Conselho Nacional de Desenvolvimento Científico e Tecnológico / This thesis reports the synthesis of various series of trifluoromethyl substituted nitrogenated heterocycles, such as pyrroles, pyrazoles, pyrimidines and 1,2,3-triazoles, exploiting the synthetic versatility of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one in reactions with nitrogenated nucleophiles. In this way, synthesis of a novel series of 4-amino-3-trifluoromethyl-1H-N-substituted pyrroles was performed through two reaction steps. In the first stage is an addition reaction of primary or secondary amine in the 4-position of 5-bromo-1,1,1-trifluoro-4-methoxy-3-penten-2-one furnishing 4-amino-5-bromo-1,1,1-trifluoropent-3-en-2-one. The second stage is a nucleophilic substitution of the bromine by a primary amine followed by an intramolecular cyclocondensation reaction resulting in the formation of pyrroles with yields from 50 to 98%. Through the reaction of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one with sodium azide, 5-azido-1,1,1-trifluoro-4-methoxypent-3-en-2-one was obtained. This compound was subjected to cycloaddition reaction [3 + 2] with terminal alkynes, allowing the synthesis of a novel series of 1,1,1-trifluoro-4-methoxy-5-(4-alkyl/aryl-1H-1,2,3-triazol-1-yl)-pent-3-en-2-one (I) in good yields (74-90%). Through this reaction a wide range of bi-heterocycle compounds was obtained. For example, the reaction of compound I with 2-methylisothiourea sulfate gave a series of 4-(1H-1,2,3-triazol-1-yl)-methyl-6-trifluoromethyl pyrimidine (72-79%). In a second step, the SCH3 group of these pyrimidines was oxidized to SO2CH3 and subsequently substituted by primary and secondary amines to give a series of 2-aminopyrimidines derivatives in yields of 70-93%. Furthermore, the reaction with N1-substituted 2-methylisothiourea sulphates furnished two products: a 4-pyrimidinone and 1,4-dihydropyrimidine derivatives, depending on the reaction conditions employed. From the reaction of compound I with hydrazines and hydrazides a series of 4-[(4-alkyl/aryl-1H-1,2,3-triazol-1-yl)methyl]-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazole, in yields of 77-90%, was obtained. The products obtained in this study were characterized by 1H- and 13C- NMR, mass spectrometry, high resolution mass spectrometry, elemental analysis, and X-ray diffraction. Keywords: 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one, 5-bromo-4-enaminoketone, 4-amino-3-trifluoromethyl-1H-pyrroles N-substituted, 1,2,3-triazole, pyrimidine, pyrazolines, bi-heterocycles. / Esta tese apresenta a síntese de várias séries de heterociclos nitrogenados trifluormetil substituidos, tais como pirróis, pirazóis, pirimidinas e 1,2,3-triazóis, explorando-se a versatilidade sintética de 5-bromo-1,1,1-trifluor-4-metoxipent-3-en-2-ona em reações com nucleófilos nitrogenados. Dessa forma, a síntese de uma série inédita de 4-amino-3-trifluormetil-1H-pirróis N-substituídos foi realizada através de duas etapas reacionais. Na primeira etapa ocorre uma reação de adição de amina primária ou secundária na posição-4 da 5-bromo-1,1,1-trifluor-4-metoxipent-3-en-2-ona