This study experiments with the methods of 1-(4, 4'-Dinitrodiphenylmethyl)-Piperidines; 1-(4-Nitrobenzyl)-and 1-(4-Nitrobenzoyl)-Piperdines.

Organoboron compounds have shown a wide variety of applications in both organic synthesis and the pharmaceutical field in the past decades. Transition metal-catalyzed boration of unsaturated compounds has been studied extensively as an efficient method to install C-B bonds. Most of the previous examples employed symmetrical diboron reagents such as B₂(pin)₂ (pin = pinacolate) and B₂(cat)₂ (cat = catecholate). There are, however, limited examples of boration using unsymmetrical diboron reagents. This dissertation discloses two transition metal-catalyzed borations of unsaturated compounds with unsymmetrical diboron compounds. A Cu-catalyzed β-boration of electrophilic allenoates with a novel sp²-sp³ hybridized diboron reagent (PDIPA) is described. This unsymmetrical diboron reagent is preactivated and allows the boration to go smoothly under mild reaction conditions. The reaction provides β-borylated β,γ- unsaturated esters with exclusive (Z)-double bond geometry. These borylated products are useful intermediates for subsequent Suzuki-Miyaura cross-coupling reaction. In order to install two C-B bonds in one reaction, a Pt-catalyzed diboration of allenes with a differentially protected diboron reagent (PDAN) is presented. This unsymmetrical diboron reagent is prepared from the sp²-sp³ hybridized diboron compound, and it reacts with a series of 1,1- disubstituted allenes chemo- and regioselectively. Steric control ensures that both boryl moieties add to the terminal double bond, and the pinacol boronate preferentially attaches to the sp-hybridized carbon. The bis-boronyl products can be further converted to other functional groups as well as cross-coupling reactions. A collaborative project with Department of Physics and Department of Chemical Engineering is also discussed. In this project, a series of 𝑜-nitrobenzyl ligands containing a disulfide group as the anchor to gold surfaces are synthesized. The 𝑜-nitrobenzyl group uncages an amine upon photoexcitation. Attempts to make a water soluble analog failed, however, the mixture of methanol and water as the solvent was sufficient to attach them on gold surfaces. / Ph. D.

Mechanistische und kinetische Untersuchungen von komplexen zellulären Prozessen in situ sind in den vergangenen Jahren durch den Einsatz photoaktivierbarer Biomoleküle, sogenannter caged Verbindungen, möglich geworden. Bei den caged Verbindungen handelt es sich um photolabile inaktive Derivate von biologisch aktiven Molekülen, aus denen durch ultraviolettes Licht mit Hilfe einer photochemischen Reaktion die natürliche, biologisch aktive Substanz schnell freigesetzt werden kann. Im Rahmen der vorliegenden Arbeit wurden caged Verbindungen von den Neurotransmittern Octopamin und Dopamin, dem Octopamin-Antagonist Epinastin, den Proteinsyntheseinhibitoren Emetin und Anisomycin, dem Protonophor CCCP und dem Riechstoff Bourgeonal hergestellt. Zur Synthese dieser caged Verbindungen wurden sowohl bekannte als auch verschiedene im Rahmen dieser Arbeit neu entwickelte photolabile Schutzgruppen mit einem (Cumarin-4-yl)methyl- bzw. einem 2-Nitrobenzyl-Gerüst eingesetzt. Entsprechende Syntheseverfahren wurden erarbeitet. Anschließend erfolgte eine umfassende physikalisch-chemische sowie photochemische Charakterisierung der erhaltenen caged Verbindungen. Dabei wurde besonders auf gute Löslichkeit in Wasser bei physiologischer Ionenstärke, schnelle und effiziente Photoreaktivität, hohe Extinktion bei Wellenlängen von 350-430 nm und gute solvolytische Stabilität bei geringer Toxizität der freigesetzten Schutzgruppe geachtet. Ein Schwerpunkt bei der photochemischen Charakterisierung bildeten die Untersuchungen zur Quantifizierung der 2-Photonen-Anregung, uncaging action cross-sections, der Cumarinylmethyl-caged Verbindungen, aufgrund ihrer Bedeutung für die Photofreisetzung von Biomolekülen, da die gleichzeitige Absorption von 2 IR-Photonen eine höhere dreidimensionale Auflösung und eine wesentlich tiefere Gewebepenetration erlaubt. Mit Hilfe von Kooperationspartnern wurden zeitaufgelösten Fluoreszenz- und IR-Messungen an verschiedenen (Cumarin-4-yl)methoxycarbonyl-caged Modellverbindungen durchgeführt, mit denen die Geschwindigkeitskonstanten k1 und kdecarb des Photolysemechanismus ermittelt wurde. Am Ende folgten