published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Title from title screen. Interactive three dimensional molecular data and multiple colour images. Text presented in Hypertext Markup Language (.htm); images in standard formats (.jpg, .gif); molecules presented mostly as Cambridge Protein Data Bank format (.pdb); some molecules presented in alternative X.Mol cartesian co-ordinates format (.xyz); search facility in PERL script. Includes bibliographical references. Text, numeric and representational data System requirements: for text, any standard web browser on any platform, Netscape 2.x or higher, Internet Explorer 3.x or higher; for molecular structures, viewer such as Rasmol or preferably MDL's Chemscape Chime; for search facility , an appropriately configured web server. Links to all required software for browsing on various platforms are included in the software directory in the thesis. Mode of access: World Wide Web.

Thesis (Ph. D.)--University of Hong Kong, 1991.

The need for renewable and cleaner sources of energy has made biofuels an interesting alternative to fossil fuels, especially in the case of butanol isomers, with their favorable blend properties and low hygroscopicity. Although C4 alcohols are prospective fuels, some key reactions governing their pyrolysis and combustion have not been adequately studied, leading to incomplete kinetic models. Butanol reactions kinetics is poorly understood. Specifically, the unimolecular and H-assisted tautomerism of propen-2-ol to acetone, which are included in butanol combustion kinetic models, are assigned rate parameters based on the analogous unimolecular tautomerism vinyl alcohol ↔ acetaldehyde and H addition to the double bound of iso-butene, respectively. In an attempt to update current kinetic models for tert- and 2-butanol, a theoretical kinetic study of the unimolecular and H-assisted tautomerism, i-C3H5OH⟺CH3COCH3 and i-C3H5OH+Ḣ⟺CH3COCH3+Ḣ, was carried out by means of CCSD(T,FULL)/aug-cc-pVTZ//CCSD(T)/6-31+G(d,p) and CCSD(T)/aug-cc-pVTZ//M062X/cc-pVTZ ab initio calculations, respectively. For H-assisted tautomerism, the reaction takes place in two consecutive steps: i-C3H5OH+Ḣ⟺CH3ĊOHCH3 and CH3ĊOHCH3⟺CH3COCH3+Ḣ. Multistructural torsional anharmonicity and variational transition state theory were considered in a wide temperature and pressure range (200 K – 3000 K, 0.1 kPa – 108 kPa). It was observed that decreasing pressure leads to a decrease in rate constants, describing the expected falloff behavior for both isomerizations. Results for unimolecular tautomerism differ from vinyl alcohol ↔ acetaldehyde analogue reactions, which shows lower rate constant values. Tunneling turned out to be important, especially at low temperatures. Accordingly, pyrolysis simulations in a batch reactor for tert- and 2-butanol with computed unimolecular rate constants showed important differences in comparison with previous results, such as larger acetone yield and quicker propen-2-ol consumption. In the combustion and pyrolysis batch reactor simulations, using all the rate constants computed in this work, H-assisted reactions are limited because H radicals become abundant once the propen-2-ol has been consumed by other reactions, such as the non-catalyzed tautomerism i-C3H5OH⟺CH3COCH3, which becomes one of the main source of acetone. The intermediate radical (CH3ĊOHCH3) is formed exclusively from tert-butanol, with its concentration in 2-butanol oxidation being smaller because the secondary alcohol is unable to produce the radical directly. In all cases, the intermediate is converted effectively to acetone.