para a formação de 4-amino-5-bromo-1,1,1-trifluorpent-3-en-2-ona. Na segunda etapa ocorre a substituição nucleofílica do bromo por uma amina primária e consequente ciclocondensação intramolecular para a formação dos pirróis com rendimentos entre 50 a 98%. Através da reação da 5-bromo-1,1,1-trifluor-4-metoxipent-3-en-2-ona com azida de sódio, obteve-se a 5-azido-1,1,1-trifluor-4-metoxipent-3-en-2-ona, a qual, pela reação de cicloadição [3+2] com alcinos terminais possibilitou a síntese de uma série inédita de 1,1,1-trifluor-4-metóxi-5-(4-alquil/aril-1H-1,2,3-triazol-1-il)-pent-3-en-2-ona (I), com bons rendimentos (74-90%). Por intermédio destes compostos foi obtida uma vasta gama de bi-heterociclos. Por exemplo, a reação do composto I com sulfato de 2-metilisotioureias possibilitou a obtenção da série de 4-(1H-1,2,3-triazol-1-il)metil-6-trifluormetil pirimidinas (72-79%). Em uma segunda etapa, o grupamento SCH3 destas pirimidinas foi oxidado a SO2CH3 e, posteriormente substituído por aminas primárias e secundárias, obtendo-se, assim, uma série de 2-aminopirimidinas derivadas com rendimentos de 70-93%. Além disso, a reação com os sulfatos de 2-metilisotioureia N1-substituídos levou a obtenção de dois produtos: uma 4-pirimidinona e uma 1,4-diidropirimidina, dependendo da condição reacional empregada. A partir da reação do composto I com hidrazinas e hidrazidas proporcionou a obtenção de uma série de 4-[(4-alquil/aril-1H-1,2,3-triazol-1-il)metil]-5-hidróxi-5-trifluormetil-4,5-diidro-1H-pirazol com rendimentos de 77-90%. Os produtos obtidos neste trabalho foram caracterizados por Ressonância Magnética Nuclear de Hidrogênio e Carbono-13, Espectrometria de Massas, Espectrometria de Massas de Alta Resolução, Análise Elementar e Difratometria de Raio-X.

Gegenstand der vorliegenden Arbeit ist die UV/Vis-spektroskopische Bestimmung der Kamlet-Taft-Polaritätsparameter von strukturell unterschiedlichen Ionischen Flüssigkeiten (ILs), mit Hilfe von spezifischen solvatochromen Sondenmolekülen. Dabei wurden der Einfluss des Anions und Kations auf die Polarität, sowie die Stärke der Wechselwirkung zwischen beiden Ionen untersucht. Es konnte für Ionischen Flüssigkeiten mit dem 1-Butyl-3-methylimidazoliumkation eine 1H-NMR-spektroskopische Methode zur Ermittlung der Polaritätsparameter entwickelt werden. Diese bietet den Vorteil, dass sie auch bei farbigen, hydrolyseempfindlichen oder höher schmelzenden ILs eingesetzt werden kann, wenn die Anwendung solvatochromer Sondenmoleküle nicht möglich ist. Ein weiteres Augenmerk lag auf der Untersuchung der Wechselwirkung zwischen den ILs und silikatischen Oberflächen. Neben der Studie der anionenvermittelten starken Physisorption von 1-Methylimidazoliumchlorid an Aerosil®300 konnte auch eine neuartige Methode zur gezielten Chemisorption von Imidazolium- und Phosphoniumkationen an Siliziumdioxidoberflächen entwickelt werden. Dabei wurden verschieden Carbene und Ylide als basische IL-typische Kationenprecursoren eingesetzt. Die Analyse der erhaltenen Materialien erfolgte mit Hilfe verschiedener Methoden der Festkörper-NMR-Spektroskopie.

