Thesis (M.S.)--University of Wisconsin--Madison, 1961. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaf 27).

Lam Chun Pong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references. / Abstracts in English and Chinese. / Table of Contents --- p.i / Acknowledgements --- p.v / Abstracts --- p.vi / Abbreviations --- p.viii / Chapter CHAPTER 1. --- SYNTHESIS AND REACTIVITY STUDIES OF MODEL COMPLEXES FOR INTRADIOL DIOXYGENASES WITH BENZIMIDAZOLE- CONTAINING LIGAND / Chapter I.1 --- Introduction / Chapter I.1.1 --- General Background --- p.1 / Chapter I.1.2 --- A General Review on the Modeling Chemistry for Catechol Dioxygenases --- p.3 / Chapter I.1.3 --- Intradiol Dioxygenases --- p.3 / Chapter I.1.3.1 --- Early model studies for intradiol dioxygenases --- p.5 / Chapter I.1.3.2 --- Factors affecting enzymatic reactivity for intradiol dioxygenases --- p.6 / Chapter I.1.3.3 --- Other functional models for intradiol dioxygenases --- p.7 / Chapter I.1.3.4 --- Reactivity studies of model complexes --- p.8 / Chapter I.1.4 --- Extradiol Dioxygenases --- p.8 / Chapter I.1.4.1 --- Early model studies for extradiol dioxygenases --- p.11 / Chapter I.1.4.2 --- Iron(III) complexes with extradiol properties --- p.12 / Chapter I.1.5 --- Objective of This Work --- p.14 / Chapter I.2 --- Results and Discussion / Chapter I.2.1 --- Synthesis of the Ligand Ntb --- p.15 / Chapter I.2.2 --- Synthesis of the Model Complex [Fe(ntb)Cl2]Cl --- p.16 / Chapter I.2.3 --- Synthesis of Enzyme-Substrate Model Complexes --- p.16 / Chapter I.2.4 --- Oxygenation Reactivities of Enzyme-Substrate Model Complexes 2-4 --- p.18 / Chapter I.2.4.1 --- Oxygenation of [Fe(ntb)(dbc)](C104) (2) in DMF --- p.18 / Chapter I.2.4.2 --- Oxygenation of [Fe(ntb)(cat)](Cl04) (3) in DMF --- p.21 / Chapter I.2.4.3 --- Oxygenation of [Fe(ntb)(tcc)](ClO4) (4) in DMF --- p.23 / Chapter I.2.4.4 --- Comparison of the oxygenation reactivities of complexes2-4 --- p.25 / Chapter I.2.5 --- Identification of Oxidative Cleavage Products --- p.27 / Chapter I.2.5.1 --- Isolation of oxidative cleavage products of complex 2 --- p.27 / Chapter I.2.5.2 --- Identification of cleavage products --- p.27 / Chapter I.2.6 --- Physical Characterization of Complexes 1-4 --- p.29 / Chapter I.2.6.1 --- Melting-points --- p.29 / Chapter I.2.6.2 --- Cyclic Voltammograms --- p.30 / Chapter I.2.6.3 --- EPR spectra --- p.31 / Chapter I.2.7 --- Molecular Structures of Complexes 1-4 --- p.34 / Chapter I.2.7.1 --- Molecular structure of [Fe(ntb)Cl2]Cl-4H20 (1) --- p.34 / Chapter I.2.7.2 --- Molecular structure of [Fe(ntb)(dbc)](Cl04)-2Me0H-H20 (2) --- p.36 / Chapter I.2.7.3 --- Molecular structure of [Fe(ntb)(cat)](ClO4) H20 (3) --- p.38 / Chapter I.2.7.4 --- Molecular structure of [Fe(ntb)(tcc)](Cl04).Me2C(0).H20 (4) --- p.41 / Chapter I.2.7.5 --- Comparison of the molecular structures of complexes 1-4 --- p.43 / Chapter I.3 --- Experimentals for Chapter 1 --- p.45 / Chapter I.4 --- References for Chapter 1 --- p.49 / Chapter CHAPTER II --- iron(iii) complexes containing N202 and N3O type ligands as models for INTRADIOL DIOXYGENASES / Chapter II.1 --- Introduction / Chapter II.1.1 --- Brief Remarks on Model Studies of Intradiol Dioxygenases. --- p.53 / Chapter II.1.2 --- Objective of This Work --- p.53 / Chapter II.2 --- Results and Discussion / Chapter II.2.1 --- Synthesis of N202 and N30 Type Ligands --- p.55 / Chapter II.2.2 --- Synthesis of Model Complexes --- p.57 / Chapter II.2.2.1 --- Model complex with ligand L1H --- p.57 / Chapter II.2.2.2 --- Model complex with ligand L2H2 --- p.58 / Chapter II.2.3 --- Synthesis of Enzyme-Substrate Model Complexes --- p.59 / Chapter II.2.3.1 --- Synthesis of enzyme-substrate model complexes from 14.… --- p.59 / Chapter II.2.3.2 --- Attempted synthesis of enzyme-substrate model complexes starting from 15 --- p.61 / Chapter II.2.4 --- Reaction of Complex 16 with Dioxygen --- p.61 / Chapter II.2.4.1 --- Oxygenation of [Fe(L1)(dbc)] (16) in DMF --- p.65 / Chapter II.2.5 --- Identification of Oxidative Cleavage Products --- p.64 / Chapter II.2.5.1 --- Isolation of oxidative cleavage products of complex 16 --- p.64 / Chapter II.2.5.2 --- Identification of cleavage products --- p.65 / Chapter II.2.6 --- "Physical Characterization of L1H, L2H2, Complexes 14-18" --- p.66 / Chapter II.2.6.1 --- NMR spectra --- p.67 / Chapter II.2.6.2 --- Melting-points --- p.69 / Chapter II.2.6.3 --- Mass spectra --- p.69 / Chapter II.2.6.4 --- Cyclic voltammogram --- p.69 / Chapter II.2.6.4 --- EPR spectra --- p.70 / Chapter II.2.7 --- "Molecular Structures of Complexes 14,15 and 18" --- p.71 / Chapter II.2.7.1 --- Molecular structure of [Fe(L1)(MeOH)Cl][BPh4].MeOH (14) --- p.72 / Chapter II.2.7.2 --- Molecular structure of [Fe(L2)Cl].MeOH (15) --- p.75 / Chapter II.2.7.3 --- Molecular structure of [Et3 Nh]3［Fe(tcc)3］.H2O(18) --- p.78 / Chapter II.3 --- Experimentals for Chapter 2 --- p.80 / Chapter II.4 --- References for Chapter 2 --- p.87 / APPENDIX 1 General Procedures and Physical Measurements --- p.89 / "APPENDIX 2 Selected Crystallographic Data for Complexes 1-4, 15,16 and 18.