Les groupements protecteurs photolabiles sont utilisés pour de nombreuses applications, notamment en neuroscience pour la libération de neurotransmetteurs avec un contrôle spatio-temporel très fin. La démocratisation des lasers pulsés infrarouges a permis la mise au point de nouveaux composés sensibles à l’excitation à deux photons, de plus en plus efficace. Cependant, l’ingénierie moléculaire des cages n’est pas la seule méthode qui peut être utilisée pour améliorer l’efficacité des de ces composés. Mon travail de thèse a ainsi abordé cette problématique sous l’angle de la nanostructuration de groupements protecteurs photolabiles sensibles à l’excitation à deux photons. Nous avons débuté cette étude avec des composés de petite taille (dimère et tétramère) basés sur des groupements photosensible type ortho-nitrophénéthyle. Nous avons ensuite fonctionnalisé des dendrimères de type polyamidoamine, cependant les propriétés photophysiques et photochimiques de ces nouveaux composés suggèrent que des interactions intramoléculaires perturbent l’efficacité de la réaction de photolibération. Des dendrimères partiellement fonctionnalisés ont ensuite été envisagés. / Photosensitive protecting groups have been used for many applications, including neuroscience for the release of neurotransmitters with an amazing spatio-temporal control. New compounds sensitive to two-photon excitation were developed with the spread out of pulsed infrared lasers. However, cages molecular engineering is not the only way to improve such compounds. This manuscript focuses on nanostructuration to improve the overall efficiency of two-photon sensitive protecting groups. We started our study with small compound as dimer and tetramer based on the ortho-nitrophenethyl architecture. Next, polyamidoamine dendrimers were tested, but photophysics and photochemistry properties of these new compounds suggest that intramolecular interactions disturb photochemical reaction. Synthesis of partially functionalized dendrimer was considering in a next step.

Near-infrared (NIR) light, with wavelengths of 650 to 900 nanometers, effectively penetrates tissues. The high signal to noise ratio and low phototoxicity of NIR light makes this wavelength range ideal for deep tissue imaging. However, current NIR fluorophores are generally large hydrophobic molecules that are prone to aggregation. Sulfonation can enhance aqueous solubility, but their anionic nature prevents membrane diffusion, and thus, restricts the applications of sulfonated molecules to in vitro or fixed cells. The repertoire of commercially available sulfonated NIR probes is mostly limited cyanines, which have low photostability. Moreover, larger cyanines require multiple sulfonates to maintain aqueous solubility. For example, Indocyanine Green is only sparingly soluble in PBS, despite having two sulfonates. My work has focused on the delivery of sulfonated dyes into live cells and the development of a new, ultra-compact NIR dye scaffold. First, to expand the in-cell applications of sulfonated fluorophores, I designed reductively-labile sulfonate protecting groups. Using these scaffolds, I have successfully delivered the fluorophore dansyl sulfonate into live cells, where the cytosolic reducing environment unmasks the anionic sulfonate. Secondly, to create a compact, photostable NIR fluorophore, I pioneered the discovery of azasilines dyes. The two azasiline derivatives, ASiFluor710 and ASiFluor730, fluoresce over 700 nanometers and are among the most compact NIR fluorophores currently known. ASiFluor730 also retains the high photostability of oxazine dyes, highlighting their potential in long exposure applications. Beyond the immediate applications in fluorescence microscopy and in vivo imaging, I envision that my work will serve as a framework for the future design of soluble, membrane permeable, NIR fluorescent probes.

No description available.