Ziele: Mittels absolutquantifizierender Protonen-Magnet-Resonanz-Spektroskopie (1H-MRS) wollten wir das Ergebnis einer Vorstudie bestätigen, die im Frontallappen einen reduzierten Quotienten von myo-Inositol/Gesamtcreatin (mI/tCr) bei Depressiven fand. Darüber hinaus testeten wir den antidepressiven Effekt von Inositol als Add-on-Therapie. Methodik: Wir untersuchten Einzelvoxel (2 x 2 x 2 cm3) in der weißen Substanz der rechten und linken Präfrontalregion mit Hilfe eines 3-Tesla Bruker Medspec Systems (STEAM Sequenz, TR/TE/TM = 6000/20/30 ms). Die einzelnen Metabolite wurden anhand des cerebralen Wassers als internem Standard quantifiziert (nach dem LCModell). Es wurden 24 unmedizierte Patienten mit unipolaren depressiven Episoden mit 24 alters- und geschlechtsgematchten gesunden Kontrollen verglichen. In doppelblindem, Plazebo-kontrollierten Parallelgruppen-Design erhielten die Patienten täglich 18 Gramm Inositol oder Plazebo zusätzlich zu Citalopram über vier Wochen. Ergebnisse: An der Baseline unterschieden sich die mI-, Cholin- und N-Acetyl-Aspartat-Konzentrationen der Patienten nicht von jenen der Kontrollen. Es fanden sich keine sich keine signifikanten Unterschiede zwischen Inositol- und Plazebo-Gruppe. Überraschenderweise zeigten die depressiven Patienten an der Baseline gegenüber den Kontrollen signifikant höhere tCr-Konzentrationen (mmol/kg) links (5,57 ± 0,96 vs. 4,87 ± 0,63; + 15 %, p < 0,01) und rechts präfrontal (5,29 ± 0,92 vs. 4,46 ± 0,41; + 17 %, p < 0,01). Nach der Behandlung ergab sich eine Reduktion der tCr-Konzentration links- (Tag 28: 5,05 ± 1,16; – 12 %, p = 0,08) und rechtsfrontal (Tag 28: 4,61 ± 1,07; – 9 %, p = 0,09). Die tCr-Konzentrationen der Patienten am Tag 28 unterschieden sich nicht mehr von jenen der Kontrollen. Zusammenfassung: Wir zeigten eine reversible Steigerung der tCr-Konzentration der Patienten im Vergleich zu Kontrollen, die auf Veränderungen des Creatin-Transports oder der ATP-Synthese bei unmedizierter unipolarer Depression hinweisen könnte. / Objectives: By means of proton magnetic resonance spectroscopy (1H-MRS) with absolute quantification we wanted to confirm our previous finding of decreased ratios of the metabolites myo-Inositol/total creatine (mI/tCr) in the right frontal brain of depressives. Moreover, we tested the antidepressive effect of oral Inositol ingestion as add-on-therapy. We measured concentrations (mmol/kg ww) of mI, tCr (= Creatine + Phosphocreatine), Choline (Cho) and N-Acetyl-Aspartate (NAA) in the frontal brain. Methods: Single voxels (2x2x2 cm3) in the white matter of the left and right prefrontal region were examined in a three Tesla Bruker Medspec System (STEAM sequence, TR/TE/TM = 6000/20/30 ms). Metabolites were quantified using the LCModel. At baseline, 24 drug-free patients with unipolar depressive episodes were compared to 24 age and sex matched healthy controls. In a double blind, placebo controlled parallel-group design patients received daily 18 grams Inositol or placebo as an add on therapy to Citalopram over four weeks. Results: At baseline, mI, Cho and NAA concentrations showed no significant differences between patients and controls. The treatment with Inositol did not result in any significant differences to the treatment with placebo. Surprisingly the patients showed significant higher tCr concentrations in the left (5.57 ± 0.96 vs. 4.87 ± 0.63; + 15 %, p < 0.01) as well as in the right prefrontal region (5.29 ± 0.92 vs. 4.46 ± 0.41; + 17 %, p < 0.01) compared to controls. The treatment caused a trend towards a decrease of tCr in the left (day 28: 5.05 ± 1.16; – 12 %, p = 0.08) and in the right frontal hemisphere (day 28: 4.61 ± 1.07; – 9 %, p = 0.09) compared to baseline. The differences between the patients’ tCr at day 28 and the tCr of controls were no more significant. Conclusion: We have found a state dependent increase of tCr concentration indicating bifrontal deviations in Creatine transport or ATP synthesis in drug free unipolar depressives.

