Ce travail de thèse a consisté en la conception et la réalisation d’une nano-sonde hybride luminescente visant à permettre la détection précoce du cancer de la prostate. La première partie de ce projet a été consacré à la synthèse, par une voie de chimie click, d’une bibliothèque d’acides 4-triazolyl dipicoliniques substitués en position 4 du triazole par une large gamme de substituants. Ces diacides ont permis d’obtenir les complexes d’europium(III) et de terbium(III) correspondant, qui ont montré d’excellentes propriétés optiques, avec des rendements quantiques de luminescence sous excitation UV pouvant atteindre 60% et 36%, pour les complexes d’europium(III) et deterbium(III) respectivement. D’autre-part, ces fluorophores ont pu être excités efficacement en régime biphotonique, à la fois au travers des transitions S0 ®S1 et S0 ®T1. Sur la base de ces résultats, certains de ces chélates ont été sélectionnés afin de les incorporer dans des nanoparticules de silice. Le procédé d’élaboration par microémulsion inverse s’est révélé efficace pour l’incorporation des complexes électriquement neutres, mais n’a pas permis celle de nanohybrides incorporant des complexes chargés négativement. Ces nanohybrides présentent des propriétés optiques caractéristiques des lanthanides, avec des rendements quantiques allant jusqu’à 30%. La surface de ces nano-objets a ensuite été fonctionnalisée par des groupements amino, qui ont permis le greffage de bras espaceur et d’un vecteur ciblant la PSMA, l’un des signaux du cancer de la prostate, nous donnant ainsi accès à un modèle de nano-sonde luminescente. Un autre volet de ce travail a été dédié à l’étude de nouveaux analogues du NAAG, substrat naturel de la PSMA. Bien que la synthèse des deux composés cibles, sélectionnés parmi une vingtaine de structures par modélisation moléculaire, n’ait pu aboutir, elle a été largement avancée. Enfin, la dernière partie de ce travail décrit les premiers résultats obtenus in vitro et in vivo avec les nanosondes. Ces études ont porté sur l’évaluation de la cytotoxicité des nanoparticules ainsi que sur leur biodistribution chez la souris saine et chez la souris porteuse d’une tumeur prostatique. Cette étude a révélé une élimination rapide des nanoparticules par l’organisme, mais n’a malheureusement pas pu mettre en évidence un marquage des zones tumorales par les nanosondes. / The aim of this project was the design of a luminescent nanoprobe allowing the early prostate cancer detection.The first part of this project was the synthesis, through a click chemistry approach, of a library of 4-triazolyl dipicolinic acid substituted in position 4 of the triazole by a wide range of substitutive groups. These diacids were used to synthesise the corresponding europium(III) and terbium(III) complexes, which showed excellent optical properties, with photoluminescence quantum yield under UV excitation reaching 60% for europium(III) complexes and 36% for terbium(III) complexes. Moreover, these phosphores have been efficiently excited in biphotonic regime through the transitions S0 ®S1 and S0 ®T1. The more interesting chelates were selected for their further embedding into silica nanoparticles. The water-in-oil emulsion process showed a great efficiency for the incorporation of electrically neutral complexes, but did not allow the embedding of negatively charged ones. The resulting nanohybrids showed optical properties typical of lanthanides, presenting photoluminescence quantum yields up to 30%. The nanoparticles surface was then functionalised by amino groups, which were used to graft a spacer then a prostate tumour cells vector, giving us a luminescent nanoprobe model. The third section of this work was devoted to the study of new analogues of NAAG, the natural substrate of the PSMA, one of the prostatic cancer signals. Although the synthesis of the two target compounds, selected from more than 20 structures by molecular modelling, was uncompleted, they are now within easy reach. The last part describes the preliminary results obtained in vitro and in vivo with the nanoprobes. These studies were focused on the nanoparticles cytotoxitcity assessment, depending on the surface functionalisation, and on their distribution, in healthy and in prostatic tumour bearing mice. This study revealed the fast elimination of the nanoparticles by the organism, but did not show any concentration of nanoprobes in tumoral area.