die Anwendungserprobungen ausgewählter caged Verbindungen in einem Translationsassay bzw. in Zelluntersuchungen. / In the last years mechanistic and kinetic in situ studies of complex cellular processes become possible by employing photoactivate Biomolecules, also called caged compounds, as a tool for these studies. Caged compounds are photolabile inactive derivates of biologic active molecules which are fast laid off the nature biologic active molecule by a photochemical reaction which was triggered by UV-light. In the present dissertation caged compounds of the neurotransmitters octopamine and dopamine, of the octopamine antagonist epinastine, of the proteine synthesis inhibitors emetine and anisomycine, of the ionophore CCCP and of the odorus substance Bourgeonal are synthesized. As precursors for the synthesis of that caged compounds some reported and several in these work newly developed photolabile protecting groups with (coumarin-4-yl)methyl- or 2-nitrobenzyl-scaffold were used. Corresponding Synthesis were designed. Afterwards the received caged compounds were global physical-chemical and photochemical characterised. In favour it was specifically valued for highly water solubility at pH 7,2, fast and efficient photo reactivity, high extinctions at wavelength 350-430 nm, well solvolytic stability and less toxicity of the redundant protecting groups. One key aspect of photochemical characterisation were the studies of uncaging action cross-sections of the coumarinylmethyl-caged molecules, because of their relevance for the photorelease of biomolecules in tissues. The simultaneous absorption of 2 IR-photons allowed highly three-dimensional release and a essentially deeper penetration in tissues. With the aid of co-operation partners were time-released fluorescence- and IR- measurements with several (coumarin-4-yl)methoxycarbonyl-caged molecules realised and therefore the rate constant k1 und kdecarb of the photolyse mechanismus were determined. At the end of the dissertation the achieved caged compounds were testet in translation assays and several cell cultures.

Les nanotechnologies sont devenues depuis plusieurs années un axe majeur de développement dans les domaines du diagnostic, de l’imagerie, de la délivrance de médicament, du suivi thérapeutique et de l’ingénierie tissulaire. L’administration de produits non injectables sous leur forme libre ou bien possédant une toxicité élevée, peut être facilitée par l’utilisation de nanovecteurs, modifiant leur distribution. Ils permettent donc de réduire les doses administrées, limiter les effets secondaires et diriger le contenu du vecteur (agent de contraste, drogue) vers un organe cible ou une tumeur, en présentant à la surface de celui-ci des molécules de ciblage de ces zones spécifiques.Cette thèse s'inscrit dans cette thématique : nous avons exploré les possibilités de former des gels chimiques à partir des nanoparticules lipidiques qui sont constituées d'un cœur huileux pouvant encapsuler de petites molécules hydrophobes et d'une couche de surfactants permettant la stabilisation des gouttelettes en phase aqueuse.Nous avons pu synthétiser plusieurs surfactants PEGylés fonctionnalisés (thiol, maléimides, amine, oxyamines et ONB-maléimide). Les protocoles de synthèse de ces surfactants sont affinés et reproductibles.Ces surfactants ont été incorporés à la surface des nanoparticules lipidiques. Les nanoparticules fonctionnalisées ainsi obtenues ont été caractérisées et les fonctions présentes à leur surface sont mises en évidence.Différentes sortes de gels chimiques stables, résistant à la dilution, rapides à fabriquer et contrôlables ont été élaborés.Ces gels chimiques peuvent être utilisés dans l’avenir pour encapsuler des protéines ou des drogues. / Nanotechnology became for several years a major development in the areas of diagnostics, imaging, drug delivery, therapeutic monitoring, and tissue engineering. The administration of non-injectable products in their free form or with high toxicity, can be facilitated by the use of nanocarriers, changing their distribution. They therefore reduce the doses administered, limit side effects and direct the contents of the vector (contrast agent, drug) to a target organ or tumor, by presenting to the surface thereof targeting molecules of these areas specific.This thesis fits into this theme : we have explored the possibilities of forming chemical gels based