…" --- p.90 / Table A-l.Selected crystallographic data for complexes 1-4 --- p.91 / "Table A-2.Selected crystallographic data for complexes 15, 16 and 18" --- p.92 / "APPENDIX 3 Other Physical Data for Ligand L1H L2H2, Complexes 2 and 16" --- p.93 / Figure A-l.1H NMR spectrum of ligand L1H --- p.94 / Figure A-2.13C NMR spectrum of ligand L1H --- p.94 / Figure A-3.1H NMR spectrum of ligand L2H2 --- p.95 / Figure A-4.13C NMR spectrum of ligand L2H2 --- p.95 / Figure A-5.GC spectrum of the oxidative cleavage products of complex 2 --- p.96 / Figure A-6.- A-l 1.Mass spectra of the oxidative cleavage products of Complex 2 --- p.96 / Figure A-12.GC spectrum of the oxidative cleavage products of complex 16 --- p.99 / Figure A-13.- A-23.Mass spectra of the oxidative cleavage products of Complex 16 --- p.99 / Figure A-24.GC spectrum of dbcH2 standard --- p.105 / Figure A-25.Mass spectrum of dbcH2 standard --- p.106 / Figure A-26.GC spectrum of dbcq standard --- p.106 / Figure A-27.Mass spectrum of dbcq standard --- p.107

Most of the biological systems in nature are sustained by molecular self-assemblies which are the finest examples of supramolecular architectures. Non-covalent interactions are key concepts which govern these molecular assemblies. Inspired by these examples crystal engineering emerged as an important tool in supramolecular chemistry which aids in the invention of new molecular structures with desired properties. Understanding of how the molecules interact at the molecular levels enables one to rationally design novel solid forms with modulated physicochemical properties. This feature of crystal engineering has heightened its position in materials chemistry and is currently one of the most well studied fields for generating novel compounds with pre-defined composition and supramolecular architectures. One such class of compounds that has immensely attracted the scientific community and is under continuous study for wider applications is cocrystals. The applications include various interdisciplinary fields such as pharmaceutics, catalysis, organic conductors, explosives etc. Distinctly on the other side, cocrystals also provide a means to discover new supramolecular synthons which is the ultimate key to molecular assembly. Many robust supramolecular synthons have been discovered and hierarchies are also being developed which can serves as a design tool for cocrystal synthesis. The Cambridge Structural Database (CSD) is an important accessory in determining the robustness of a supramolecular synthon but, this does not preclude us from discovering new synthons. The work presented here explores new persistent supramolecular synthons in polyphenols utilizing the basic concepts of crystal engineering and the CSD statistical analysis. This contribution also includes the implementation of cocrystallization for various categories of compounds which includes nutraceuticals, pharmaceuticals and ionic salts for the design and synthesis of molecular and ionic cocrystals. Chapter 1 highlights how supramolecular synthon approach can be used to design and synthesize multi-component crystals, namely, cocrystals. The role of the CSD and its importance in crystal engineering has also been discussed. Chapters 2 and 3 focus on new persistent supramolecular synthons in the context of nutraceuticals. The cocrystals isolated in the study are also compared with the existing cocrystals in the CSD supramolecularly in terms of synthon formation. These persistent supramolecular synthons are helpful in developing hierarchies which could be utilized and applied to similar and analogous compounds. The main feature of Chapter 4 is expanding the field of cocrystallization by studying the properties of cocrystals. Some of the properties which have been examined here include effects of cocrystallization on solubility and correlations between the solubility of cocrystal with cocrystal former (CCF) and melting point of the cocrystal. The extension of cocrystals to the active pharmaceutical ingredients (APIs) has been explored in the context of pharmaceutical cocrystals by selecting a BCS class IV drug, hydrochlorothiazide in Chapter 5. Chapter 6 highlights the hybridization of organic and inorganic components for the synthesis of ionic cocrystals and is exemplified by considering lithium salts with achiral and homochiral amino acids for the generation of 1:1 and 1:2 cocrystals.