Plusieurs maladies rénales et cardiovasculaires présentent une altération de l’expression des récepteurs de type 1 de l'angiotensine (AT1R) et sont traitées par le candésartan ou le losartan. Le radiomarquage de cette famille de molécules développé au sein de notre laboratoire a démontré une liaison spécifique pour les AT1R rénaux chez les rats et les cochons. Le [11C]méthyl-candésartan présente une cinétique supérieure à celle du [11C]méthyl-losartan. Néanmoins, la présence d’un radiométabolite hydrophobe, interférant avec le signal TEP du traceur d’origine, rend la quantification des AT1R complexe. Le [18F]fluoropyridine-losartan est un antagoniste qui possède une affinité de liaison élevée ainsi que peu de métabolites radiomarqués dans les reins de rats. Cependant, sa faible activité molaire ne permet pas de visualiser les niveaux d’AT1R myocardiques présents en faible densité. Le but de cette recherche est de développer les radiosynthèses automatisées d'analogues 18F-fluoropyridinés du candésartan et du losartan en très hautes puretés et activités molaires et d'évaluer l'efficacité du [18F]fluoropyridine-candésartan comme traceur TEP sélectif aux AT1R. Le [18F]fluoropyridine-candésartan et le [18F]fluoropyridine-losartan ont été synthétisés via la cycloaddition de Huisgen catalysée au cuivre(I) entre le 2-[18F]fluoro-3-(pent-4-yn-1-yloxy)pyridine ([18F]FPyKYNE) et un dérivé azidé du candésartan ou du losartan. Le [18F]FPyKYNE est préalablement obtenu par radiofluoration de NO2PyKYNE puis purifié par HPLC, empêchant ainsi la formation de sous-produits nitropyridinés. Après optimisation, les traceurs sont obtenus avec un rendement radiochimique de 11% et des activités molaires (>380 GBq/μmol), des puretés chimiques et radiochimiques (>97%) très élevées. Les tests de contrôle de qualité complet du [18F]fluoropyridine-losartan permettant son utilisation dans des études cliniques futures ont aussi été développés. Le fluoropyridine-candésartan a révélé une affinité élevée (Ki=5,9 nM) dans des membranes exprimant les AT1R, comparable au fluoropyridine-losartan (Ki=5,6 nM) mais inférieure à celle du candésartan (Ki=0,4 nM). Des études d’ultrafiltration ont démontré que le [18F]fluoropyridine-candésartan se lie fortement aux protéines plasmatiques (99,3%). La liaison spécifique aux AT1Rs a été confirmée ex vivo par biodistribution. Une réduction significative (-86%) de la captation dans le cortex rénal de rats prétraités (candésartan ou losartan) est constatée. Des résultats similaires sont obtenus in vitro par autoradiographie avec co-incubation en présence de losartan. La présence de métabolites radiomarqués a été évaluée ex vivo dans du plasma et dans les reins d’animaux témoins ou prétraités (candésartan ou losartan) par HPLC. Le [18F]fluoropyridine-candésartan a été métabolisé en composés radiomarqués hydrophiles, affichant une interférence minimale sur la liaison rénale aux AT1R avec 82% de traceur inchangé dans les reins 20 min après injection. Les images TEP/TC dynamiques du [18F]fluoropyridine-candésartan, acquises pendant 60 min, ont révélé des accumulations élevées et éliminations lentes dans le cortex rénal et le foie avec des rapports tissu-sang élevés. La spécificité de liaison aux AT1R a été démontrée par le blocage des sites de liaison avec du losartan 20 min après l'injection (réductions des rapports tissu-sang dans le cortex rénal (-84%) et dans le foie (-93%)). Aucun changement n'a été observé dans les reins de rats prétraités avec l'antagoniste des AT2R PD123,319, confirmant la sélectivité de liaison pour les AT1R. Les radiosynthèses reproductibles automatisées, les propriétés de liaison ainsi que la stabilité in vivo font du [18F]fluoropyridine-candésartan et du [18F]fluoropyridine-losartan des radiotraceurs potentiels permettant l’imagerie TEP des AT1R dans plusieurs maladies cardiovasculaires ou rénales, offrant ainsi la possibilité de suivre la