on lipid nanoparticles which are composed of an oily heart can encapsulate small hydrophobic molecules and a layer of surfactants allowing stabilization of the droplets in the aqueous phase.We have synthesized several PEGylated functionalized surfactants (thiol, maleimide, amine, and oxyamines ONB-maleimide). synthesis protocols of these surfactants are refined and repeatable.These surfactants were incorporated into the surface of lipid nanoparticles. The functionalized nanoparticles thus obtained have been characterized and the functions present at their surface are highlighted.Different kinds of chemical gels stable, resistant to dilution, fast and controllable manufacturing have been developed.These chemical gels can be used in the future for encapsulating proteins or drugs.

Cell adhesion is the first step of cell response to materials and the extracellular matrix (ECM), and is essential to all cell behaviours such as cell proliferation, differentiation, migration and apoptosis for anchor-dependent cells. Therefore, studies of cell attachment have important implications to control and study cell behaviours. During many developed techniques for cell attachment, the manipulation of surface chemistry is a very important method to control initial cell attachment. To control cell adhesion on a two-dimensional surface is a simple model to study cell behaviours, and is a fundamental topic for cell biology, tissue engineering, and the development of biosensors. From the engineering point of view, the preparation of a material with controllable surface chemistry can help studies of cell behaviours and help scientists understand how surface features and chemistry influence cell behaviours. During the fabrication, the challenge is to create a surface with heterogeneous surface properties in the micro scale and subsequently to guide cell initial adhesion. In order to control cell adhesion in a spatial and temporal manner, a photochemical method to control surface chemistry was employed to control the surface property for cell adhesion in this project. Two photocleavable derivatives of the nitrobenzyl group were tried on two types of surfaces: a model self-assembled monolayer (SAM) with alkanethiol-gold surface and biodegradable chitosan. Reactive functional groups on two different surfaces can be inactivated by covalent binding with these photocleavable molecules, and light can be further introduced into the system as a stimulus to recover their reactivity. By simply applying a photomask with diffe

Cell adhesion is the first step of cell response to materials and the extracellular matrix (ECM), and is essential to all cell behaviours such as cell proliferation, differentiation, migration and apoptosis for anchor-dependent cells. Therefore, studies of cell attachment have important implications to control and study cell behaviours. During many developed techniques for cell attachment, the manipulation of surface chemistry is a very important method to control initial cell attachment. To control cell adhesion on a two-dimensional surface is a simple model to study cell behaviours, and is a fundamental topic for cell biology, tissue engineering, and the development of biosensors. From the engineering point of view, the preparation of a material with controllable surface chemistry can help studies of cell behaviours and help scientists understand how surface features and chemistry influence cell behaviours. During the fabrication, the challenge is to create a surface with heterogeneous surface properties in the micro scale and subsequently to guide cell initial adhesion. In order to control cell adhesion in a spatial and temporal manner, a photochemical method to control surface chemistry was employed to control the surface property for cell adhesion in this project. Two photocleavable derivatives of the nitrobenzyl group were tried on two types of surfaces: a model self-assembled monolayer (SAM) with alkanethiol-gold surface and biodegradable chitosan. Reactive functional groups on two different surfaces can be inactivated by covalent binding with these photocleavable molecules, and light can be further introduced into the system as a stimulus to recover their reactivity. By simply applying a photomask with diffe