This work refers to the area of bio-nanotechnology and concerns the selective immobilization of DNA or other bio-template on microstructured gold contacts and which then permit a coordinated cooperation of several of these nanotemplate, e.g., within a microreactor. The immobilization of such nano-objects should be realized through functional thin polymer films which provide binding groups. Thus, the main aim of this work was the development of polymeric materials for thin functional films which permit to deposit on different substrates a wide variation of functional elements or metal structures and to achieve a pattern formation using optical grid methods. In order to realize this concept it was necessary to design and develop a polymer system based on suitable photolabile units and in addition having anchoring groups which attach on specific substrates like gold. In this terpolymer concept was aimed for which consists of three components with particular functions in suitable molar ratios, which allow the tune the properties of the materials, and provide: amino photolabile protected groups for the photolithographic creation of patterned areas with free amino groups, which are available for further modifications like attachment of colloids, metallization or attachment of DNA strands; disulfide derivative anchor groups providing anchoring capacity for gold surface and spacer groups for adjusting the film quality. These multifunctional terpolymers should be synthesised by free radical polymerisation of suitable monomers. Although these techniques are successful, they are limited by their complexity, rigorous synthetic demands, as well as incompatibility with many functional termolabile and highly reactive functionalities. To overcome these difficulties a polymerisation technique based on “living” free radical polymerisation has been used in this work. A highly efficient polymer-analogous modification allows to introduce the functionalities after the polymer construction reaction. The production of suitable prepolymers [poly(styrene-r-4-propargyl-oxystyrene)] was carried out with the help of a controlled synthesis methodology “nitroxide mediate radical polymerization" followed by polymer analogous reaction using one of the most efficient click reactions, the Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition between terminal acetylenes and azides to attach further functionalities through the formation of a stable 1,4-disubstituted 1,2,3-triazol ring . The combination of nitroxide mediated radical polymerization (NMRP) and click chemistry was used to produce well-defined random copolymer. It could already be shown that also block copolymers can be prepared which give the chance to combine nanostructure formation in block copolymers with special functionality. Thus, the special properties of these functional polymers like the capability for photopatterning and anchoring onto gold substrates make them very interesting for nanotechnology applications. / Diese Arbeit bezieht sich auf das Gebiet der Bionanotechnologie und betrifft ein neuartiges Verfahren zur selektiven Immobilisierung der DNA oder anderer Biomoleküle auf mikrostrukturierten Goldkontakten, welche dann ein koordiniertes Zusammenwirken von einzelnen Nanomolekülen ermöglichen, z.B. in einem Mikroreaktor. Die Immobilisierung solcher Nanoobjekte soll durch dünne Funktionsschichten realisiert werden, die die Anbindungsgruppen liefern. Folglich war das Hauptziel dieser Arbeit die Entwicklung von Polymermaterialien für dünne Funktionsschichten, die die Aufbringung einer großen Vielzahl von Funktionselementen oder metallischen Strukturen auf verschiedenen Substraten gestatten und die Strukturierung durch den Einsatz von lithographischen Methoden ermöglichen. Um dieses Konzept zu realisieren, war es notwendig, ein Polymersystem zu gestalten und zu entwickeln, welches auf geeignete photolabile Einheiten basiert und zusätzlich Ankergruppen hat, die mit spezifischen Substraten wie Gold verbunden ist. Dieses Terpolymerkonzept wurde gezielt aus drei Komponenten mit speziellen Funktionen in entsprechenden molaren Verhältnissen gebildet, die eine Abstimmung der Materialeigenschaften ermöglicht und folgendes bereitstellt: photolabile geschützte Aminogruppen für die photolitographische Strukturerzeugung mit freien Aminogruppen, welche für weitere Modifikationen verfügbar sind wie das Anhängen von Kolloiden, die Metallisierung oder Anfügung von DNA-Strängen; disulfide Derivate für die kovalente Anbindung auf der Goldoberfläche und Spacer-Gruppe für Verbesserung der Schichtenbildung. Diese multifunktionalen Terpolymere sollen durch eine freie radikalische Polymerisation von entsprechenden Monomeren synthetisiert werden. Obwohl diese Techniken erfolgreich sind, sind sie eingeschränkt durch ihre Komplexität, den strengen synthetischen Anforderungen, sowie der Inkompatibilität mit vielen funktionalen thermolabilen und hochreaktiven Funktionalitäten. Um diese Schwierigkeiten zu überwinden wurde eine Polymerisationstechnik für diese Arbeit genutzt, die auf der „lebenden“ freien radikalischen Polymerisation basiert. Eine hoch effiziente polymeranaloge Modifizierung erlaubt die Einführung von Funktionalitäten nach der Polymeraufbaureaktion. Die Herstellung von entsprechenden Präpolymeren Poly(Styrol-r-4-Propargyl-oxystyrol) wurde mittels einer kontrollierten Synthesemethodik „Nitroxid-mediated controled radical polymerisation“ (NMRP) durchgeführt, gefolgt von der Polymeranalogreaktion, die eine der effizientesten Click-Reaktion - die Cu(I) katalysierte 1,3-dipolar Cycloaddition von terminalen Alkinen an Aziden nach Huisgen nutzt, um weiter Funktionalitäten durch die Bildung eines stabilen 1,4-disubstituierten-[1,2,3]-Triazolringes anzufügen. Die Kombination von NMRP und Click-Chemie wurde zur Herstellung eines exakt definierten Random Copolymers genutzt. Es konnte bereits gezeigt werden, dass auch Blockcopolymere geschaffen werden können, die eine Möglichkeit zur Kombination von Nanostrukturformationen in Blockcopolymeren mit speziellen Funktionaltäten bieten. Folglich sind die speziellen Eigenschaften dieser Funktionalpolymere wie die Fähigkeit zur Photostrukturierung und Verankerung auf Goldsubstraten für nanotechnologische Anwendungen sehr interessant.

