by Ka Lok Cheng. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 115-122). / Abstracts in English and Chinese. / Abstract --- p.i / Abstract (in Chinese) --- p.ii / Acknowledgement --- p.iii / Table of Contents --- p.iv / List of Figures --- p.viii / List of Tables --- p.xi / Abbreviations --- p.xii / Chapter PART I --- SYNTHESIS OF FERROCENE-CONTAINING PUSH-PULL DIPHENYLPORPHYRINS --- p.1 / Chapter Chapter 1 --- Introduction --- p.2 / Chapter 1.1 --- Introduction to Nonlinear Optics --- p.2 / Chapter 1.1.1 --- Interactions of Light with Matters --- p.2 / Chapter 1.1.2 --- Structural Requirements of Second-Harmonic Generating Molecules --- p.4 / Chapter 1.2 --- Ferrocene as an Electron Donor in Second Harmonic Generating Molecules --- p.7 / Chapter 1.3 --- Porphyrin as a Platform of Second Harmonic Generating Molecules --- p.16 / Chapter 1.4 --- Target Molecules of this Project --- p.22 / Chapter Chapter 2 --- Result and Discussion --- p.23 / Chapter 2.1 --- Preparation of Alkynyl Fragments --- p.23 / Chapter 2.1.1 --- Preparation of 2-ferrocenylethyne (24) --- p.23 / Chapter 2.1.2 --- Preparation of 1 -ethynyl-4-nitrobenzene (26) --- p.24 / Chapter 2.1.3 --- "Preparation of l-ethynyl-4-(N,N-dimethylaminophenyl) benzene (28)" --- p.25 / Chapter 2.2 --- Preparation of Porphyrin Precursors --- p.26 / Chapter 2.3 --- "Synthesis and Characterizations of 5-(2'-Ferrocenylethynyl)-l5- formyl-10,20-diphenylporphyrinatonickel(II) (36)" --- p.29 / Chapter 2.4 --- "Synthesis and Characterizations of 5-(2',2'-Dicyanoethenyl)-l5- (2""-Ferrocenylethynyl)-10,20-diphenylporphyrinatonickel(II) (38)" --- p.33 / Chapter 2.5 --- "Synthesis and Characterizations of 5-Ferrocenylethynyl-l 5-(4""- nitrophenylethynyl)-10,20-diphenylporphyrinatonickel(II) (40)" --- p.37 / Chapter 2.6 --- "Synthesis and Characterizations of 5-Ferrocenylethynyl-l 5-(4'- (N,N-dimethylamino)phenyl)ethynyl)-10,20-diphenyl porphyrinatonickel(II) (47)" --- p.43 / Chapter 2.7 --- Conclusion for Part One --- p.47 / Chapter Chapter 3 --- Experimental Section --- p.48 / Chapter 3.1 --- General Information --- p.48 / Chapter 3.2 --- Physical Measurements --- p.48 / Chapter 3.3 --- Preparation of Alkynyl Fragments --- p.49 / Chapter 3.4 --- Preparation of Some Known Porphyrins --- p.54 / Chapter 3.5 --- "Synthesis of Ferrocenyl ""Push-pull"" Porphyrin" --- p.58 / Chapter PART II --- LIGHT-HARVESTING NAPHTHALENE-PHTHALOCYANINE SYSTEMS --- p.65 / Chapter Chapter 4 --- Introduction --- p.55 / Chapter 4.1 --- Porphyrin-based Light-harvesting systems --- p.66 / Chapter 4.1.1 --- Multiporphyrins --- p.57 / Chapter 4.1.2 --- Carotenoid-porphyrins --- p.74 / Chapter 4.1.3 --- Boron-dipyrrin porphyrins --- p.75 / Chapter 4.1.4 --- Anthracene-porphyrin systems --- p.73 / Chapter 4.1.5 --- Dendritic porphyrins --- p.79 / Chapter 4.2 --- Phthalocyanine-based Light-harvesting systems --- p.80 / Chapter 4.3 --- Objective of this project --- p.83 / Chapter Chapter 5 --- Result and Discussion --- p.84 / Chapter 5.1 --- Preparation of naphthalene-phthalocyanine systems --- p.84 / Chapter 5.1.1 --- Synthesis of zinc(II) tetra( 1 -naphthoxy)phthalocyanines --- p.84 / Chapter 5.1.2 --- Synthesis of tetra[2-(l´ة-naphthoxy)ethoxy] phthalocyaninatozinc(II) (83) --- p.85 / Chapter 5.1.3 --- "Synthesis of 2,3,9,10,16,17,23,24-octa( 1 -naphthoxy) phthalocyaninatozinc(II) (89)" --- p.86 / Chapter 5.2 --- Absorption spectra of naphthalene-phthalocyanine systems --- p.88 / Chapter 5.2.1 --- Absorption spectra at different concentrations --- p.89 / Chapter 5.2.2 --- Comparison of the absorption spectra of the naphthoxy phthalocyanine with the spectra of the mixture of corresponding 1-ethoxynaphthalene and alkoxyphthalocyanines --- p.92 / Chapter 5.3 --- Fluorescence