The doxorubicin (DOX) assumes a prominent position among the drugs widely applied in treatment human cancer. This chemotherapeutic presents efficiency in the regression of various neoplasms, although adverse reactions may occur. As a result several strategies have been developed to reduce the adverse effects caused by the continued use of DOX. One of these strategy is the incorporation of doxorubicin into MOF (Metal Organic Framework), since these materials can act as excellent carriers of drugs. The color change exhibited by doxorubicin as a function of pH, or even possibly when adsorbed in MOF, motivated the present work. This work consists in finding the possible factors that culminate in color change presented by DOX. This way, calculations involving the reactivity, and the UV/Vis spectroscopy of the possible tautomeric species of doxorubicin were performed. Thus, we applied the semiempirical methods, AM1, PM3, PM6 and RM1, and also DFT. We used the method INDO/S-CIS to calculate the spectroscopic of ground state geometries of various tautomer. All calculations revealed DOX1 as the most stable and DOX2 as the most unstable for protonated species. The method PM6 method was the more similar to the DFT by comparing the absorption spectra of DOX1 as well as the relative stabilities of the tautomers. The relative energies between deprotonated tautomers calculated by applied methods were smaller than protonated species, because the deprotonated tautomers denote considerable structural similarities between them. The reactivity study showed that the methods AM1 andPM3 exhibit the same qualitative behavior about the prediction of the transition state structure involved in each proton transfer reaction in the gas phase. The method PM6 resembled more to RM1, being the only exception was the conversion DOX1 → DOX4. Each absorption spectrum calculated from the optimized geometries with the DFT method to the different tautomeric species showed simply a band in the region of longer wavelengths (around 400 nm), which correspond to the visible region. In contrast, the absorption spectra obtained experimentally in acidic showed three bands in the region between 400 to 650 nm, thus cannot be attributed to a single predominant tautomer system, but the simultaneous contributing of all tautomers. The spectroscopic study of deprotonated tautomers, in order to simulate the effect of basic pH, suggests the presence also of the four tautomers deprotonated in the system, thus explaining the appearance of several absorption bands. The spectrum obtained at pH 7 can be explained from the presence of both doxorubicin protonated as deprotonated species. Thus, the application of computational tools proved to be able to elucidate some events associated with spectroscopy and reactivity of doxorubicin. / Dentre os fármacos largamente aplicados na prática oncológica humana, a doxorrubicina (DOX) assume uma posição de destaque. Apesar de este quimioterápico apresentar eficiência na regressão de várias neoplasias, reações adversas podem surgir. Em decorrência disso várias estratégias vêm sendo desenvolvidas para reduzir os efeitos adversos provocados pelo uso contínuo da DOX. Uma dessas estratégias consiste na incorporação da doxorrubicina em MOF s (Metal Organic Framework), uma vez que estes materiais podem atuar como excelentes carreadores de fármacos. A mudança de coloração exibida pela doxorrubicina como função do pH, ou até mesmo quando possivelmente adsorvida na MOF, motivou a realização do presente trabalho, o qual consiste na busca dos possíveis fatores que culminam na mudança de coloração apresentada pela DOX. Diante isso, cálculos envolvendo a reatividade, assim como, a espectroscopia UV/Vis das possíveis espécies tautoméricas da doxorrubicina foram realizados. Para tanto, foram aplicados os métodos semiempíricos, AM1, PM3, PM6 e RM1, e também DFT. Para realização dos cálculos espectroscópicos das geometrias no estado fundamental dos diferentes tautômeros da doxorrubicina, foi utilizado o método INDO/S-CIS. Para as espécies protonadas, todos os cálculos revelaram a DOX1 como sendo a espécie tautomérica mais estável e a DOX2 como sendo a mais instável. O método PM6 foi o método que se mostrou mais similar ao DFT, comparando os espectros de absorção da DOX1, assim como as estabilidades relativas entre os tautômeros. As energias relativas entre os tautômeros desprotonados calculadas pelos diferentes métodos aplicados foram menores para os protonados, pois os tautômeros desprotonados denotam maiores similaridades estruturais entre si. O estudo de reatividade mostrou que os métodos PM3 e AM1 apresentam o mesmo comportamento qualitativo quanto à predição da estrutura do estado de transição envolvido em cada reação de transferência de próton em fase gasosa. O método PM6 assemelhou-se mais ao RM1, divergindo apenas na conversão DOX1 → DOX4. Cada espectro de absorção calculado a partir das geometrias otimizadas com o método DFT para as diferentes espécies tautoméricas apresentou simplesmente uma banda na região de comprimentos de onda maiores (por volta de 400 nm), as quais equivalem à região do visível. Diferentemente, o espectro de absorção obtido experimentalmente em meio ácido apresentou três bandas na região compreendida entre 400 nm a 650 nm, dessa forma não se pode atribuir a predominância de um único tautômero no sistema, mas sim, a contribuição simultânea de todos os tautômeros. O estudo espectroscópico dos tautômeros desprotonados visando simular o efeito do pH básico sugere a presença, também, dos quatro tautômeros desprotonados no sistema, explicando dessa forma o aparecimento das várias bandas de absorção. A atipicidade apresentada pelo espectro obtido a pH 7 pode ser explicado a partir da presença tanto de espécies de doxorrubicina protonadas como desprotonadas. Dessa forma, a aplicação das ferramentas computacionais mostrou-se capaz de elucidar alguns eventos associados a espectroscopia e a reatividade da doxorrubicina.