progression de ces maladies dans des études longitudinales mais aussi de mieux guider la thérapie. / Numerous renal and cardiovascular diseases exhibit alterations in the Angiotensin type 1 receptor (AT1R) levels that are treated with candesartan or losartan. Our previous radiolabeled derivatives of these drugs displayed specific binding for renal AT1R in rats and pigs. [11C]Methyl-candesartan exhibited superior kinetics than [11C]methyl-losartan, but a hydrophobic radiometabolite interfered with the PET signal and AT1R quantification. High binding affinity, full antagonistic efficacy and minimal interference of labeled metabolites in rat kidneys were observed with [18F]fluoropyridine-losartan. However, the tracer’s low molar activity prevented visualization of low-density myocardial AT1R. The aim of this research was to develop automated radiosyntheses of 18F-fluoropyridinated analogs of candesartan and losartan in very high purities and molar activities and to evaluate [18F]fluoropyridine-candesartan efficacy as a selective AT1R PET tracer. [18F]Fluoropyridine-candesartan and [18F]fluoropyridine-losartan were synthesized via the copper(I)-catalyzed Huisgen cycloaddition between 2-[18F]fluoro-3-(pent-4-yn-1-yloxy)pyridine ([18F]FPyKYNE) and an azido-derivative of candesartan or losartan, respectively, followed by acid deprotection and C18-HPLC purification. [18F]FPyKYNE was obtained by radiofluorination of NO2PyKYNE and purified by silica-gel HPLC, preventing the formation of nitropyridinated by-products in the second step. The reaction parameters and purifications were optimized to provide tracers in 11% radiochemical yield with very high molar activities (>380 GBq/μmol), chemical and radiochemical purities (>97%). Full quality control testing of [18F]fluoropyridine-losartan was performed to validate its safe use in future clinical studies. The binding and pharmacokinetic properties of the novel [18F]fluoropyridine-candesartan were evaluated in vitro and ex/in vivo in male Sprague-Dawley rats. Competition binding assays in AT1R-expressing membranes revealed a high affinity of fluoropyridine-candesartan (Ki=5.9 nM), which is similar to fluoropyridine-losartan (Ki=5.6 nM) but lower than candesartan (Ki=0.4 nM). [18F]Fluoropyridine-candesartan bound strongly to plasma proteins (99.3%) as assessed by ultrafiltration. Specific binding was confirmed by ex vivo biodistribution 20 min after tracer injection, with a significant uptake reduction (-86%) in the AT1R-rich kidney cortex of pretreated (candesartan or losartan) rats and by in vitro autoradiography with losartan co-incubation. Radiolabeled metabolites in plasma and kidneys of control and pretreated (candesartan or losartan) animals were analyzed by column-switch HPLC. [18F]Fluoropyridine-candesartan was mainly metabolized to radiolabeled hydrophilic compounds, displaying minimal interference on renal AT1R binding with 82% of unchanged tracer in the kidneys at 20 min post-injection. Dynamic PET/CT images of [18F]fluoropyridine-candesartan, acquired for 60 min at baseline, revealed high accumulation and slow clearance from the kidney cortex and liver with high tissue-to-blood ratios. Binding specificity for AT1R was demonstrated with marked reductions in kidney-cortex (-84%) and liver (-93%) tissue-to-blood ratios at 20 min post-injection, when blocking with losartan. No change was observed in kidneys of rats pre-treated with the AT2R antagonist PD123,319, confirming binding selectivity for AT1 over AT2 receptors. The favorable binding properties and in vivo stability of [18F]fluoropyridine-candesartan support further studies to validate its potential as AT1R PET radioligand. The reproducible automated radiosyntheses developed in my research will allow innovative in-vivo PET imaging of AT1R-expression in several diseases, offering the possibility to follow disease progression in longitudinal studies and guide therapy.