Made available in DSpace on 2014-12-17T14:14:04Z (GMT). No. of bitstreams: 1 GeorgeESC.pdf: 1518565 bytes, checksum: bcd5e83ea0cd501b6573d93e3ef15380 (MD5) Previous issue date: 2005-11-03 / Funda??o de Amparo a Pesquisa do Estado da Bahia / Aim: The aim of this work was to investigate the hypothesis that catechol and 3MC inhibit FADH2-linked basal respiration in mitochondria isolated from rat liver and brain homogenates. Moreover, catechol ability to induce DNA damage in rat brain cells through the comet assay (alkaline single-cell gel electrophoresis assay) was also observed. Methods: Two different catechols were evaluated: pirocatechol (derived from benzene) and 3-methylcatechol (derived from toluene); rat liver and brain homogenates were incubated with 1mM catechol at pH 7.4 for up to 30 minutes. After that, mitochondrial fractions were isolated by differential centrifugation. Basal oxygen uptake was measured using a Clark-type electrode after the addition of 10 mM sodium succinate for a period of 12 minutes. In additional experiments, rat brain cells were treated with 1, 5 and 10mM pirocatechol for up to 20 minutes at 37? C, and submitted to electrophoresis. Results: Catechols (pirocatechol and 3methylcatechol) induced a time-dependent partial inhibition of FADH2-linked basal mitochondrial respiration. Indeed, pirocatechol was able to produce a dosedependent DNA oxidative damage in rat brain cells by 2 and 4 injury levels. These results suggest that reactive oxygen species generated by the oxidation of catechols, induced an impairment on mitochondrial respiration and a DNA damage, which might be related to their citotoxicity. Conclusion: Catechols produced an inhibition of basal respiration associated to FADH2 in isolated liver and brain mitochondria; 3-methylcatechol, at the same concentration, produced similar toxicity in the mitochondrial model. Indeed, pirocatechol induced a DNA damage in rat brain cells, mainly observed in comets formation and consequent DNA degradation / Objetivo Testar a hip?tese de catec?is inibirem a respira??o basal associada ao FADH2 em fra??es mitocondriais hep?ticas e cerebrais de rato. Tamb?m, procurou-se estudar a ocorr?ncia de danos no DNA induzidos por catecol em c?lulas de c?rebro de ratos. M?todos: Foram avaliados dois catec?is: O pirocatecol (derivado do benzeno) e o 3-metilcatecol (derivado do tolueno); Os homogeneizados de f?gado e c?rebro de ratos foram incubados com catecol a 1 mM em pH fisiol?gico. Depois disso, as fra??es mitocondriais foram isoladas por centrifuga??o diferencial. O consumo basal de oxig?nio foi medido com um eletrodo do tipo Clark ap?s inje??o de succinato a 10 mM, e o consumo foi observado por 12 minutos. Em experimentos adicionais, amostras de tecidos cerebrais foram tratadas com pirocatecol em diferentes concentra??es (1 mM, 5 mM e 10 mM), durante 0 (sem incuba??o), 10 e 20 minutos a 37?C, e posteriormente submetidas a el etroforese. Resultados: Os resultados demonstram que os catec?is induziram uma inibi??o parcial da respira??o basal mitocondrial associada ao FADH2 de forma dependente do tempo. J? no caso dos experimentos com o ensaio cometa, os dados obtidos demonstram um aumento na ocorr?ncia de cometas de n?veis 2 a 4 de forma dose dependente, sugerindo que as esp?cies reativas de oxig?nio geradas pela oxida??o do catecol induzem danos de DNA, o que pode tamb?m estar relacionado com citotoxicidade deste composto. Conclus?o O pirocatecol produz inibi??o da respira??o basal associada ao FADH2 em mitoc?ndrias isoladas de f?gado e c?rebro de ratos; o 3-metilcatecol, nessa mesma concentra??o, produziu toxicidade semelhante no modelo mitocondrial. Adicionalmente, o pirocatecol induziu a um dano de DNA em c?lulas cerebrais de ratos, observado na forma??o de cometas e conseq?ente degrada??o do DNA

