resistance reported worldwide and the continuous spreading of MDR pathogens, EPs are interesting targets for the discovery of new antimicrobial drugs. Therefore, to overcome this mechanism, efflux pump inhibitors (EPIs) are being developed as adjuvants in order to restore or improve the activity of usual antibiotics. The AcrAB-TolC archetype is particularly widespread in Enterobacter spp. presenting clinical relevance (ESKAPE pathogens). In this study, we described the drug design strategy based on fluoroquinolone antibiotic analogs, against the AcrB pump of E. aerogenes. Thus, synthesis and microbiological evaluation of quinazolin-4(3H)-one derivatives were performed. The structural and molecular properties of the tested compounds (i. e. rigidity and flexibility) were also investigated. In this purpose, a scaffold hopping of the quinazolinone core to homologous benzoquinazolinones and precursors benzamides were carried out. Several molecules increased the bacterial susceptibility towards norfloxacin and chloramphenicol. The obtained results, supported by molecular modeling, suggest that molecular flexibility and the nature of chemical functions play a critical role to improve activity and selectivity on fluoroquinolone potentiation targeting AcrB efflux pump.

SYNTHESIS AND EVALUATION OF N-PYRIDYLBENZAMIDES AS POTENTIAL ANTIMICROBIAL COMPOUNDS Eliška Suchánková Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic The derivatives of N-pyridylbenzamide were designed and synthesized to be in vitro tested for antimycobacterial activity against Mycobacterium tuberculosis H37Ra, M. smegmatis, M. aurum and in vitro cytotoxicity in HepG2 cells. These compounds are pyridinyl analogues of previously prepared N-pyrazinylbenzamides that have shown a significant in vitro antimycobacterial activity. The title compounds were synthesized by acylation of aminopyridine or chloropyridine-2-amine by selected benzoyl chlorides. Final compounds were described by elementary analysis, melting point, 1 H and 13 C spectra and IR spectroscopy. Generally, prepared compounds possess lower antimycobacterial activity than previously tested N-pyrazinylbenzamides. However, there are some cases, in which the derivatives of pyridine were more effective compared to the derivatives of pyrazine; mainly against M. smegmatis. The best antimycobacterial activity was proved for derivatives of 2-amino-6-chloropyridine and substituted benzoyl chloride, corresponding with higher lipophilicity of these compounds;...

Wong, Ho Ting. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 66-77). / Abstracts in English and Chinese. / Acknowledgement --- p.i / List of abbreviations --- p.ii / List of tables and figures --- p.iv / Abstract in English --- p.vi / Abstract in Chinese --- p.viii / Table of content --- p.x / Chapter Chapter 1 --- Literature review / Chapter 1.1 --- Nasopharyngeal carcinoma (NPC) and treatments --- p.1 / Chapter 1.2 --- EBV and NF-kB signaling in NPC / Chapter 1.2.1 --- Role of EBV and NF-kB in NPC --- p.2 / Chapter 1.2.2 --- NF-kB signaling in cancer --- p.4 / Chapter 1.2.3 --- NF-kB activation in NPC --- p.7 / Chapter 1.2.3.1 --- NF-kB activation by LMP1 --- p.8 / Chapter 1.2.3.2 --- NF-kB and LMP2A --- p.10 / Chapter 1.2.3.3 --- NF-kB activation by non-viral factors --- p.10 / Chapter 1.2.4 --- NF-kB target genes in NPC --- p.11 / Chapter 1.3 --- NF-kB targeting / Chapter 1.3.1 --- NF-kB targeting agents --- p.14 / Chapter 1.3.2 --- "DHMEQ, a novel blocker of NF-kB Transactivation" --- p.15 / Chapter Chapter 2 --- Aim of study and Research plan --- p.18 / Chapter Chapter 3 --- Materials and Methods / Chapter 3.1 --- Cell lines and Reagents --- p.20 / Chapter 3.2 --- Cell viability assay --- p.21 / Chapter 3.3 --- Cell apoptosis detection / Chapter 3.3.1 --- PARP cleavage --- p.22 / Chapter 3.3.2 --- DNA fragmentation --- p.22 / Chapter 3.4 --- Cell cycle analysis --- p.22 / Chapter 3.5 --- Transwell migration or Matrigel invasion assay --- p.23 / Chapter 3.6 --- Soft agar colony formation assay --- p.24 / Chapter 3.7 --- Drug treatment for western blotting --- p.25 / Chapter 3.8 --- "Protein extraction and quantification, SDS-PAGE and western blotting" / Chapter 3.8.1 --- Protein extraction and quantification --- p.25 / Chapter 3.8.2 --- SDS-PAGE and western blotting --- p.26 / Chapter 3.9 --- Fractionation --- p.28 / Chapter 3.10 --- NF-kB transcriptional activity assay / Chapter 3.10.1 --- Construction of NF-kB reporter system --- p.29 / Chapter 3.10.2 --- Luciferase assay --- p.29 / Chapter 3.11 --- Statistical Analysis --- p.30 / Chapter Chapter 4 --- Results / Chapter 4.1 --- Anti-tumor activity of DHMEQ in NPC / Chapter 4.1.1 --- Growth inhibition in NPC cell lines --- p.31 / Chapter 4.1.2 --- Apoptotic induction in NPC cell lines --- p.35 / Chapter 4.1.3 --- Cell cycle arrest in NPC cell lines --- p.38 / Chapter 4.1.4 --- Inhibition of migration and invasive behavior of NPC cell lines --- p.38 / Chapter 4.1.5 --- Abrogation of soft agar colony formation ability of NPC cell lines --- p.43 / Chapter 4.2 --- Mechanistic study of DHMEQ in NPC / Chapter 4.2.1 --- Blockade of p65 nuclear translocation --- p.48 / Chapter 4.2.2 --- Attenuation of NF-kB transcriptional activity --- p.48 / Chapter 4.2.3 --- Downregulation of NF-kB target genes --- p.53 / Chapter Chapter 5 --- Discussion --- p.54 / Chapter Chapter 6 --- Summary --- p.60 / Chapter Chapter 7 --- Future Study --- p.63 / Reference List --- p.66 / Appendix / Chapter Appendix 1 --- Construction of NF-kb report plasm id --- p.78 / Chapter Appendix 2 --- Wound healing assay --- p.86 / Chapter Appendix 3 --- Reverse-phase protein Array --- p.88