Quantum yields of Naphthalene-Phthalocyanine Systems --- p.96 / Chapter 5.4 --- Singlet-singlet energy transfer efficiencies of Naphthalene- phthalocyanine Systems --- p.98 / Chapter 5.4.1 --- Methodology --- p.98 / Chapter 5.4.2 --- Determination of energy transfer quantum yields --- p.99 / Chapter 5.5 --- Conclusion for Part II --- p.103 / Chapter Chapter 6 --- Experimental Section --- p.104 / Chapter 6.1 --- General Information --- p.104 / Chapter 6.2 --- Synthesis of tetra( 1 -naphthoxy)phthalocyanines --- p.105 / Chapter 6.3 --- Synthesis of tetra(naphthoxyethoxy)phthalocyanine --- p.108 / Chapter 6.4 --- Synthesis of octa( 1 -naphthoxy)phthalocyanine --- p.111 / References --- p.115 / Appendix A: Spectra of new compounds not discussed in the main text --- p.123 / Appendix B: X-ray crystallographic data of compound40 --- p.133

Thesis (Ph.D.)--Brown University, 2005. / Vita. Thesis advisor: Samuel I. Beale. Includes bibliographical references (leaves 123-146). Also available online.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

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Presented work is focused on heme metabolism with the main interest in bile pigments. Recent data indicate that bilirubin is not only a waste product of the heme catabolic pathway, but also emphasize its important biological impacts, including possible antiproliferative effects. Until today metabolism of bilirubin has not been completely elucidated, which has prevented detailed evaluation of its potential anticancer action. The aim of this study was to clarify some aspects of heme catabolism with respect for antiproliferative properties of its products. Based on the fact that bilirubin potently affects carcinogenesis of the intestine, we initially investigated not properly known bilirubin metabolism by intestinal bacteria. We studied bilirubin neurotoxic effects in hyperbilirubinemic Gunn rats - its distribution in the brain tissue and its degradation during pathological conditions, such as severe newborn jaundice or Crigler-Najjar syndrome. Possible approaches to improve the treatment of severe unconjugated hyperbilirubinemias, combination of the phototherapy and human albumin administration were also investigated. The main reason of these studies was the fact that mechanisms of neurotoxic effects of bilirubin are predominantly identical with those, by which bilirubin inhibits cancer cells growth....

Presented work is focused on heme metabolism with the main interest in bile pigments. Recent data indicate that bilirubin is not only a waste product of the heme catabolic pathway, but also emphasize its important biological impacts, including possible antiproliferative effects. Until today metabolism of bilirubin has not been completely elucidated, which has prevented detailed evaluation of its potential anticancer action. The aim of this study was to clarify some aspects of heme catabolism with respect for antiproliferative properties of its products. Based on the fact that bilirubin potently affects carcinogenesis of the intestine, we initially investigated not properly known bilirubin metabolism by intestinal bacteria. We studied bilirubin neurotoxic effects in hyperbilirubinemic Gunn rats - its distribution in the brain tissue and its degradation during pathological conditions, such as severe newborn jaundice or Crigler-Najjar syndrome. Possible approaches to improve the treatment of severe unconjugated hyperbilirubinemias, combination of the phototherapy and human albumin administration were also investigated. The main reason of these studies was the fact that mechanisms of neurotoxic effects of bilirubin are predominantly identical with those, by which bilirubin inhibits cancer cells growth....