This work refers to the area of bio-nanotechnology and concerns the selective immobilization of DNA or other bio-template on microstructured gold contacts and which then permit a coordinated cooperation of several of these nanotemplate, e.g., within a microreactor. The immobilization of such nano-objects should be realized through functional thin polymer films which provide binding groups. Thus, the main aim of this work was the development of polymeric materials for thin functional films which permit to deposit on different substrates a wide variation of functional elements or metal structures and to achieve a pattern formation using optical grid methods. In order to realize this concept it was necessary to design and develop a polymer system based on suitable photolabile units and in addition having anchoring groups which attach on specific substrates like gold. In this terpolymer concept was aimed for which consists of three components with particular functions in suitable molar ratios, which allow the tune the properties of the materials, and provide: amino photolabile protected groups for the photolithographic creation of patterned areas with free amino groups, which are available for further modifications like attachment of colloids, metallization or attachment of DNA strands; disulfide derivative anchor groups providing anchoring capacity for gold surface and spacer groups for adjusting the film quality. These multifunctional terpolymers should be synthesised by free radical polymerisation of suitable monomers. Although these techniques are successful, they are limited by their complexity, rigorous synthetic demands, as well as incompatibility with many functional termolabile and highly reactive functionalities. To overcome these difficulties a polymerisation technique based on “living” free radical polymerisation has been used in this work. A highly efficient polymer-analogous modification allows to introduce the functionalities after the polymer construction reaction. The production of suitable prepolymers [poly(styrene-r-4-propargyl-oxystyrene)] was carried out with the help of a controlled synthesis methodology “nitroxide mediate radical polymerization" followed by polymer analogous reaction using one of the most efficient click reactions, the Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition between terminal acetylenes and azides to attach further functionalities through the formation of a stable 1,4-disubstituted 1,2,3-triazol ring . The combination of nitroxide mediated radical polymerization (NMRP) and click chemistry was used to produce well-defined random copolymer. It could already be shown that also block copolymers can be prepared which give the chance to combine nanostructure formation in block copolymers with special functionality. Thus, the special properties of these functional polymers like the capability for photopatterning and anchoring onto gold substrates make them very interesting for nanotechnology applications. / Diese Arbeit bezieht sich auf das Gebiet der Bionanotechnologie und betrifft ein neuartiges Verfahren zur selektiven Immobilisierung der DNA oder anderer Biomoleküle auf mikrostrukturierten Goldkontakten, welche dann ein koordiniertes Zusammenwirken von einzelnen Nanomolekülen ermöglichen, z.B. in einem Mikroreaktor. Die Immobilisierung solcher Nanoobjekte soll durch dünne Funktionsschichten realisiert werden, die die Anbindungsgruppen liefern. Folglich war das Hauptziel dieser Arbeit die Entwicklung von Polymermaterialien für dünne Funktionsschichten, die die Aufbringung einer großen Vielzahl von Funktionselementen oder metallischen Strukturen auf verschiedenen Substraten gestatten und die Strukturierung durch den Einsatz von lithographischen Methoden ermöglichen. Um dieses Konzept zu realisieren, war es notwendig, ein Polymersystem zu gestalten und zu entwickeln, welches auf geeignete photolabile Einheiten basiert und zusätzlich Ankergruppen hat, die mit spezifischen Substraten wie Gold verbunden ist. Dieses Terpolymerkonzept wurde gezielt aus drei Komponenten mit speziellen Funktionen in entsprechenden molaren Verhältnissen gebildet, die eine Abstimmung der Materialeigenschaften ermöglicht und folgendes bereitstellt: photolabile geschützte Aminogruppen für die photolitographische Strukturerzeugung mit freien Aminogruppen, welche für weitere Modifikationen verfügbar sind wie das Anhängen von Kolloiden, die Metallisierung oder Anfügung von