The known 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones 122 were dehydrogenated using thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to afford the 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136. Palladium-catalyzed Sonogashira cross-coupling of the 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones with terminal alkynes in the presence of PdCl2(PPh3)2-CuI (as homogeneous catalyst source) and 10% Pd/C-PPh3-CuI (as heterogeneous catalyst source) catalyst mixture and NEt3 as a base and co-solvent in ethanol under reflux afforded the corresponding 6,8-dialkynyl-2-aryl-2,3-dihydroquinolin-4(1H)-ones 138 and 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones 137, respectively. PdCl2-catalyzed electrophilic cyclization of the 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones in acetonitrile under reflux afforded the 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 or the 2-aryl-6-bromo-8-(4-hydroxybutanoyl)-2,3-dihydroquinolin-4(1H)-ones 140 from the 4-phenylethynyl-substituted or 4-alkylethynyl-substituted precursors, respectively. The 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136 wturn, subjected to similar homogeneous and heterogeneous palladium catalyst sources using NEt3 as a base in DMF-water mixture under reflux and K2CO3 as a base in dioxane under reflux afforded 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 143 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142, respectively. The monoalkynylated 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142 were subsequently transformed using palladium-catalyzed Suzuki-Miyaura cross-coupling with arylboronic acids in the presence of PdCl2(PPh3)2-PCy3 catalyst mixture and K2CO3 as a base in dioxane-water mixture to afford the corresponding novel 8-substituted 2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 141 and 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 144, respectively. All the new compounds were characterized using a combination of 1H NMR, 13C NMR, IR, mass spectroscopic techniques and X-ray crystallography. / Chemistry / D. Phil. (Chemistry)

La protéine du TGF-[bêta]1 est une protéine multifonctionnelle qui agit dans plusieurs types cellulaires. Son action varie selon le type de cellulaire. Bien qu'elle ait un rôle inhibiteur chez les astrocytes normaux, elle posséderait un rôle principalement activateur de nombreuses voies carcinogéniques chez les tumeurs astrocytaires primaires malignes. L'isoforme du TGF-[bêta]1 est celle qui est la plus impliquée dans ces processus. Elle joue un rôle dans l'activation des voies d'invasion tissulaire et d'angiogenèse, mais inhibe des mécanismes d'apoptose et d'immunosuppression.La présente étude vise à évaluer l'effet de l'inhibition de la protéine du TGF-[bêta]1 sur le modèle cellules de glioblastome F98/Fischer sur la prolifération et la migration cellulaire. Pour ce faire, un inhibiteur sélectif au récepteur a d'abord été utilisé. Par la suite, des techniques d'inhibitions nucléotidiques (oligoantisens, siRNA, shRNA) ont été testées. Nous avons d'abord validé l'utilisation du modèle F98/Fischer dans l'étude des fonctions du TGF-[bêta]1 et de l'inhibition de la production de cette protéine. Nous avons observé la production importante de TGF-[bêta]1 par les cellules F98 avec des essais immunologiques (Western, ELISA). Avec l'essai ELISA, nous avons observé la production considérable de TGF-[bêta]1 actif d'emblée.La présence de notre protéine d'intérêt a été détectée dans le cerveau de rat Fischer implanté avec les cellules F98 contrairement aux animaux sains qui ne montrent aucune trace de TGF-[bêta]1. Ensuite, nous avons tenté de mettre au point une approche nucléotidique pour inhiber la production du TGF-[bêta]1. Pour les oligoantisens et les siRNA qui ont été couplés avec le vecteur liposomale Metafecten, nous n'avons pas réussi à obtenir de diminution significative du TGF-[bêta]1 dans les surnageants des cultures de F98 . Pour l'approche au shRNA/lentivirus, nous n'avons pas réussi à former de bactéries contenant la construction recherchée. Par la suite, nous avons testé sur notre modèle cellulaire un inhibiteur pharmacologique sélectif, le SB-431642, du récepteur permettant la phosphoryllation de la voie instracellulaire Smad, le T[bêta]R-I. Les essais de prolifération (WST-1) ont permis de constater un ralentissement dans la croissance des F98 traitées au SB-431542. Un essai immunologique western a permis de constater que la production de VEGF était d'ailleurs influencée par cette inhibition du TGF-[bêta]1. L'utilisation d'un vecteur luciférase couplé à un élément de réponse Smad a permis de constater que la voie du TGF-[bêta]1 était bel et bien affectée à la baisse par cet inhibiteur. En effet, le dosage luminescent de la luciférase a permis de noter une diminution significative de sa quantité. L'activité d'un tel vecteur est proportionnelle à l'activité Smad intracellulaire. Nous avons aussi testé cet inhibiteur sur le modèle de croissance tumorale tridimensionnelle de sphéroïdes F98.La croissance des sphéroïdes a été ralentie par la présence de l'inhibiteur et l'invasion de la matrice de collagène observée chez les sphéroïdes contrôles a été freinée par l'ajout de SB-431542. Bien que certains de nos essais n'aient pas donné les résultats escomptés, l'utilisation de l'inhibiteur SB-431542 nous a permis de voir l'implication à du TGF-[bêta]1 dans les mécanismes de progression tumorale chez la lignée cellulaire F98, tel que la prolifération et la migration cellulaire. Ces résultats sont le préalable à d'éventuels essais avec le modèle d'étude animal, le rat Fischer avec l'utilisation de cellules de glioblastomes F98.