La description des interactions protéine-ligand est d'une importance capitale pour la compréhension de phénomènes biologiques de toutes sortes, et dans le procédé de conception de nouvelles molécules bioactives. Avec l'avènement de nouveaux moyens de calculs numériques, la modélisation des équilibres d'interaction utilisant la dynamique moléculaire est de plus en plus utilisée pour l'étude au niveau microscopique permettant ainsi de guider la conception et l'optimisation de nouveaux inhibiteurs biologiques. Cette thèse est centrée sur l'utilisation de la funnel-métadynamique pour la prédiction d'affinités protéine-ligand et la description des interactions, en corrélation avec des données expérimentales de RMN et de cinétique enzymatique. Sur le modèle biologique des peroxyrédoxines humaines impliquées dans la cascade inflammatoire survenant après un choc ischémique, l'interaction et l'inhibition de composés catéchols ont été étudiées. Les données obtenues par dynamique sur l'interaction de dérivés catéchols ont été utilisées pour guider l'optimisation de cette molécule fragment pour une meilleure affinité et inhibition des peroxyrédoxines humaines. Nos résultats ont montré que la funnel-métadynamique, en plus de permettre la prédiction des affinités protéine-ligand, donnait une description réaliste de l'interaction pouvant mener à l'identification et l'optimisation de nouvelles molécules bioactives dont le potentiel inhibiteur a pu être examiné par cinétique enzymatique. Cette recherche fournit un aperçu des possibilités offertes par les nouvelles méthodes numériques, et leur application en chimie médicinale par exemple / Description of protein-ligand interactions is crucial for the understanding of all biological phenomena, and the drug design process. Thanks to new developments in computational devices, simulation of interaction equilibria using molecular dynamics are becoming state-of-the-art approach for the microscopic study of these molecular interactions. These new methods guide the conception and the optimization of new biological inhibitors. This project is focused on the use of funnel metadynamics for the prediction of protein-ligand affinities, and the description of interactions. Data obtained by metadynamics are correlated with experimental data from NMR and enzymatic assays.On the biological model of human peroxiredoxins, involved in the post ischemic inflammation cascade, interaction an inhibition of catechols derivatives have been studied. Data obtained from simulations have been used in the optimization process of the catechol fragment, to reach a better affinity and inhibition of human peroxiredoxins. Our results have shown that funnel-metadynamics allows the prediction of protein-ligand affinities, and the realistic description of the interaction, that lead to identify and optimize new bioactive molecules. Their inhibitory strengths and mechanisms have been examinated using enzymatic assays.Our research gives an overview of the possibilities brought by new numerical approaches, and their application in medicinal chemistry for example

In the present thesis we propose the development of hybrid polymer titanium dioxide (TiO2) nanoparticles for use in biomedical applications. TiO2 exhibits high biocompatibility in the dark however, upon illumination in aqueous media with near UV light it produces an array of reactive oxygen species (ROS) which have the capability to induce death in neighbouring cells. The process of inducing cell death using a photosensitive material which produces ROS is known as photodynamic therapy (PDT) and is used to treat a wide range of maladies from psoriasis to cancer.We have demonstrated the ability to produce anatase nanoparticles with high control over their resulting size through a novel water mediated sol-gel synthetic method in benzyl alcohol, using either Ti(OnPr)4, Ti(OnBu)4 or Ti(OiPr)4 as the metal precursor. Through dynamic light scattering (DLS) analysis we have shown that the mechanism of nanoparticle growth appears to proceed through the agglomeration of primary nanoparticles formed instantly upon adding the reagents together. After synthesis the nanoparticles could be easily redispersed in aqueous media at pH2 with any further agglomeration being controlled by the parent alkoxide.After synthesis the nanoparticles were coated with PEG, conjugated to either a catechol or phosphate as ligand, in order to stabilise the nanoparticles at neutral pH. Uncoated nanoparticles exhibited good photoactive capability in the photooxidation of methylene blue. However, on coating with catechols the photoactivity of the nanoparticles was abolished. Coating with phosph(on)ates on the other hand preserved or even enhanced the photoactivity which makes this system promising for in vivo applications.At the same time this thesis also reports preliminary investigations on the use of TiO2 embedded into the walls of model drug loaded poly electrolyte multilayer microspheres for UV triggered delivery applications.