DNA-Strängen; disulfide Derivate für die kovalente Anbindung auf der Goldoberfläche und Spacer-Gruppe für Verbesserung der Schichtenbildung. Diese multifunktionalen Terpolymere sollen durch eine freie radikalische Polymerisation von entsprechenden Monomeren synthetisiert werden. Obwohl diese Techniken erfolgreich sind, sind sie eingeschränkt durch ihre Komplexität, den strengen synthetischen Anforderungen, sowie der Inkompatibilität mit vielen funktionalen thermolabilen und hochreaktiven Funktionalitäten. Um diese Schwierigkeiten zu überwinden wurde eine Polymerisationstechnik für diese Arbeit genutzt, die auf der „lebenden“ freien radikalischen Polymerisation basiert. Eine hoch effiziente polymeranaloge Modifizierung erlaubt die Einführung von Funktionalitäten nach der Polymeraufbaureaktion. Die Herstellung von entsprechenden Präpolymeren Poly(Styrol-r-4-Propargyl-oxystyrol) wurde mittels einer kontrollierten Synthesemethodik „Nitroxid-mediated controled radical polymerisation“ (NMRP) durchgeführt, gefolgt von der Polymeranalogreaktion, die eine der effizientesten Click-Reaktion - die Cu(I) katalysierte 1,3-dipolar Cycloaddition von terminalen Alkinen an Aziden nach Huisgen nutzt, um weiter Funktionalitäten durch die Bildung eines stabilen 1,4-disubstituierten-[1,2,3]-Triazolringes anzufügen. Die Kombination von NMRP und Click-Chemie wurde zur Herstellung eines exakt definierten Random Copolymers genutzt. Es konnte bereits gezeigt werden, dass auch Blockcopolymere geschaffen werden können, die eine Möglichkeit zur Kombination von Nanostrukturformationen in Blockcopolymeren mit speziellen Funktionaltäten bieten. Folglich sind die speziellen Eigenschaften dieser Funktionalpolymere wie die Fähigkeit zur Photostrukturierung und Verankerung auf Goldsubstraten für nanotechnologische Anwendungen sehr interessant.

To study the functions of glycoconjugates in biological systems reliable and efficient protocols for glycoconjugate synthesis are needed. To reach this goal we have developed methods for solid-phase synthesis of glycoconjugates that can be monitored with gel-phase 19F spectroscopy using fluorinated linkers, building blocks, and protecting groups. We have developed a new fluorine containing linker suitable for solid-phase synthesis of glycoconjugates. The linker was more acid-labile than similar linkers in order to enable cleavage under mild conditions of the target compound from the linker resin.  A carbamate-based strategy has been applied to attach a spacer carrying an amino group to a fluorinated Wang linker for synthesis of amino-functionalized glycoconjugates using thioglycoside donors with fluorinated protective groups. Cleavage from the solid support was performed with trifluoroacetic acid and subsequent protecting group removal gave the target compound. The terminal amine was conjugated with didecyl squarate and this derivative can be attached to various proteins and solid surfaces carrying primary or secondary amines. To evaluate this methodology we have immobilized glycoconjugates in amino-functionalized microtiter plates and successfully probed them with lectin. In addition, a novel fluorine containing protecting group has been designed, synthesized and evaluated. The protecting group was used for protection of the unreactive 4-OH in a galactose building block that was applied in the synthesis of 6-aminohexyl galabioside and was removed with TBAF in THF. Adenovirus serotype 8 (Ad8), Ad19, and Ad37 cause the severe ocular infection, epidemic keratoconjunctivities (EKC). During infection, the adenoviruses interact with sialic acid containing glycoconjugates on the epithelial cells via fiber structures extending from the viral particles. The virus particle most likely binds to the host cell in a multivalent way by simultaneously using multiple fiber proteins and binding sites. Multivalent sialic acid containing conjugates could efficiently inhibit Ad37 cell attachment and subsequent infection of human corneal epithelial (HCE) cells. Three compact tri- and tetravalent sialic acid conjugates were prepared and evaluated as inhibitors of adenoviral host cell attachment and subsequent infection and all conjugates were potent as anti-adenoviral agents. The conjugates can readily be synthesized from accessible starting materials. A crystal structure of the Ad37 fiber knob protein and the trivalent sialic acid conjugate showed that the three binding sites were all occupied by one sialic acid residue each.