This thesis focuses on the development of carbohydrate coupling chemistry on nanomaterials and their biological activity studies. It is divided into two parts: In part one, two carbohydrate immobilization approaches, based on perfluorophenyl azide (PFPA)-functionalized silica nanoparticles (SNPs), are presented, where the binding affinity of the glyconanoparticles was evaluated through carbohydrate-lectin interaction. In the first approach, PFPAfunctionalized SNPs were treated with propargylated glycosides and functionalized under copper-catalyzed azide-alkyne cycloaddition (CuAAC) conditions to give glyconanoparticles. For the second approach, a metal-free coupling chemistry based on perfluorophenyl azide-aldehyde-amine cycloaddition (AAAC) was developed for carbohydrate immobilization on PFPA-functionalized SNPs using glycosyl amine and phenylacetaldehyde. Subsequently, a quantitative fluorine nuclear magnetic resonance (19F qNMR) technique was developed to determine the carbohydrate density on the glyconanoparticles. The addition of an internal standard allowed the accurate determination of carbohydrate density, which was then used to calculate the apparent dissociation constant (Kd ) of the glyconanoparticles with lectin by a ligand competition assay. The developed approaches proved general and versatile, and the carbohydrate-presenting nanoplatforms showed high binding specificity in lectin binding. In part two, microwave irradiation was used to functionalize carbon nanomaterials with PFPA followed by carbohydrate conjugation. The microwave-assisted method proved efficient for a number of carbon nanomaterials including carbon nanotubes (CNTs), graphene and fullerene. The carbohydrates on the glyconanomaterials retained their binding patterns towards cognate lectins. / <p>QC 20150907</p>

The covalent chemistry of individual reactants bound within a protein nanopore can be monitored by observing the ionic current flow through the pore, which acts as a nanoreactor responding to bond-making and bond-breaking events. However, chemistry investigated in this way has been largely confined to the reactions of thiolates, presented by the side chains of cysteine residues. The introduction of unnatural amino acids would provide a large variety of reactive side chains with which additional single-molecule chemistry could be investigated. An efficient method to incorporate unnatural amino acid is semisynthesis, which allows site-specific modification with a chemically-defined functional group. However, relatively little work has been done on engineered membrane proteins. This deficiency stems from attributes inherent to proteins that interact with lipid bilayer, notably the poor solubility in aqueous buffer. In the present work, four different derivatives &alpha;-hemolysin (&alpha;HL) monomer were obtained either by two- or three-way native chemical ligation. The semisynthetic &alpha;HL monomers were successfully refolded to heptameric pores and used as nanoreactors to study single-molecule chemistry. The semisynthetic pores show similar biophysical properties to native &alpha;HL pores obtained from an in vitro transcription and translation technique. Interestingly, when &alpha;HL pores with one semisynthetic subunit containing a terminal alkyne group were used to study Cu(I)-catalyzed azide-alkyne cycloaddition, a long-lived intermediate in the reaction was directly observed.

No description available.