Nanoparticules de magnétite fonctionnalisées pour l’imagerie bimodale IRM/TEPLes nanoparticules d’oxydes de fer superparamagnétiques (SPIONs en anglais) font l’objet de recherches intenses dans le domaine biomédical, notamment comme nanomédicament et agent de contraste T2 en imagerie par résonance magnétique (IRM). Au cours de cette étude, des nanoparticules de magnétite (Fe3O4) à destination de l’imagerie IRM/TEP (Tomographie par Emission de Positons) ont été développées. Dans un premier temps, des SPIONs modifiées en surface, stables et superparamagnétiques ont été synthétisées via un dispositif hydrothermal en continu. A leur surface ont été greffées, durant la synthèse, des molécules hydrophiles : l’acide citrique, la LDOPA, le DHCA et le PHA. La fonctionnalisation des nanoparticules a été optimisée en modifiant des paramètres de synthèse tels que la température et le lieu de mélange, occasionnant des modifications de morphologie, taille et phase. Dans un second temps, pour améliorer leur stabilité et furtivité, des polymères de type PolyEthylène Glycol (PEG) ont été greffés à leur surface, deux longueurs de chaîne ont été évaluées. Pour une application en TEP, des macrocycles, complexant le radionucléide 64Cu, tels que le MANOTA, le NODAGA et le DOTA ont été couplés à ces SPIONs. Les essais de radiomarquage sont concluants. Ces nanohybrides, pleinement caractérisés (MET, XPS, IR, DLS, potentiels zêta, ATG, Raman) sont très prometteurs pour le diagnostic via l’imagerie bimodale IRM/TEM, notamment le composé Fe3O4-LDOPA-NODAGA (øDLS = 85±1 nm, r2 = 197±7 mM.s-1, 87% 64Cu). Des études préliminaires de cytotoxicité et génotoxicité de SPIONs modifiés par de l'APTES ont également été réalisées via des biotests très sensibles et novateurs. / Functionalized magnetite nanoparticles for bimodal MRI/PET imagingSuperParamagnetic Iron Oxide Nanoparticles (SPIONs) have been widely studied in the biomedical field due to their promising application as nanodrugs and MRI (Magnetic Resonance Imaging) contrast agents (T2). In this study, magnetite (Fe3O4) nanoparticles have been developed for use as contrast agents for MRI/PET (Positron emission tomography) double imaging. First, functionalized stable superparamagnetic SPIONs have been synthesized in a continuous hydrothermal reactor. During the synthesis, hydrophilic agents (citric acid, LDOPA, DHCA and PHA) have been grafted on the surface of the nanoparticles. The functionalization of the nanoparticles has been optimized by modifying various synthesis parameters such as the temperature and the addition sequence of the organic molecules. The morphology, the size and the structure of the nanoparticles have been shown to depend on these different parameters. Then PolyEthylene Glycol (PEG) polymers have been grafted on their surface to make them stealth and biocompatible. Two different lengths have been considered. For PET imagery, macrocycles which are chelating agents of the 64Cu radionuclide such as MANOTA, NODAGA and DOTA have been grafted on these SPIONs. The radiochemical purities are very conclusive. These nanohybrids have been extensively characterized (TEM, XPS, IR, DLS, ?-potential, TGA, Raman) and are very promising as a diagnostic tool for bimodal imaging MRI/PET in particular the Fe3O4-LDOPA-NODAGA nanoplatform (øDLS = 85±1 nm, r2 = 197±7 mM.s-1, 87% 64Cu). Preliminary cytotoxicity and genotoxicity studies on SPIONs modified by APTES have also been performed via very sensitive and innovative biotests.