La réévaluation des impacts toxicologique et environnemental des répulsifs synthétiques conduit à reconsidérer les répulsifs d'origine naturelle pour la prévention des maladies transmises par les insectes (dengue, chikungunya, paludisme,…). Cette étude se rapporte aux structures de type bis(oxazolidine) envisagées comme prodrogues de répulsifs naturels par leur conversion avec le tris(hydroxyméthyl)aminométhane (TRIS). Différents protocoles et voies de synthèse ont été étudiés sur une série représentative d'aldéhydes pour définir l'étendue et les limites de l'approche permettant de concentrer deux unités d'un même principe actif au sein de bis(oxazolidines) symétriques et de reproduire un effet synergique avec deux unités différentes formant des bis(oxazolidines) dissymétriques. La fonctionnalisation des bis(oxazolidines) a été également envisagée pour moduler leur balance hydrophile-lipophile. L'étude de la réaction de cyclocondensation met en évidence l'influence des paramètres structuraux sur le procédé de synthèse des bis(oxazolidines), la stabilité des intermédiaires (monooxazolidines) et la stéréosélectivité de la réaction. L'interprétation des résultats est proposée sur la base des effets (stéréo)-électroniques. Cette étude démontre l'intérêt de cette approche chimique pour la production de prodrogues de répulsifs naturels qui peuvent constituer des atouts pour le développement durable. / The more sensitive human and environmental risk assessments of non natural repellents have encouraged the rehabilitation of botanical-based repellents for the prevention of insect-transmitted diseases (dengue, chikungunya, malaria…). This study is related to bis(oxazolidine) structures envisaged as prodrug derivatives of natural repellents by their conversion with tris(hydroxymethyl)aminomethane (TRIS). The scope and limitations of various procedures and pathways have been assessed with structurally diverse aldehydes to concentrate two identical units in the symmetrical structures and to reproduce a synergistic effect with two different units in the unsymmetrical ones. Subsequent functionalization of the heterocyclic derivatives has been achieved to modulate their hydrophilic-lipophilic balance. The study of the cyclocondensation reaction shows evidence for the influence of structural effects not only on the chemical process but also on the relative stability of the monocyclic intermediates and the stereochemical outcomes of the reaction. The results are discussed on the basis of (stereo)-electronic effects. Finally, this study confirms the feasibility of this chemical approach to produce prodrugs of natural repellents which could appear as a contributive effort to sustainable development.

http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands.

http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands.