This thesis concerns the development of surface ligation techniques for the preparation of carbohydrate biosensors. Several methodologies were developed based on efficient photochemical insertion reactions which quickly functionalize polymeric materials, with either carbohydrates or functional groups such as alkynes or alkenes. The alkyne/alkene surfaces were then treated with carbohydrate azides or thiols and reacted under chemoselective Cu-catalyzed azide-alkyne cycloaddition (CuAAC) or photo-radical thiol-ene/yne click chemistry, thus creating a range of carbohydrate biosensor surfaces under ambient conditions. The methodologies were evaluated by quartz crystal microbalance (QCM) and surface plasmon resonance (SPR) flow through instrumentations with recurring injections of a range of lectins, allowing for real-time analysis of the surface interactions. The developed methods were proven robust and versatile, and the generated carbohydrate biosensors showed high specificities and good capacities for lectin binding.  The methods were then used to investigate how varying the glycan linker length and/or a sulfur-linkage affect the subsequent protein binding. The survey was further explored by investigating the impact of sulfur in glycosidic linkages on protein binding, through competition assays with various O/S-linked disaccharides in solution interactions with lectins. / QC 20120309

The development of materials for advanced applications requires innovative macromolecules with well-defined structures and the inherent ability to be tailored in a straightforward manner. Dendrimers, being a subgroup of the dendritic polymer family, possess properties which fulfill such demands. They have a highly branched architecture with a high number of functional groups and are one of the most well-defined types of macromolecules ever synthesized. However, despite their well-defined nature and high functional density, traditional dendrimers commonly lack diverse chemical functionalities. Therefore, this thesis focuses on the synthesis of more complex dendritic materials to extend their tailoring capacity by introduction of dualfunctionalities for multipurpose actions. It covers the synthesis of dualfunctional dendrimers, dendritic modification of linear poly(ethylene glycol) polymers and cellulose surfaces, and the synthesis of linear dendritic hybrids. The building blocks enabling this synthesis, AB2C monomers, were also developed during this work. The orthogonal nature between click groups (azide, alkyne and alkene) and hydroxyl groups have efficiently been utilized for postfunctionalization by robust click chemistry and traditional esterification reactions. Furthermore, linear dendritic hybrids were synthesized, merging the properties of linear and dendritic macromolecules. The dendritic frameworks were tailored towards the production of bone fracture adhesives, novel biofunctional dendritic hydrogels, biosensors and micellar drug delivery vehicles. / Utveckling av material för avancerade applikationer kräver innovativa makromolekyler med väldefinierade strukturer och som kan skräddarsys på ett enkelt sätt. Dendrimerer är en undergrupp av dendritiska polymerer vars egenskaper uppfyller dessa krav. De har en mycket förgrenad arkitektur med många funktionella grupper och är en av de mest väldefinierade befintliga syntetiska makromolekylerna. Trots dess väldefinierade karaktär och höga funktionalitet saknar ofta traditionella dendrimerer multipla kemiska funktionaliteter. Denna avhandling fokuserar därför på syntesen av mer komplexa dendritiska material för att förbättra deras kapacitet att skräddarsys, detta görs genom att introducera fler funktionaliteter som kan utnyttjas för multipla ändamål . Avhandlingen redogör för syntesen av difunktionella dendrimerer, dendritiska modifikationer av polyetylenglykol och cellulosaytor samt syntes av traditionella dendritiska hybrider. Byggstenarna som möjliggör syntesen, AB2C monomerer, framställdes också under detta arbete. Den ortogonala karaktären mellan klick grupper (azid, alkyn och alkene) och hydroxylgrupper har utnyttjats effektivt för funktionaliseringar genom användande av robust ”Click”-kemi och traditionella esterifikationsreaktioner. Vidare tillverkades de linjära dendritiska hybrider för att kombinera egenskaperna hos både linjära och traditionella dendritiska polymerer i en och samma makromolekyl. Samtliga dendritiska strukturer skräddarsyddes för applikationer så som benlimmer, biofunktionella dendritiska hydrogeler, biosensorer och läkemedels-bärande miceller. / <p>QC 20130830</p>