<p>The first part of the work describes a procedure of oligonucleotide purification using a reversed-phase cartridge. The developed method employs a very efficient yet mild oligonucleotide detritylation on the cartridge support allowing fast purification of oligonucleotides regardless of their 5´-modification. Thiol- and amino-modified oligonuc-leotides were detritylated and purified with the same high efficiency as non-modified oligonucleotides. The method enables fast, parallel and automated purification of many oligonucleotide probes that was not possible before. In combination with the method of removal of tritylated failure fragments oligonucleotides were produced with purity superior to that of oligonucleotides purified using RP HPLC.</p><p>In the second part of the present study a method of solid-phase RNA synthesis using 2´-tert-butyldithiomethyl (2´-O-DTM) is discussed. The stability of the DTM group during oligonucleotide assembly and deprotection in ammonia, together with its ability for rapid deprotection under mild conditions, allowed the synthesis of RNA with the quality similar to that of synthetic DNA oligonucleotides. The advantage of the 2´-O-DTM group is that it is completely orthogonal to all protecting groups used for the traditional solid-phase DNA synthesis. Therefore, the synthesis can be performed using a standard DNA synthesis procedure – no changes are needed for the product assembly. RNA oligonucleotides synthesized with retained 5´-terminal trityl group can be subjected to a cartridge-based purification using the procedure described in the first part of the study. The phosphoramidite synthesis was optimized for a large scale preparation and gives versatility for introduction of other alkyldithiomethyl groups according to the preference to their certain properties.</p><p>The third part of the thesis describes the synthesis of a dithiomethyl linker and its utility for reversible conjugation of oligonucleotides. A dithiomethyl group, cleavable under mild conditions, was introduced onto 3´-OH of tritylated nucleosides via 3´-O-methylthiomethyl derivatives. The influence of different alkyl substituents on the disulfide bond stability was investigated, and stable analogues were employed in oligosyntheses. Two applications were developed using the present linker: 1) purification of oligonucleotides linked to the solid support; and 2) cartridge-based purification of tritylated oligonucleotides having an additional hydrophobic group on their 3´- terminus.</p>

Les carbapénèmes occupent actuellement une place centrale dans la lutte contre les bactéries résistantes aux antibiotiques classiques de type pénicilline. Notre thèse a pour objectif de développer une synthèse de leurs intermédiaires dans l'optique d'une application à l'échelle industrielle. Nous avons exploité, comme stratégie de fermeture de l'hétérocycle, la formation du lien C-3/C-4 par attaque nucléophile intramoléculaire sur un époxyde. Celui-ci est obtenu à partir de la L thréonine qui fournit deux stéréocentres et permet d'induire le troisième carbone asymétrique. Nous avons utilisé le groupe benzhydryle comme groupe protecteur, nouveau dans cette chimie, pour remplacer le groupe para-anisyle habituel qui pose des problèmes industriels. Ce nouveau groupe change fortement la réactivité de l'époxyamide impliquant une optimisation délicate des conditions et un choix judicieux des substituants. De plus, une nouvelle méthode de déprotection par bromation photochimique a été mise au point, complètement compatible avec la fragilité du cycle beta-lactame. Enfin, pour générer le groupe partant en C-4, nous avons utilisé une oxydation de Baeyer-Villiger. La régiosélectivité de cette étape dépend fortement des substituants et apparaît contradictoire avec les exigences de la fermeture de cycle. L'étude de l'influence des substituants sur ces deux étapes nous a permis de sélectionner le substituant optimal. Dans la seconde partie de cette thèse, nous nous intéressons à l'introduction du 4e centre asymétrique caractéristique des carbapénèmes. Nous avons étudié la possibilité de l'effectuer avec des dérivés de l'acide de Meldrum pour substituer la position C-4 de l'intermédiaire-clef, suivi d'une décarboxylation asymétrique. Nous clôturons ce travail par une