This thesis describes a computational investigation of the mutagenicity of 5-bromouracil (BrU). In Chapter 1, three models of spontaneous and BrU-induced base mispairing (rare tautomer, wobble pair, and ion) are reviewed. Chapter 2 presents the computational techniques used: electronic structure methods (Hartree–Fock-based and density functional theory) and molecular dynamics. Chapter 3 presents optimisations of the keto and enol tautomers of BrU and uracil (U) in water clusters. The enol tautomer of BrU is found to be more stable than that of U. Chapter 4 is a molecular dynamics study of the keto-enol tautomerism of BrU and U in a periodic water box. The pKₐ of BrU at N3 is found to be lower than that of U. Chapter 5 is a study of stacked base dimers containing BrU, U, or thymine (T) stacking with natural bases. Some structures were taken from the Protein Data Bank, while others were generated using an in-house methodology. BrU is found to stack more strongly than T in vacuo, but solvation and thermal effects nullify this difference. Chapter 6 discusses the significance of the results in Chapters 3–5 in terms of BrU-induced mutagenesis. Appendices A and B–D provide supplementary material to Chapters 2 and 5, respectively. Appendix E is an investigation of the “base flipping” pathway of 2-aminopurine (2AP). Both 2AP/N and A/N dinucleosides (N = thymine or guanine) are found to adopt a wide range of energy-minimum conformations – not only stacked and “flipped”, but also intermediate – and the stacked are not the most favourable by free energy. Appendix F is a list of publications and papers in preparation. One publication concerns BrU stacking. The other is a conformational study of the dipeptide tyrosine-glycine: the theoretical results are shown to be consistent with experiment (R2PI spectra) if thermal effects are taken into account.

The work presented in this thesis has broadly established a few findings about the structure¬hyperpolarizability relation in molecular compounds: First, by measuring βHRS of an organic keto-enol tautomer, benzoylacetanilide in a binary solvent, I have shown that the first hyperpolarizability can be manipulated favourably by changing the composition of the solvent or by altering the pH of the solution. BA which exists in the pure keto form in water and as a keto-enol tautomer in ethanol, co-exists in equilibrium with the keto and enol forms at pH 11 in aqueous solution. The β value of the anion form is 709 x 10¬30 esu , whereas that of the enol is 232 x 10-30 esu and of the keto is 88 x 10-30 esu. There is an enhancement of β by ~ 8 times for the anion and ~3 times for the enol compared to the keto form. This opens up the possibility of finding large nonlinearities in organic molecules by simply ionizing it. Second, in organometallic complexes of divalent Ru, the first hyperpolarizability could be manipulated by altering the valence state of the metal center by oxidation or reduction or by introducing highly polarisable halogen atoms as substitutions in ligands attached to the metal center. The enhancement of first hyperpolarizability was observed in mononuclear [RuII(acac)2(CH3CN)2] complex by 1.7 times when the metal center was oxidized from RuII to RuIII. As it is already known that the complexes like [(acac)2Ru-bptz-Ru(acac)2] produce stable mixed valent compound, the enhancement of β by ~1.6 times is appearing because of that species only. Exploring Large Nonlinearity in Tautomers In this thesis I have taken a linear ketone for studying the effect of structure on β via the enol and anion formation mediated by solvent and pH of the medium. In the present study the proton transfer in BA took place in the ground state of the ketone and the enol or anion are produced in the ground states. The proton transfer reaction (tautomerism) can also happen in the excited state as well in some molecules where there is a substantial barrier to the proton transfer reaction in the ground state. In such systems, once the ketone is excited using ultraviolet light the barrier to proton transfer in the medium is overcome and a proton transfer in the excited state takes place and the enol is produced. Since such a system will be at higher energy, it will be interesting to do a two-laser experiment where the excited state hyperpolarizability is measured in a time resolved manner and the β value is determined in the excited state. Building Molecular Nonlinearity in Step-by-Step Electron Transfer In this thesis, I have dealt with a binuclear complex of Ru(II) which in one-step electrochemical oxidation produced a mixed valence compound which had substantially higher β value compared to the unoxidized complex. In this way it is possible to build a multicentered complex and see if sequential one-electron transfer and subsequent oxidation/reduction of the metal centers produce a mixed-valent metal compound with large molecular nonlinearity. The indication from the present study is that such a scheme should double the β value in each one-electron transfer step. Also the linker group/moiety between the successive metal centers will play an important role in dictating the efficiency of electron transfer. If the metal d-electrons in a multinuclear complex are linked through a π-conjugation, one would expect manifold enhancement of β. Such metal arrays can also be designed in 2 or 3 dimensions. The dimensionality of the multinuclear metal complexes can easily be changed by supramolecular design and synthesis strategy. Such metal networks may or may not generate large β molecules since electronic polarization in such systems may not be superimposable in a coherent fashion and may not add in a positive sense. All these remain to be tested and explored in the future.