Glucosidases são enzimas que catalisam a hidrólise de ligações glicosídicas liberando unidades monossacarídicas de um terminal não redutor de um oligossacarídeo ou glicoconjugado. Iminoaçúcares são alcalóides piperidínicos polihidroxilados isolados de plantas (gênero Morus) e microrganismos (Bacillus), como nojirimicina (NJ) (1) e 1-desoxinojirimicina (DNJ) (2), os quais são descritos como inibidores de glucosidase. O potencial uso destes inibidores no tratamento de infecções virais, crescimento tumoral, metástases, diabetes, doença de Gaucher e osteoartrite tem motivado a comunidade científica na busca por novos derivados iminoaçúcares. Desse modo, a síntese de pseudodissacarídeos, contendo ambos resíduos de iminoaçúcar e glicopiranose, constitui uma estratégia interessante de obtenção desses derivados, apesar dos desafios envolvidos na geração da ligação entre estes dois açúcares. Por esta razão, foi utilizada a estratégia de click chemistry como uma ferramenta para introduzir uma ponte de grupo 1,2,3-triazol entre os açúcares a partir do acoplamento de azido-glicosídeo com N-propargil-iminoaçúcar. Desta forma, a síntese do iminoaçúcar N-propargílico (73), com função acetileno terminal, foi realizada em cinco etapas e foi usado na reação de cicloadição 1,3- dipolar com três derivados glicosídicos contendo grupo azido nas posições anomérica (C-1), C-3 ou C-6. A partir desta reação CuAAC (Copper(I)-catalyzed Azide-Alkyne Cycloaddition), três novos pseudo-dissacarídeos (77, 81 e 85) foram sintetizados em rendimentos moderados e foram, então, avaliados em ensaios de - D-glucosidase isolada de Sacharomyces cerevisiae. Nestes testes preliminares, o composto 77 foi o mais ativo, o qual foi capaz de inibir a atividade da enzima em 40% a 1mM. Esses resultados encorajam a realização de novos experimentos, principalmente, a determinação de Ki e avaliação da atividade relativa à replicação do vírus HIV. Portanto, a obtenção destes pseudodissacarídeos trouxe uma contribuição importante no que diz respeito à química de carboidratos e também ao tratamento das doenças citadas. / Glucosidases are enzymes that catalyze the hydrolysis of glycosidic bonds releasing monosaccharide units from a non-reducing end of an oligosaccharide or glycoconjugate. Iminosugars are polihydroxilate piperidinic alkaloids isolated from plants (Morus alba) and microorganisms (Bacillus), such as nojirimicin (NJ) (1) and 1- deoxynojirimicin (2), which are described as glucosidase inhibitors. The potential use of these inhibitors in the treatment of viral infection, tumoral growing, metastasis, diabetes, Gaucher´s disease and osteoarthritis has stimulated the scientific community on the search for novel iminosugar derivatives. Thereby, the synthesis of pseudodisaccharides, having both iminosugar and glycopyranose residues, represents an interesting strategy to obtain these derivatives, despite the challenges involved in generating the link between these two sugars. For this reason, we have used click chemistry as a tool to introduce a 1,2,3-triazole bridge between the sugars from the coupling of azide-glycosides with N-propargyl-iminosugar. Thus, the synthesis of N-propargyl-iminosugar (73), containing the terminal acetylene function, was performed in five steps, and was used in the 1,3-dipolar cycloaddition reaction with three glycosidic derivatives containing the azide group at anomeric (C-1), C-3 or C-6 positions. By applying this CuAAC (Copper(I)-catalyzed Azide-Alkyne Cycloaddition), three novel pseudo-disaccharides (77, 81 and 85) were synthesized in moderate yields and then, evaluated in -D-glucosidase assays isolated from Sacharomyces cerevisiae. In these preliminary test, compound 77 was the most active from the series, which was able to inhibit 40% of the enzyme activity at 1 mM. These results encourage us to perform new experiments, notably the determination of Ki and evaluation towards HIV replication. Thus, a contribution regarding carbohydrate chemistry and treatment of the supracited diseases was achieved by the synthesis of these pseudodisaccharides.

