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As propriedades das ligações do complexo com metal de transição Cu(II)-L-alanil-L-valina e do composto orgânico Taurina foram determinadas por difração de raios-X a alta resolução. A análise da densidade de carga foi feita com o modelo multipolar de Hansen-Coppens para o estudo topológico da densidade de carga e determinação de populações dos orbitais d do metal. Radiação síncrotron (0.394 Å) e temperatura de hélio vaporizado foram utilizados na coleta de dados de difração de raios-X do complexo metálico. Para o orbital dx2-y2, a população reduzida é descrita pelas zonas de fuga de carga com eixo de simetria 4 nos mapas de deformação estática da densidade e do Laplaciano. Os valores da densidade de carga e das curvaturas nos pontos críticos localizados nas ligações Cu-N e Cu-O, indicam o caráter não iônico dessas ligações. Foi desenvolvido um algoritmo para obter as orientações preferenciais dos orbitais d de metais de transição da primeira linha coordenados em sítios assimétricos. As cargas atômicas foram determinadas por integração da densidade no esquema de partição de átomos topológicos (basins). O estudo de densidade de carga da Taurina foi realizado com dados coletados no difratômetro KappaCCD, usando radiação K\'alfa\' -Mo à temperatura de N2 vaporizado e dados de nêutrons obtidas na literatura. Propriedades topológicas de \'rô\' (\'VET.r\') foram calculadas do modelo. Os valores dos monopólos são comparados com cargas calculadas pela integração de \'rô\' (\'VET.r\') dentro de basins e determinadas por cálculos ab initio. / The bonding properties of the transition metal complex Cu(I1)-L-alanyl-L-valine and the Taurine compound have been determined by high resolution x-ray diffraction. The charge density analysis is performed using the Hansen-Coppens multipole model for both, the topological study of the electron density p(f) and the orbital population\'s analysis of the transition metal. Short wavelength synchrotron radiation (0.394 \'angstrom\') and vaporized helium temperature were used in the x-ray diffraction data collection of the metal complex. For the dx2-y2 orbital, the half population obtained is shown by the 4-fold depletion region in the static deformation and negative Laplacian maps. Values of the charge density and its curvature in the critica1 points located at the Cu-N and Cu-O bonds show the non-ionic character of these interactions. We have derived an algorithm to perform preferencial orientation search for the first row transition metal d-orbitals in non-symmetric sites. Atomic charge integration was carried out applying topological atoms partitioning (basins). The charge density of Taurine has been studied with data collected with a KappaCCD diffractometer using K\'alfa\'-Mo radiation at vaporized N2 temperature and neutron diffraction data obtained from the literature. Topological properties of \'rô\' (\'VET.r\') were calculated from the fitted model. Atomic charges given by the monopole parameters have been compared with those obtained by integration of the atomic basins and theoretical molecular calculations.

A bioatividade de complexos metálicos é de grande interesse atual na área de pesquisa de novos medicamentos. Fármacos anti-inflamatórios não-esteróides (FAINEs) são amplamente consumidos para o tratamento de doenças inflamatórias e de dor, mas seu contínuo uso pode ocasionar sérios efeitos colaterais ao trato gastrointestinal (TGI). Metalofármacos alternativos de Cu-FAINEs causam menores danos ao TGI, sem perder a atividade anti-inflamatória. No entanto, alguns destes são pouco solúveis. Adicionalmente, o desenvolvimento de materiais híbridos de FAINEs/polímeros para liberação modificada dos fármacos é interessante do ponto de vista de se aumentar a eficácia terapêutica e minimizar problemas de toxicidade. O objetivo deste trabalho foi investigar metodologia, com emprego de secagem via spray-dryer, para a preparação de materiais híbridos contendo complexos de cobre(II) com os fármacos naproxeno e sulindaco incorporados em acetato de celulose. Dois tipos de materiais híbridos foram obtidos para cada metalofármaco: CuFAINE/AC e CuFAINE/AC/OM, sendo o segundo preparado em presença de óleo mineral (OM). A caracterização destes produtos foi efetuada por análises elementares, espectroscopia vibracional no infravermelho, difratometria de raios X, análise termogravimétrica acoplada a espectrômetro de massas, ressonância paramagnética eletrônica, microscopia eletrônica de varredura e espalhamento de luz dinâmico. Os métodos utilizados levaram à interação dos metalofármacos de CuFAINEs com a matriz polimérica biocompatível de acetato de celulose, gerando materiais híbridos bioinorgânicos-orgânicos. Duas espécies de CuFAINEs: uma dimérica mantendo a estrutura original ([Cu2(FAINE)4(Laxial)2]) e outra monomérica - provavelmente do tipo ([Cu(FAINE)2(Laxial)2]) - foram identificadas nestes materiais. As partículas apresentaram tamanho nanométrico. Os resultados aqui obtidos abrem novas perspectivas para futuros estudos que visem à investigação da viabilidade de usar sistemas como estes para liberação mofidicada dos metalofármacos de CuFAINEs / The bioactivity of metal complexes has current and high interest in the field of development of new drugs. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely consumed to treat inflammatory diseases and pain. The continuous use of these drugs causes serious side-effects on the gastrointestinal tract (GT). Alternative copper(II)-metallodrugs (CuNSAIDs) show lower GT side-effects without loss of anti-inflammatory activity. However, some of them are poorly water-soluble. In addition, the development of NSAID/biocompatible polymeric hybrid materials for modified-release of pharmaceuticals is of interest to increase therapeutic efficacy and to lower toxicity of drugs. The aim of this work was to investigate a methodology adding the use of spray-drying technique to prepare hybrid materials containing copper(II) complexes with naproxen and sulindac drugs incorporated into cellulose acetate (CA). Two different materials were obtained for each metallodrug: CuNSAID/CA and CuNSAID/CA/MO, being the second one prepared in the presence of mineral oil (MO). The characterization of these products was conducted by elemental analysis, vibrational spectroscopy, powder x-ray diffraction, thermogravimetric analysis coupled to mass spectrometry, electron paramagnetic resonance, scanning electron microscopy and dynamic light scattering. The developed methodologies led to the interaction between the CuNSAIDs and the polymeric matrix generating bioinorganic-organic hybrid materials. Two CuNSAIDs species: a dimeric one that kept the complex original structure [Cu2(FAINE)4(Laxial)2] and a monomeric species, ([Cu(FAINE)2(Laxial)2] were identified in these materials. The particles have shown nanometric size. The obtained results open up new perspectives for future studies with the aim of investigating the availability of using this type of system for modified release of CuNSAIDs metallodrugs.

A bioatividade de complexos metálicos é de grande interesse atual na área de pesquisa de novos medicamentos. Fármacos anti-inflamatórios não-esteróides (FAINEs) são amplamente consumidos para o tratamento de doenças inflamatórias e de dor, mas seu contínuo uso pode ocasionar sérios efeitos colaterais ao trato gastrointestinal (TGI). Metalofármacos alternativos de Cu-FAINEs causam menores danos ao TGI, sem perder a atividade anti-inflamatória. No entanto, alguns destes são pouco solúveis. Adicionalmente, o desenvolvimento de materiais híbridos de FAINEs/polímeros para liberação modificada dos fármacos é interessante do ponto de vista de se aumentar a eficácia terapêutica e minimizar problemas de toxicidade. O objetivo deste trabalho foi investigar metodologia, com emprego de secagem via spray-dryer, para a preparação de materiais híbridos contendo complexos de cobre(II) com os fármacos naproxeno e sulindaco incorporados em acetato de celulose. Dois tipos de materiais híbridos foram obtidos para cada metalofármaco: CuFAINE/AC e CuFAINE/AC/OM, sendo o segundo preparado em presença de óleo mineral (OM). A caracterização destes produtos foi efetuada por análises elementares, espectroscopia vibracional no infravermelho, difratometria de raios X, análise termogravimétrica acoplada a espectrômetro de massas, ressonância paramagnética eletrônica, microscopia eletrônica de varredura e espalhamento de luz dinâmico. Os métodos utilizados levaram à interação dos metalofármacos de CuFAINEs com a matriz polimérica biocompatível de acetato de celulose, gerando materiais híbridos bioinorgânicos-orgânicos. Duas espécies de CuFAINEs: uma dimérica mantendo a estrutura original ([Cu2(FAINE)4(Laxial)2]) e outra monomérica - provavelmente do tipo ([Cu(FAINE)2(Laxial)2]) - foram identificadas nestes materiais. As partículas apresentaram tamanho nanométrico. Os resultados aqui obtidos abrem novas perspectivas para futuros estudos que visem à investigação da viabilidade de usar sistemas como estes para liberação mofidicada dos metalofármacos de CuFAINEs / The bioactivity of metal complexes has current and high interest in the field of development of new drugs. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely consumed to treat inflammatory diseases and pain. The continuous use of these drugs causes serious side-effects on the gastrointestinal tract (GT). Alternative copper(II)-metallodrugs (CuNSAIDs) show lower GT side-effects without loss of anti-inflammatory activity. However, some of them are poorly water-soluble. In addition, the development of NSAID/biocompatible polymeric hybrid materials for modified-release of pharmaceuticals is of interest to increase therapeutic efficacy and to lower toxicity of drugs. The aim of this work was to investigate a methodology adding the use of spray-drying technique to prepare hybrid materials containing copper(II) complexes with naproxen and sulindac drugs incorporated into cellulose acetate (CA). Two different materials were obtained for each metallodrug: CuNSAID/CA and CuNSAID/CA/MO, being the second one prepared in the presence of mineral oil (MO). The characterization of these products was conducted by elemental analysis, vibrational spectroscopy, powder x-ray diffraction, thermogravimetric analysis coupled to mass spectrometry, electron paramagnetic resonance, scanning electron microscopy and dynamic light scattering. The developed methodologies led to the interaction between the CuNSAIDs and the polymeric matrix generating bioinorganic-organic hybrid materials. Two CuNSAIDs species: a dimeric one that kept the complex original structure [Cu2(FAINE)4(Laxial)2] and a monomeric species, ([Cu(FAINE)2(Laxial)2] were identified in these materials. The particles have shown nanometric size. The obtained results open up new perspectives for future studies with the aim of investigating the availability of using this type of system for modified release of CuNSAIDs metallodrugs.

Η εργασία αυτή αποτελεί τη διπλωματική εργασία που εκπονήθηκε στα πλαίσια του διατμηματικού μεταπτυχιακού προγράμματος “Ιατρική Χηµεία: Σχεδιασμός και Ανάπτυξη Φαρμακευτικών Προϊόντων” του Πανεπιστημίου Πατρών. Στη φύση, η καταλυτική οξείδωση οργανικών μορίων με υψηλή εκλεκτικότητα αποτελεί σημαντικό εργαλείο στη σύνθεση πολύπλοκων φυσικών προϊόντων και επιτυγχάνεται με εξειδικευμένα ένζυμα που έχουν ως βάση κυρίως το χαλκό και το σίδηρο. Αντικείμενο της εργασίας ήταν ο σχεδιασμός και ανάπτυξη πρωτότυπων καταλυτικών συστημάτων οξείδωσης αλειφατικών δεσμών C-H με βάση τον χαλκό που εν δυνάμει προσομοιάζουν τη λειτουργία των βιολογικών συστημάτων. Εξετάστηκε μεθοδικά η σχέση χαλκού-υποκαταστάτη με τις συνθήκες της αντίδρασης σε συνάρτηση με την τόπο-και χημειοεκλεκτικότητα της αντίδρασης. Τα βέλτιστα αποτελέσματα απόδοσης και εκλεκτικότητας στην οξείδωση του κυκλοεξανίου επιτυγχάνονται σε διαλύτη ακετονιτρίλιο ή ακετόνη με νιτρικό ή τριφλικό δισθενή χαλκό σε συνδυασμό με 1,10-φαινανθρολίνη ή 4-άμινο τριαζόλη. Συγκεκριμένα επετεύχθησαν αποδόσεις 25-35% και εκλεκτικότητες Α/Κ 13-32:1. Παράλληλα έγινε σύγκριση με τα state-of-the-art συστήματα που αναφέρονται στη σύγχρονη βιβλιογραφία. Οι εκλεκτικότητες που επετεύχθησαν σε αυτήν την έρευνα είναι οι υψηλότερες που έχουν αναφερθεί όχι μόνο για συστήματα με βάση το χαλκό αλλά και με άλλα μέταλλα. Αντίθετα, τα καταλυτικά αυτά συστήματα δεν φαίνεται να είναι αποτελεσματικά στις οξειδώσεις αλλυλικών και βενζυλικών δεσμών C-H. / This work is the final year’s thesis of the inter-departmental postgraduate program “Medicinal Chemistryː Design and Development of Pharmaceutical Products” of the University of Patras. Nature uses catalytic selective oxidation of C-H bonds in order to construct complex natural products by utilizing specialized enzymes mainly based on copper or iron. The aim of the work is the design and development of novel copper-based catalytic systems capable of C-H oxidation that could mimic the performance of the biological systems. The investigation focused on the interrelationships/dependencies between the type of copper ion and ligand with the reaction conditions in relation to the observed regio- and chemoselectivity. In the oxidation of cyclohexane the best results for yield and chemoselectivity were achieved using 1,10-phenanthroline or 4-amino-1,2,4-triazole as ligands, copper (II) triflate or nitrate as metal sources and acetone or acetonitrile as solvents. Reaction yields of 25-35% and A/K ratios of 13-32 : 1 where achieved and a comparison with state-of-the-art systems from the recent literature was also made. The A/K ratios obtained in this work are the highest reported not only for copper based systems but also for other metals. In contrast, these systems showed no catalytic activity with the weaker allylic or benzylic C-H bonds.