évaluation économique de notre synthèse d'un précurseur équivalent à l'acétoxyazétidinone. /Carbapenems occupy a central role in the fight against bacteria that are resistant to classical antibiotics such as penicillins. Our thesis has the aim to develop a synthesis of their principal intermediates with the objective to apply it at the industrial scale. We have explored, as strategy of the heterocycle closing, the formation of the C-3/C-4 bond by a nucleophilic attack on an epoxide. This one was obtained from L-threonine which brings two stereocenters and allows the induction for the creation of the third asymmetric carbon. We used the benzhydryl group as protecting group, new in this chemistry, to replace the usual para-anisyl group which causes industrial problems. This new group strongly affects the reactivity of the epoxyamide imposing a fine optimization of the conditions and an adequat choice of substituents. Furthermore, a new deprotection method by photochemical bromination was developed, entirely compatible with the fragility of the beta-lactam ring. Finally, to create the leaving group in C-4, we used a Baeyer-Villiger oxidation. Regiochemistry of this step strongly depends on substituents and appears contradictory with the requirements of the ring closing. The study of the influence of the substituents on these two steps permits us to choose the optimal substituent. In a second part of the work, we were interested in the introduction of the fourth asymmetric center of carbapenems. We studied the feasibility to perform it with Meldrum's acid derivatives by substituting the C-4 position of the key-intermediate, followed by an asymmetric decarboxylation. We ended this work by an economic evaluation of the synthesis of our precursor similar to acetoxyazetidinone.

The first part of the work describes a procedure of oligonucleotide purification using a reversed-phase cartridge. The developed method employs a very efficient yet mild oligonucleotide detritylation on the cartridge support allowing fast purification of oligonucleotides regardless of their 5´-modification. Thiol- and amino-modified oligonuc-leotides were detritylated and purified with the same high efficiency as non-modified oligonucleotides. The method enables fast, parallel and automated purification of many oligonucleotide probes that was not possible before. In combination with the method of removal of tritylated failure fragments oligonucleotides were produced with purity superior to that of oligonucleotides purified using RP HPLC. In the second part of the present study a method of solid-phase RNA synthesis using 2´-tert-butyldithiomethyl (2´-O-DTM) is discussed. The stability of the DTM group during oligonucleotide assembly and deprotection in ammonia, together with its ability for rapid deprotection under mild conditions, allowed the synthesis of RNA with the quality similar to that of synthetic DNA oligonucleotides. The advantage of the 2´-O-DTM group is that it is completely orthogonal to all protecting groups used for the traditional solid-phase DNA synthesis. Therefore, the synthesis can be performed using a standard DNA synthesis procedure – no changes are needed for the product assembly. RNA oligonucleotides synthesized with retained 5´-terminal trityl group can be subjected to a cartridge-based purification using the procedure described in the first part of the study. The phosphoramidite synthesis was optimized for a large scale preparation and gives versatility for introduction of other alkyldithiomethyl groups according to the preference to their certain properties. The third part of the thesis describes the synthesis of a dithiomethyl linker and its utility for reversible conjugation of oligonucleotides. A dithiomethyl group, cleavable under mild conditions, was introduced onto 3´-OH of tritylated nucleosides via 3´-O-methylthiomethyl derivatives. The influence of different alkyl substituents on the disulfide bond stability was investigated, and stable analogues were employed in oligosyntheses. Two applications were developed using the present linker: 1) purification of oligonucleotides linked to the solid support; and 2) cartridge-based purification of tritylated oligonucleotides having an additional hydrophobic group on their 3´- terminus.