The β-acyloxyalkyl radical rearrangement has been known since 1967 but its mechanism is still not fully understood, despite considerable investigation. Since the migration of a β-trifluoroacetoxy group generally proceeds more rapidly and with more varied regiochemistry than its less electronegative counterparts, this reaction was studied in the hope of understanding more about the subtleties of the mechanism of the β- acyloxyalkyl radical rearrangement. The mechanism of the catalysed rearrangement of Nalkoxy- 2(1H)-pyridinethiones was also explored because preliminary studies indicated that the transition state (TS) for this process was isoelectronic with TSs postulated for the β-acyloxyalkyl radical and other novel rearrangements. ¶ A kinetic study of the rearrangement of the 2-methyl-2-trifluoroacetoxy-1-heptyl radical in solvents of different polarity was undertaken using a radical clock method. Arrhenius equations for the rearrangement in each solvent were: hexane, log10[kr (s-1)] = 11.8±0.3 – (48.9±0.7)/ θ; benzene, log10[kr (s-1)] = 12.0±0.2 – (43.7±0.8)/ θ; and propionitrile, log10[kr (s-1)] = 11.9±0.2 – (42.0±0.3)/ θ. Rate constants at 75˚C were: hexane, kr = 2.9 × 104; benzene, kr = 2.8 × 105; and propionitrile, kr = 4.0 × 105 s-1. The equilibrium constant for the reversible rearrangement at 80°C in benzene was 15.1 <K < 52.9. ¶ A regiochemical study with oxygen-labelled radicals revealed that trifluoroacetoxy group migration occurs with 66-83% label transposition (3,2 shift). The proportion of 3,2 shift is decreased by polar solvent, high temperature and low concentration of the reducing agent. Results of labelling experiments were consistent with cooperative 1,2 and 3,2 shifts, the former having Ea 9.5 kJmol-1 higher than the latter in benzene solution. ¶ An esr study of nine β-oxygenated radicals revealed that the temperaturedependent equilibrium conformation is controlled by a balance between steric and stereoelectronic effects. The influence of the latter is increased by electron-attracting β- substituents. Barriers to C α–C β rotation in β-oxyethyl radicals are approximately the same as for the propyl radical. Consequently, there is no significant through-space interaction between the β-substituent and the unpaired electron. ¶ Experimental results were consistent with a mechanism involving a combination of polarized 1,2 and 3,2 concerted shifts. The results may also be rationalised by the intermediacy of a contact ion pair, as well as combinations of the three options. ¶ The rearrangement of N-alkoxy-2(1H)-pyridinethiones is catalysed by oxidants, Lewis acids and protic acids. Pseudo first order kinetics are observed and there are moderate solvent effects. The migration of a 1,1-dideuteroallyl group occurs almost exclusively in a 1,4 sense. Migration of an enantiomerically enriched 1-phenylethyl group proceeds with predominant retention of configuration in chloroform, but with virtual racemisation in acetonitrile. Migrating groups do not become diffusively free during the rearrangement. Substituents which stablise positive charge at C1 migrate more rapidly. The bulk of evidence indicates that a catalyst activates the pyridinethione for rearrangement by promoting aromatisation. Mass-spectrometric analysis of an isolated intermediate and kinetic results are consistent with an intermolecular mechanism.