Un photosensibilisateur est un composé chimique capable de générer, sous l'effet d'une irradiation lumineuse, des espèces réactives de l'oxygène (ROS) et donc d'induire directement ou indirectement l'altération d'autres composés. La rétention sélective de ces molécules, dites photo-activables, par les tissus en prolifération leur confère des applications en thérapie anti-tumorale (Photo-Chimio-Thérapie, PDT). La plupart des photosensibilisateurs sur le marché sont des dérivés structuraux de porphyrines et sont généralement fluorescents. Cette propriété est utilisée pour déterminer leur localisation, tant au niveau systémique que cellulaire. Certains composés sont ainsi utilisés pour le diagnostic par fluorescence de certain cancers (FD). Au niveau intracellulaire, un certain nombre de ces photosensibilisateurs se localisent dans les membranes des vésicules d'endocytose. Ils peuvent ainsi induire, sous irradiation lumineuse, la libération dans le cytosol du contenu de ces vésicules, y compris des molécules exogènes incorporées dans la cellules par endocytose et dont la cible intracellulaire est cytosolique ou nucléique (ADN, protéines, nombreux médicaments...). Ces phénomènes sont à la base d'une approche permettant l'activation de macromolécules, l'Internalisation Photo-Assistée (PCI). Cette méthode potentialise considérablement l'activité biologique d'un très large spectre de molécules d'intérêt.Tant la sélectivité de ces photosensibilisateurs pour les tissus en prolifération que leur localisation intracellulaire sont à mettre en relation avec les propriétés physico-chimiques et biologiques du micro-environnement. Leur interaction avec les lipoprotéines de basse densité (LDL) peut favoriser leur entrée dans les cellules du fait de la surexpression par les cellules néoplasiques des récepteurs aux LDL. Cependant, pour certaines molécules photo-activables, un passage transmembranaire par diffusion passive a été mis en évidence. L'incorporation cellulaire est alors facilitée par l'acidification du pH stromatique. Nous nous sommes donc attaché à déterminer l'importance de tels paramètres. Notre objectif a été de définir des caractéristiques structurales déterminant le comportement cellulaire des photosensibilisateurs.Dans un premier temps, afin d'élucider les mécanismes impliqués, les interactions de photosensibilisateurs avec des LDL et des liposomes (SUV, utilisés comme modèles simples de membranes) ont été étudiées à l'équilibre et de façon dynamique. Trois photosensibilisateurs ont été utilisés : la deuteroporphyrin (DP), une porphyrine dicarboxylique et la phtalocyanine d'aluminium disulfonnée (AlPcS2). Ces études ont été menées en nous attachant tout particulièrement aux effets liés au pH. Il faut noter ici que seuls les composés carboxyliques sont susceptibles de subir une neutralisation, ne serait-ce que partielle, de leurs chaînes latérales dans une gamme de pH correspondant à des valeurs physiologiques. Les données obtenues sur ces systèmes simples nous ont ensuite permis de comprendre la localisation sub-cellulaire des photosensibilisateurs sur une lignée humaine de fibroblastes. Enfin, bien que les LDL soient des vecteurs importants des photosensibilisateurs et facilitent leur entrée dans les cellules, la localisation sub-cellulaire semble être directement liée à la dynamique du transfert des photosensibilisateurs par des membranes. En conclusion, les paramètres physico-chimiques déterminés en solutions sont des outils efficaces pour concevoir des photosensibilisateurs, prédire leur capacité d'incorporation cellulaire ainsi que leur localisation sub-cellulaire.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Delta-aminolevulinic acid dehydratase (δ-ALA-D) is an essential metalloprotein found in several biological processes, since it is able to catalyze the formation of porphobilinogen (PBG), a precursor monopyrol of tetrapyrroles (heme and chlorophyll). This enzyme is sensible to heavy metals and other pro-oxidant agents and, consequently, it has been classically used as a protein marker for lead intoxication. Both in vitro and in vivo studies has shown that the organochalcogen diphenyl diselenide [(PhSe)2] could be a promising drug due to present antioxidant, neuroprotective, anti-inflammatory, anti-atherosclerotic and other activities. Contrariwise, (PhSe)2 could also be toxic because it can inhibit the activity of important sulfhydryl enzymes, including δ-ALA-D. Regarding some experimental data, it has been speculated that mammalian δ-ALA-D inhibition can occur via the oxidation of two vicinal thiols located in it active center site. However, no molecular model had been proposed in order to explain this interaction