Cell adhesion is the first step of cell response to materials and the extracellular matrix (ECM), and is essential to all cell behaviours such as cell proliferation, differentiation, migration and apoptosis for anchor-dependent cells. Therefore, studies of cell attachment have important implications to control and study cell behaviours. During many developed techniques for cell attachment, the manipulation of surface chemistry is a very important method to control initial cell attachment. To control cell adhesion on a two-dimensional surface is a simple model to study cell behaviours, and is a fundamental topic for cell biology, tissue engineering, and the development of biosensors. From the engineering point of view, the preparation of a material with controllable surface chemistry can help studies of cell behaviours and help scientists understand how surface features and chemistry influence cell behaviours. During the fabrication, the challenge is to create a surface with heterogeneous surface properties in the micro scale and subsequently to guide cell initial adhesion. In order to control cell adhesion in a spatial and temporal manner, a photochemical method to control surface chemistry was employed to control the surface property for cell adhesion in this project. Two photocleavable derivatives of the nitrobenzyl group were tried on two types of surfaces: a model self-assembled monolayer (SAM) with alkanethiol-gold surface and biodegradable chitosan. Reactive functional groups on two different surfaces can be inactivated by covalent binding with these photocleavable molecules, and light can be further introduced into the system as a stimulus to recover their reactivity. By simply applying a photomask with diffe

Ce travail est consacré au développement de la stratégie TDAE dans le cadre de la synthèse de nouveaux composés à visée thérapeutique. Dans une première partie, la pharmacomodulation d’un composé potentiellement ligand sélectif du récepteur 5-HT7 nous a conduit à développer une méthodologie d’addition et d’estérification séquentielle « one-pot » initiée par le TDAE. Par la suite, nous avons étendu la réactivité initiée par le TDAE aux réactions de substitution nucléophile de type 2 sur des électrophiles -halogénoesters et -halogénoamides en série nitrobenzylique. Cette méthodologie nous a permis de synthétiser différents 3-(2-nitrophényl)propanamides qui ont manifesté, pour certains, une activité analgésique significative chez la souris. La deuxième partie est consacrée à la synthèse de divers 3-phénylpropanamides et à l’évaluation de leur propriété analgésique. L’un des ces composés s’est révélé puissant mais modérément efficace par rapport à l’aspirine, que ce soit par voie injectable ou par voie orale. La troisième partie traite de la réactivité initiée par le TDAE sur le noyau 4-chloroquinazoline. Outre la mise en évidence de réactivités particulières liées aux caractères basique et nucléophile du TDAE, cette étude a montré la possibilité de réaliser des réactions de substitution nucléophile aromatique. La synthèse de diverses 4-benzyl-2-trichlorométhylquinazolines par cette méthodologie, s’inscrit dans une étude de pharmacomodulation de nouveaux agents antiplasmodiaux. / This work is focused on the development of the TDAE strategy aiming at the preparation of new bioactive compounds. In a first part, the pharmacomodulation study of a potential 5-HT7 receptor ligand led us to develop a “one-pot” methodology of addition and sequential esterification initiated by the TDAE. Later, we extended the reactivity of carbanions generated by TDAE to type 2 nucleophilic substitution (SN2) reactions on various -haloesters and -haloamides in nitrobenzylic series. This methodology allowed us to synthesize different 3-(2-nitrophenyl)propanamides which expressed a significant analgesic activity on mice. The second part is dedicated to the synthesis of various 3-phenylpropanamide and the evaluation of their analgesic potentiality. One of those compounds appeared active but moderately effective with regard to aspirin, both by infusion or oral route. The third part concerns the TDAE-initiated reactivity with the 4-chloroquinazoline scaffold. In addition to the description of two particular reactivities related to its basic and nucleophilic characters, this study showed the possibility to carry out aromatic nucleophilic reactions (SNAr). The synthesis of several 4-benzyl-2-trichloromethylquinazolines using this original methodology was related to a program of new antiplasmodial agents pharmacomodulation.