Förfrågan efter nya och mer avancerade applikationer är en pågående process vilket leder till en konstant utveckling av nya material. För att förstå relationen mellan en applikations egenskaper och dess sammansättning krävs full förståelse och kontroll över materialets uppbyggnad. En sådan kontroll över uppbyggnaden hos material hittas i en undergrupp till dendritiska polymerer som kallas dendrimerer. I den här doktorsavhandlingen belyses nya metoder för att framställa dendrimer med hjälp av selektiva kemiska reaktioner. Sådana selektiva reaktioner kan hittas inom konceptet klickkemi och har i detta arbete kombinerats med traditionell anhydrid- och karbodiimidmedierad kemi. Denna avhandling diskuterar en accelererad tillväxtmetod, dendrimerer med inre och yttre reaktiva grupper, simultana reaktioner och applikationer baserade på dessa dendritiska material. En accelererad tillväxtmetod har utvecklats baserad på AB2- och CD2-monomerer. Dessa monomerer tillåter tillväxt av dendrimerer utan att använda sig av skyddsgruppkemi eller aktivering av ändgrupper. Detta gjordes genom att kombinera kemoselektiviteten hos klickkemi tillsammans med traditionell syraklorid kopplingar. Dendrimerer med inre alkyn- eller azidfunktionalitet syntetiserades genom att använda AB2C-monomerer. Den dendritiska tillväxten skedde med hjälp av karbodiimidmedierad kemi. Monomererna som användes bär på en C-funktionalitet, alkyn eller azid, och på så sätt byggs får interiören i de syntetiserade dendrimeren en inneburen aktiv funktionell grupp. Ortogonaliteten hos klickkemi användes för att sammanfoga monomerer till en dendritisk struktur. Traditionell anhydridkemi- och klickemireaktioner utfördes samtidigt och på så sätt kunde dendritiska strukturer erhållas med färre antal uppreningssteg. En ljusemitterande dendrimer syntetiserades genom att koppla azidfunktionella dendroner till en alkynfunktionell cyclenkärna. Europiumjoner inkorporerades i kärnan varpå dendrimerens fotofysiska egenskaper analyserades. Mätningarna visade att den bildade triazolen hade en sensibiliserande effekt på europiumjonen. Termiska studier på några av de syntetiserade dendrimerer utfördes för att se om några av dem kunde fungera som templat vid framställning av isoporösa filmer. / The need for new improved materials in cutting edge applications is constantly inspiring researchers to developing novel advanced macromolecular structures. A research area within advanced and complex macromolecular structures is dendrimers and their synthesis. Dendrimers consist of highly dense and branched structures that have promising properties suitable for biomedical and electrical applications and as templating materials. Dendrimers provide full control over the structure and property relationship since they are synthesized with unprecedented control over each reaction step. In this doctoral thesis, new methodologies for dendrimer synthesis are based on the concept of click chemistry in combination with traditional chemical reactions for dendrimer synthesis. This thesis discusses an accelerated growth approach, dendrimers with internal functionality, concurrent reactions and their applications. An accelerated growth approach for dendrimers was developed based on AB2- and CD2-monomers. These allow dendritic growth without the use of activation or deprotection of the peripheral end-groups. This was achieved by combining the chemoselective nature of click chemistry and traditional acid chloride reactions. Dendrimers with internal azide/alkyne functionality were prepared by adding AB2C monomers to a multifunctional core. Dendritic growth was obtained by employing carbodiimide mediated chemistry. The monomers carry a pendant C-functionality (alkyne or azide) that remains available in the dendritic interior resulting in dendrimers with internal and peripheral functionalities. The orthogonal nature of click chemistry was utilized for the simultaneous assembly of monomers into dendritic structures. Traditional anhydride chemistry and click chemistry were carried out concurrently to obtain dendritic structures. This procedure allows synthesis of dendritic structures using fewer purification steps. Thermal analyses on selected dendrimers were carried out to verify their use as templates for the formation of honeycomb membranes. Additionally, a light emitting dendrimer was prepared by coupling of azide functional dendrons to an alkyne functional cyclen core. A Europium ion was incorporated into the dendrimer core, and photophysical measurements on the metal containing dendrimer revealed that the formed triazole linkage possesses a sensitizing effect. / QC 20100629

Chemical biology encompasses the study and manipulation of biological system using chemistry, often by virtue of small molecules or unnatural amino acids. Much insight has been gained into the mechanisms of biological processes with regards to protein structure and function, metabolic processes and changes between healthy and diseased states. As an ever expanding field, developing new tools to interact with and impact biological systems is an extremely valuable goal. Herein, work is described towards the synthesis of a small library of heterocyclic-containing small molecules and the mechanistic details regarding the interesting and unexpected chemical compounds that arose; an alternative set of non-toxic copper catalyzed azide-alkyne click conditions for in vivo metabolic labelling; and the synthesis of an unnatural amino acid for further chemical modification via [3+2] cycloadditions with nitrones upon incorporation into a peptide of interest. Altogether, these projects strive to supplement pre-existing methodology for the synthesis of small molecule libraries and tools for metabolic labelling, and thus provide further small molecules for understanding biological systems.