with details. Thus, we aimed to get a further understanding about the interaction involving δ-ALA-D and diselenides using in silico molecular modeling methods, which are consisted in theoretical methods applied in to represent or mimic the behavior and interaction of ligands and enzymes from their structural and thermodynamic information. Docking simulations indicated an important role for π-π interactions involving Phe208 and cation-π interactions involving Lys199 and Arg209 residues with the aromatic ring of (PhSe)2 and analogs bis 4-(clorophenyl) diselenide, bis 4-(methoxyphenyl)diselenide and bis 3-(trifluorometil(phenyl)diselenide. These interactions allowed an approximation between Se atoms and SH of Cys124 (3.3 3.5 Å). The analogs interacted similarly with the active site of δ-ALAD. According to the quantum method MFCC (Molecular Fractionation with Conjugated Caps), interactions involving (PhSe)2 could occur up to 8.5 Å distance from the centroid of active site. Phe208, Phe79, Cys122, Cys124, Pro125, Asp120, Lys199, Lys252 and Cys132 displayed strong attraction energy to (PhSe)2. The representative molecular model is in accordance with in vitro assays and gives mechanistic support to previous speculative mechanism of inhibition. Phenyl moieties in (PhSe)2 can be strongly attracted by aromatic and positive charged residues from δ-ALA-D active site. This allows the approximation of the reactive electrophile moiety Se-Se to the nucleophile S- groups from Cys122, Cys124 and Cys132, facilitating the release of coordinated Zn(II), thiol oxidation and formation of 2 molecules of phenylselenol (PhSeH). In conclusion, the presence of aromatic moieties in (PhSe)2 and its reactive electrophile moiety Se-Se are crucial to δ-ALA-D inhibition, which leads to thiol oxidation and consequent impairment of its activity. / A enzima δ-aminolevulinato desidratase (δ-ALA-D) é uma metaloproteína essencial em vários processos biológicos, uma vez que é responsável por catalisar a formação de porfobilinogênio (PBG), um precursor dos tetrapirrólicos (heme, clorofila). Esta enzima é sensível a metais pesados e outros pró-oxidantes e, dessa forma, tem sido classicamente usada como um marcador na intoxicação por chumbo. Estudos in vitro e in vivo têm demonstrado que o organocalcogênio disseleneto de difenila [(PhSe)2] pode ser um fármaco promissor por demonstrar várias atividades biológicas, incluindo antioxidante, neuroprotetora, anti-inflamatória, anti-aterosclerótica e outras. Por outro lado, o (PhSe)2 e análogos também são tóxicos por inibir a atividade de enzimas sulfidrílicas, incluindo a δ-ALA-D. Baseados em dados experimentais, tem-se especulado que a inibição da δ-ALA-D de mamíferos pode ocorrer via oxidação de dois tióis vizinhos localizados no centro ativo da enzima. No entanto, não se tinha conhecimento de nenhum estudo baseado em modelagem molecular com o intuito de explicar esta interação de forma mais detalhada. Diante disso, objetivamos compreender essas interações a partir da modelagem molecular in silico, que consiste em métodos teóricos aplicados para representar ou mimetizar o comportamento e interação de ligantes e enzimas a partir de informações sobre os requisitos estruturais e termodinâmicos essenciais. Os estudos de docking molecular indicaram um papel importante das interações π-π envolvendo Phe208 e cátion-π envolvendo Lys199 e Arg209 e anéis aromáticos do (PhSe)2 e análogos bis 4-(clorofenil) disseleneto, bis 4-(metoxifenil) disseleneto e bis 3-[trifluorometil(fenil)] disseleneto. Estas interações permitem uma aproximação entre átomos de Se do composto e SH da Cys124 (3.3 3.5 Å). Os análogos também interagem de forma semelhante com o sítio ativo da δ-ALA-D. De acordo com o método MFCC (Fracionamento Molecular com Capas Conjugadas), foi possível observar interações envolvendo o (PhSe)2 e resíduos posicionados até uma distância de 8,5 Å do centroide do ligante. Phe79, Cys122, Cys124, Pro125, Asp120, Lys199, Lys252 e Cys132 demonstraram as maiores energia de interação (atrativa) com o (PhSe)2. O modelo molecular representado está em conformidade com ensaios in vitro e fornece informações importantes que reforçam o mecanismo de inibição especulado. Os grupos fenil do (PhSe)2 são fortemente atraídos por resíduos aromáticos e carregados positivamente presentes no sítio ativo da δ-ALA-D. Dessa forma, permite-se a aproximação da porção eletrófila Se Se ao grupos nucleófilos S dos resíduos Cys122, Cys124 e Cys132, facilitando a liberação de Zn(II), a oxidação dos tiolatos e a formação de duas moléculas de fenilselenol (PhSeH), levando a consequente inibição da atividade da enzima.

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