[ES] El espectro de la luz solar está compuesto por una amplia gama de radiaciones electromagnéticas las cuales tienen diferentes impactos sobre la vida en la tierra. Entre ellas, las pertenecientes a la región ultravioleta toman un papel principal cuando nos referimos a la fotobiología, ya que pueden interactuar con las biomoléculas por medio de procesos tanto directos como fotosensibilizados. Como resultado, estas biomoléculas pueden sufrir modificaciones que no siempre tienen efectos beneficiosos. En este contexto, los daños fotoinducidos al ADN son de gran relevancia ya que están estrechamente relacionados con la creciente incidencia de cáncer de piel. Por ello, es necesario investigar tanto los mecanismos involucrados en dichos procesos como el desarrollo de nuevas estrategias para combatirlos. En la presente tesis se da respuesta a estas necesidades mediante el desarrollo y empleo de grupos protectores fotolábiles (PPG). En una primera parte se avanza en el desarrollo de nuevos PPG basados en filtros solares. Estos ofrecen la ventaja de actuar, una vez liberados, como un escudo protector frente a la radiación ultravioleta. En este contexto, en el Capítulo 3 se profundiza en las propiedades fotofísicas y fotoquímicas de los sistemas formados por la avobenzona como PPG de ácidos carboxílicos, más concretamente del ketoprofeno (KP) y del naproxeno (NPX). En este estudio se analiza por medio de modelado molecular y técnicas espectroscópicas la influencia que tiene la energía relativa del triplete de la avobenzona en su forma dicetónica, 3AB(K)*, respecto a la de los compuestos protegidos en el proceso de liberación. Siguiendo en esta misma línea de trabajo, en el Capítulo 4 se ha desarrollado un nuevo PPG capaz de liberar el filtro solar oxibenzona (OB) junto con compuestos carbonílicos. En una segunda parte, el foco de atención se ha puesto en el concepto de "Caballo de Troya", el cual establece que ciertas lesiones del ADN pueden actuar a su vez como fotosensibilizadores endógenos generando así nuevas lesiones en su entorno. En este contexto, en el Capítulo 5 se han estudiado, mediante métodos tanto experimentales como teóricos, las propiedades fotosensibilizantes de dos de los daños oxidativos del ADN, el 5-formiluracilo (ForU) y la 5-formilcitosina (ForC), poniendo especial énfasis en la capacidad de estos para poblar sus estados tripletes, así como de inducir la formación fotosensibilizada de dímeros ciclobutánicos de pirimidina (CPD). Por último, en el Capítulo 6 se ha desarrollado una nueva alternativa sintética para la incorporación del ForU en oligonucleótidos. Debido a la inestabilidad del grupo aldehído, esta síntesis se lleva a cabo generalmente mediante la incorporación de un precursor el cual es posteriormente convertido en el ForU mediante la acción de un agente oxidante. Por el contrario, en la nueva alternativa planteada el aldehído es protegido con un PPG, de manera que una vez insertado en el ODN, el aldehído es liberado de forma selectiva mediante el empleo de luz. Este trabajo supone un avance en el estudio de las propiedades fotosensibilizantes del ForU ofreciendo una nueva herramienta para la evaluación de las mismas en un entorno más cercano al del ADN. / [CA] L'espectre de la llum solar està compost per una àmplia gamma de radiacions electromagnètiques les quals tenen diferents impactes sobre la vida en la terra. Entre elles, les pertanyents a la regió ultraviolada prenen un paper principal quan ens referim a la fotobiologia, ja que poden interactuar amb les biomolècules per mitjà de processos tant directes com fotosensibilitzats. Com a resultat, aquestes biomolècules poden patir modificacions que no sempre tenen efectes beneficiosos. En este context, els danys fotoinduits a l'ADN són de gran rellevància ja que estan estretament relacionats amb la creixent incidència de càncer de pell. Per això, és necessari tant d'investigar els mecanismes involucrats en els processos com el desenvolupament de noves estratègies per a combatre'ls. En la present tesi es dóna resposta a aquestes necessitats per mitjà del desenvolupament i ús de grups protectors fotolàbils (PPG). En una primera part s'avança en el desenvolupament de nous PPG basats en filtres solars. Estos ofereixen l'avantatge d'actuar, una vegada alliberats, com un escut protector enfront de la radiació ultraviolada. En este context, en el capítol 3 s'aprofundeix en les propietats fotofísiques i fotoquímiques dels sistemes formats per l'avobenzona com PPG d'àcids carboxílics, més concretament del ketoprofé (KP) i del naproxé (NPX). En este estudi s'analitza per mitjà de modelatge molecular i tècniques espectroscòpiques la influència que té en el procés