Dans un contexte général de valorisation alimentaire et non alimentaire du figuier de barbarie, nous nous sommes intéressés lors de cette étude à l'analyse morphologique de la pelure et des graines du fruit. Les polysaccharides pariétaux des différentes parois ont été isolés, purifiés, et leurs caractérisations ont été réalisées grâce aux méthodes chimiques ainsi qu'à la RMN haute résolution (1H et 13C) et en phase solide (CP/MAS). L'autre aspect du travail décrit la modification chimique des microfibrilles de cellulose. Il traite, dans un premier temps, de l'oxydation de la cellulose par le système TEMPO-NaOCl-NaBr et les conditions opératoires ont été optimisées dans le but de préparer des échantillons d'acide polyglucuroniques. La seconde étape met l'accent sur le greffage, via un couplage peptidique, du poly-N-isopropylacrylamide en vue d'élaborer des biopolymères thermostimulables à partir de la cellulose oxydée.

<p>Diabetes mellitus is one of the most threatening epidemics of modern times with rapidly increasing incidence. Vanadium and peroxovanadium compounds have been shown to exert insulin–like actions and, in contrast to insulin, are orally applicable. However, problems with side–effects and toxicity remain. The exact mechanism(s) by which these compounds act are not yet fully known. Thus, a better understanding of the aqueous chemistry of vanadates and peroxovanadates in the presence of various (bio)ligands is needed.</p><p>The present thesis summarises six papers dealing mainly with aqueous speciation in different vanadate – and peroxovanadate – ligand systems of biological and medical relevance. Altogether, five ligands have been studied, including important blood constituents (lactate, citrate and phosphate), a potential drug candidate (picolinic acid), and a dipeptide (alanyl serine) to model the interaction of (peroxo)vanadate in the active site of enzymes. Since all five ligands have been studied both with vanadates and peroxovanadates, the number of systems described in the present work is eleven, including the vanadate – citrate – lactate mixed ligand system. The pH–independent formation constants have been determined for 33 ternary vanadate – ligand, 41 quaternary peroxovanadate – ligand and two vanadate – mixed ligand species in addition to the p<i>K</i>_a values of all five ligands. These constants have been used to model physiological conditions, and the biomedical relevance of the different species is discussed.</p><p>The studies have been performed at 25 ºC in the physiological medium of 0.150 M Na(Cl), i.e. the ionic strength of human blood. No buffers have been used, and wide pH–ranges have usually been covered. The applied experimental techniques comprise mostly ⁵¹V NMR and potentiometry, but ³¹P, ¹³C, ¹H and ¹⁴N NMR as well as EPR and ESI–MS have also been used to gain additional information. Multimethod data have been treated by the least–squares program LAKE and modelling has been carried out by the software package WinSGW.</p><p>Whenever possible, solution structures of the species have been proposed. In addition, simple biological tests have been carried out to determine the stability of the formed peroxovanadate complexes in the presence of human catalase. A brief comparison is given of the different vanadate – ligand and peroxovanadate – ligand systems with emphasis on observed trends and general features.</p>

Diabetes mellitus is one of the most threatening epidemics of modern times with rapidly increasing incidence. Vanadium and peroxovanadium compounds have been shown to exert insulin–like actions and, in contrast to insulin, are orally applicable. However, problems with side–effects and toxicity remain. The exact mechanism(s) by which these compounds act are not yet fully known. Thus, a better understanding of the aqueous chemistry of vanadates and peroxovanadates in the presence of various (bio)ligands is needed. The present thesis summarises six papers dealing mainly with aqueous speciation in different vanadate – and peroxovanadate – ligand systems of biological and medical relevance. Altogether, five ligands have been studied, including important blood constituents (lactate, citrate and phosphate), a potential drug candidate (picolinic acid), and a dipeptide (alanyl serine) to model the interaction of (peroxo)vanadate in the active site of enzymes. Since all five ligands have been studied both with vanadates and peroxovanadates, the number of systems described in the present work is eleven, including the vanadate – citrate – lactate mixed ligand system. The pH–independent