Des glycopolymères greffés et dibloc, amphiphiles et photosensibles, à base de poly(acrylate d'o-nitrobenzyle) (PNBA) hydrophobe et photoclivable et de dextrane hydrophile ont été préparés avec succès en utilisant notammennt une réaction d'Huisgen (Cycloaddition Azoture-Alcyne catalysée par le Cuivre (I) - CuAAC chimie click). Dans un premier temps, la polymérisation de l'acrylate d'o-nitrobenzyle a été contrôlée avec succès grâce aux développements récents de la polymérisation radicalaire vivante par transfert d'un seul électron (SET-LRP). Nous avons alors obtenu un PNBA fonctionnalisé à son extrémitié par un brome. Ce brome a ensuite été substitué par un groupe azido. En parallèle, le dextrane a été modifié pour y introduire plusieurs fonctions alcyne (dextrane alcyne) ou une seule sur son extrémité réductrice (dextrane α-alcyne). Nous avons ensuite fait réagir ces dérivés de dextrane avec le PNBA-N3 pour obtenir respectivement les glycopolymères greffés et dibloc. Tous les glycopolymères ont été caractérisés par chromatographie d'exclusion stérique (SEC), Résonnance Magnétique Nucléaire 1H, 13C, 2D DOSY 1H et par spectrométrie FT-IR. Dans un deuxième temps, nous avons optimisé les conditions pour obtenir des nanoparticules peu disperses à partir des précédents glycopolymères. Dans certains cas, des nanoparticules ont également été obtenues en utilisant le dextrane alcyne et le PNBA-N3 dans un procédé d'émulsion/évaporation de solvant organique. La stabilité de toutes les nanoparticules vis-à-vis de solutions aqueuses de diverses forces ioniques ou d'un tensioactif compétitif a été étudiée. Enfin, l'effet de la lumière sur ces nanoparticules photosensibles a été mis en évidence à l'aide de la lampe UV. Plus précisément, nous avons pu suivre la destruction des nanoparticules par spectroscopie de fluorescence et diffusion de lumière dynamique en encapsulant le Rouge du Nil (sonde fluorescente) au sein de ces particules / Photosensitive grafted and diblock amphiphilic glycopolymers based on hydrophobic photosensitive poly(o-nitrobenzyl acrylate) (PNBA) and hydrophilic dextran were successfully prepared via grafting onto techniques through a Huisgen-type Copper(I) catalyzed Azide-Alkyne Cycloaddition (CuAAC click chemistry). Firstly, recent developments in the single-electron transfer–living radical polymerization (SET–LRP) provided us an access to control the o-nitrobenzyl acrylate polymerization and we obtained PNBA with bromide end function. Then, this bromide end function was replaced by azido (N3) group. In a parallel way, we modified dextran by introducing several alkyne groups all long the polysaccharide chain (alkynated dextran) or only one group at the reducing end-chain (α-alkyne dextran). In the second step, alkynated dextran and α-alkyne dextran were reacted with PNBA-N3 by CuAAC to obtain grafted or diblock glycopolymers. All glycopolymers were characterized by Size Exclusion Chromatography, 1H, 13C, 2D DOSY 1H NMR and FT-IR spectroscopy. Secondly, conditions to formulate nanoparticles from the previous glycopolymers were optimized. In some case, we also carried out an emulsion/evaporation process using dextran alkynated and PNBA-N3 to produce nanoparticles. Then, stability of nanoparticles were studied over rang of ionic strengths as well as stability in presence of a competitive surfactant. Finally, the effect of light on these photosensitive nanoparticles was studied using UV-lamp. More precisely, we loaded these nanoparticules by Nile Red fluorescent dye and followed thier destruction by using fluorescence spectroscopy and Dynamic Light Scattering