d'alliberament l'energia relativa del triplet de l'avobenzona en la seua forma dicetònica, 3AB(K)*, respecte a la dels compostos protegits. En esta mateixa línia de treball, en el capítol 4 s'ha desenvolupat un nou PPG capaç d'alliberar el filtre solar oxibenzona (OB) junt amb compostos carbonílics. En una segona part, el focus d'atenció s'ha posat en el concepte de "Cavall de Troia", el qual estableix que certes lesions de l'ADN poden actuar al seu torn com fotosensibilitzadors endògens generant així noves lesions en el seu entorn. En este context, en el capítol 5 s'han estudiat, per mitjà de mètodes tant experimentals com teòrics, les propietats fotosensibilitzants de dos dels danys oxidatius de l'ADN, el 5-formiluracil (ForU) i la 5-formilcitosina (ForC), posant especial èmfasi tant en la capacitat d'estos per a poblar els seus estats triplet, com d'induir la formació fotosensibilitzada de dímers ciclobutànics de pirimidina (CPD). Finalment, en el capítol 6 s'ha desenvolupat una nova alternativa sintètica per a la incorporació del ForU en oligonucleòtids. A causa de la inestabilitat del grup aldehid, esta síntesi es duu a terme generalment per mitjà de la incorporació d'un precursor el qual és posteriorment convertit en el ForU per mitjà de l'acció d'un agent oxidant. Al contrari, en la nova alternativa plantejada l'aldehid és protegit amb un PPG, de manera que una vegada inserit en l'oligonucleòtid, l'aldehid és alliberat de forma selectiva per mitjà de l'ús de llum. Este treball suposa un avanç en l'estudi de les propietats fotosensibilitzants del ForU i ofereix una nova ferramenta per a l'avaluació de les mateixes en un entorn més pròxim al de l'ADN. / [EN] The solar spectrum is composed of a wide range of electromagnetic radiations which have different impacts on life on earth. Among them, those belonging to the ultraviolet region are of utmost importance when we refer to photobiology, since they can interact with biomolecules through both direct and photosensitized processes. As a result, these biomolecules can undergo modifications that do not always have beneficial effects. In this context, photoinduced DNA damage is of great relevance as it is closely related to the increasing incidence of skin cancer. Therefore, it is necessary both to investigate the mechanisms involved in these processes and to develop new strategies to avoid them. In this Thesis these issues have been addressed through the development and use of photolabile protecting groups (PPG). The first part of this Thesis involves the development of new PPG based on solar filters. Once released, these PPG offer the advantage of acting as ultraviolet shields. In this context, Chapter 3 looks into the photophysical and photochemical properties of those systems formed by avobenzone as PPG of carboxylic acids, more specifically ketoprofen (KP) and naproxen (NPX). In this study, the influence on the photorelease process of the relative energetic location of the avobenzone triplet manifold in its diketo form, 3AB(K)*, with respect to that of its caged compound, is duly analyzed by means of molecular modeling and spectroscopic techniques. Following this same line of work, a new PPG capable of releasing oxybenzone (OB) solar filter along with carbonyl compounds has been developed in Chapter 4. The second part of this Thesis focuses on the "Trojan Horse" concept, which establishes that certain DNA lesions can act as endogenous photosensitizers, thus generating new lesions in their neighborhood. In this context, in Chapter 5 the photosensitizing properties of two oxidatively generated DNA damages, namely 5-formyluracil (ForU) and 5-formylcytosine (ForC), have been studied by means of experimental and theoretical approaches. Here, special emphasis has been placed on unraveling their capacity to photoinduce the formation of cyclobutane pyrimidine dimers (CPD). Finally, in Chapter 6 a new synthetic alternative for the incorporation of ForU into oligodeoxynucleotides (ODN) has been developed. Due to the instability of the aldehyde group, this synthesis is generally carried out by incorporating a precursor which is subsequently converted into ForU by the action of an oxidative agent. On the contrary, in the new approach, the aldehyde is protected with a PPG, so that once inserted into the ODN, the aldehyde is selectively released through the use of light. This work entails a step forward in the study of the photosensitizing properties of ForU, offering a new tool for their evaluation within the DNA environment. / Lineros Rosa, M. (2021). Photoremovable protecting groups for carbonyl compounds of biological interest [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/167764 / TESIS