formation constants have been determined for 33 ternary vanadate – ligand, 41 quaternary peroxovanadate – ligand and two vanadate – mixed ligand species in addition to the pKa values of all five ligands. These constants have been used to model physiological conditions, and the biomedical relevance of the different species is discussed. The studies have been performed at 25 ºC in the physiological medium of 0.150 M Na(Cl), i.e. the ionic strength of human blood. No buffers have been used, and wide pH–ranges have usually been covered. The applied experimental techniques comprise mostly 51V NMR and potentiometry, but 31P, 13C, 1H and 14N NMR as well as EPR and ESI–MS have also been used to gain additional information. Multimethod data have been treated by the least–squares program LAKE and modelling has been carried out by the software package WinSGW. Whenever possible, solution structures of the species have been proposed. In addition, simple biological tests have been carried out to determine the stability of the formed peroxovanadate complexes in the presence of human catalase. A brief comparison is given of the different vanadate – ligand and peroxovanadate – ligand systems with emphasis on observed trends and general features.

The goal of this work was to synthesize complex macromolecular architectures such as dendrimers and dendronized polymers, and evaluate the effect from the dendrons on the optical and material properties. The work presented in this doctoral thesis, Dendrimers and Dendronized Polymers - Synthesis and Characterization, is divided into one minor and one major part. The first part deals with the synthesis and characterization of two sets of dendritic porphyrins based on 2,2-bis(methylol)propionic acid (bis-MPA). The second part deals with the synthesis and characterization of dendronized poly(hydroxyl ethyl methacylate), dendronized poly(norbornene), and dendronized triblock copolymers, were the pendant dendrons are based on bis-MPA. Both free-base and zinc containing dendritic porphyrins was synthesized up to the fifth generation by employing iterative ester coupling utilizing the acetonide protected anhydride of bis-MPA as generic building block. First and second generation dendron bearing methacrylates based on 2-hydroxyethyl methacrylate were also synthesized by utilizing the acetonide protected anhydride of bis-MPA, and subsequently polymerized by atom transfer radical polymerization. By adopting a divergent “graft-to” approach starting from the first generation dendronized poly(hydroxyl ethyl methacrylate), well-defined dendronized polymers with acetonide, hydroxyl, acetate and hexadecyl surface functionality were obtained. By utilizing the same divergent iterative esterfication, first to fourth generation dendron functionalized norbornenes were synthesized. These monomers were polymerized by ring-opening metathesis polymerization, utilizing either Grubbs´ first or second generation catalyst. Acrylate functional first to fourth generation monomers were synthesized by the copper(I) catalyzed “click” coupling of azido functional dendrons and propargyl acrylate. The monomers were polymerized to dendronized triblock copolymers by reversible addition-fragmentation chain transfer polymerization, utilizing a difunctional poly(methyl methacrylate) as macro chain transfer agent. The bulk properties of the dendronized poly(hydroxyl ethyl methacrylate) and poly(norbornene) were investigated by dynamic rheological measurements and differential scanning calorimetry. It was found that all the acetonide functional bis-MPA based dendronized polymers had glass transitions temperatures in a similar range. The rheological behaviour showed that for the dendronized polymers having the same backbone length the complex viscosity as a function of functionality was independent of the surface functionality of the polymer. The generation number of the polymer had a profound influence on the complex viscosity, changing form a Newtonian behaviour to a shear thinning behaviour when the generation of the dendrons was increased from two to four. The dendronized poly(norbornene) had increasingly shorter backbone lengths for each generational increase, and for the materials set with comparably lower degree of polymerization, the G’ part of the complex modulus was mostly affected by attaching larger dendrons. In the case of the sample set of higher degree of polymerization, the second, third, and fourth generation samples had similar slopes of the G’ and G” curves, indicating a similar relaxation behaviour. / QC 20100914