[pt] Norfloxacina (NFX) é um antibiótico fluorescente de amplo espectro bacteriológico, membro da família das fluorquinolonas (FQs). A interação das FQs com íons metálicos pode incrementar a ação bactericida e agir contra a resistência das bactérias frente aos antibióticos. Diversos exemplos de complexos mistos de norfloxacina e Cu(II) podem ser encontrados na literatura. A compreensão dos mecanismos moleculares de interação desses antibióticos com os diferentes componentes das células e com nanopartículas de ouro, como transportadores do fármaco, é extremamente importante. Para entender essas interações, neste trabalho utilizamos diferentes técnicas espectroscópicas, como espectroscopia de fluorescência estacionária e resolvida no tempo, absorção de luz UV-Visível e ressonância paramagnética eletrônica (RPE). A interação de NFX e do complexo ternário Cu(II):L:NFX, onde o ligante L é a 1,10-fenantrolina (Phen) ou 2,2-bipiridina (Bipy), com micelas e lipossomas unilamelares pequenos de fosfatidilcolina de ovo (PC) foi estudada usando espectroscopia de fluorescência em estado estacionário e resolvida no tempo. Foi estudada a estabilidade dos complexos ternários formados em micelas. Foram obtidas constantes de estabilidade no interior de micelas de SDS, as quais mostraram valores muito maiores do que em tampão. Já os espectros de RPE deram maiores detalhes sobre a estrutura dos complexos e confirmaram a formação do complexo ternário dentro das micelas. Foram estudadas as interações de FQs e seus complexos de cobre com lipossomas de PC preparados com diferentes densidades superficiais de carga elétrica negativa. No estudo da interação de FQs com nanopartículas de ouro sintetizadas por ablação a laser (nanocompósitos, AuNCs), NFX mostrou maiores mudanças, tanto na absorbância como na fluorescência, do que as FQs ciprofloxacina (CFX) e levofloxacina (LFX). Os resultados sugerem mudanças no índice de refração na superfície dos AuNCs, por associação com o fármaco e/ou formação de aglomerados como resultado da interação. Observou-se também uma supressão lenta, porém significativa, na fluorescência da NFX, sem mudança na posição do pico, indicando que NFX mantém o seu estado inicial de protonação ligando-se à superfície dos AuNCs. Também foi observada a liberação de FQs ligadas à superfície de AuNPs mediante substituição por tióis, que ocasiona recuperação parcial da fluorescência da fluorquinolona. Por último, como o surfactante aniônico SDS se mostrou promissor na interação com NFX, em comparação com surfactantes catiônicos e neutros, e como os AuNCs são estáveis em SDS, estudamos a interação de NFX com AuNCs sintetizados em presença de SDS e, para comparação, com AuNCs colocados em solução de SDS após a síntese. / [en] Norfloxacin (NFX) is a fluorescent antibiotic of broad bacteriological spectrum, member of the fluoroquinolone (FQ) family. The interaction of FQs with metal ions can increase the bactericidal action and act against antibiotics bacterial resistance. Several examples of mixed-ligand norfloxacin Cu (II) complexes can be found in the literature. Understanding the molecular mechanisms of interaction of these antibiotics with different cell components and with gold nanoparticles as drug transporters is extremely important. To clarify these interactions, we used different spectroscopic techniques, such as steady-state and time-resolved fluorescence spectroscopy, UV-Visible light absorption, and electron paramagnetic resonance (EPR). The interaction of NFX and the ternary complex Cu(II):L:NFX, where the L is the ligand 1,10-phenanthroline (Phen) or 2,2-bipyridine (Bipy), with micelles and small unilamellar liposomes of egg phosphatidylcholine (PC) was studied using steady-state and time-resolved fluorescence spectroscopy. The stability of the ternary complexes formed in micelles was studied, and stability constants were obtained inside SDS micelles, which showed values much larger than in buffer. The EPR spectra gave further details on the structure of the complexes, and confirmed the formation of the ternary complex inside the micelles. The interactions of FQs and their copper complexes with PC liposomes prepared with different surface densities of negative electrical charge were studied. In the study of the interaction of FQs with gold nanoparticles synthesized by laser ablation (nanocomposites, AuNCs), NFX showed greater changes than FQs ciprofloxacin (CFX) and levofloxacin (LFX) in both absorbance and fluorescence. The results suggest changes in the surface refractive index of the AuNCs and/or cluster formation, as result of the interaction with the drug. A slow but significant quenching of NFX fluorescence was also observed, with no change in peak position, indicating that NFX maintains its initial state of protonation by binding to the surface of the AuNCs. Release of FQs attached to the surface of AuNCs by thiols has also been observed, which causes partial recovery of FQ fluorescence. Finally, as the anionic surfactant SDS showed to be promising in the interaction with NFX, compared to cationic and neutral surfactants, and because the AuNCs are stable in SDS, we studied the interaction of NFX with AuNCs synthesized in the presence of SDS and, for comparison, with AuNCs placed in SDS solution after synthesis.

As propriedades das ligações do complexo com metal de transição Cu(II)-L-alanil-L-valina e do composto orgânico Taurina foram determinadas por difração de raios-X a alta resolução. A análise da densidade de carga foi feita com o modelo multipolar de Hansen-Coppens para o estudo topológico da densidade de carga e determinação de populações dos orbitais d do metal. Radiação síncrotron (0.394 Å) e temperatura de hélio vaporizado foram utilizados na coleta de dados de difração de raios-X do complexo metálico. Para o orbital dx2-y2, a população reduzida é descrita pelas zonas de fuga de carga com eixo de simetria 4 nos mapas de deformação estática da densidade e do Laplaciano. Os valores da densidade de carga e das curvaturas nos pontos críticos localizados nas ligações Cu-N e Cu-O, indicam o caráter não iônico dessas ligações. Foi desenvolvido um algoritmo para obter as orientações preferenciais dos orbitais d de metais de transição da primeira linha coordenados em sítios assimétricos. As cargas atômicas foram determinadas por integração da densidade no esquema de partição de átomos topológicos (basins). O estudo de densidade de carga da Taurina foi realizado com dados coletados no difratômetro KappaCCD, usando radiação K\'alfa\' -Mo à temperatura de N2 vaporizado e dados de nêutrons obtidas na literatura. Propriedades topológicas de \'rô\' (\'VET.r\') foram calculadas do modelo. Os valores dos monopólos são comparados com cargas calculadas pela integração de \'rô\' (\'VET.r\') dentro de basins e determinadas por cálculos ab initio. / The bonding properties of the transition metal complex Cu(I1)-L-alanyl-L-valine and the Taurine compound have been determined by high resolution x-ray diffraction. The charge density analysis is performed using the Hansen-Coppens multipole model for both, the topological study of the electron density p(f) and the orbital population\'s analysis of the transition metal. Short wavelength synchrotron radiation (0.394 \'angstrom\') and vaporized helium temperature were used in the x-ray diffraction data collection of the metal complex. For the dx2-y2 orbital, the half population obtained is shown by the 4-fold depletion region in the static deformation and negative Laplacian maps. Values of the charge density and its curvature in the critica1 points located at the Cu-N and Cu-O bonds show the non-ionic character of these interactions. We have derived an algorithm to perform preferencial orientation search for the first row transition metal d-orbitals in non-symmetric sites. Atomic charge integration was carried out applying topological atoms partitioning (basins). The charge density of Taurine has been studied with data collected with a KappaCCD diffractometer using K\'alfa\'-Mo radiation at vaporized N2 temperature and neutron diffraction data obtained from the literature. Topological properties of \'rô\' (\'VET.r\') were calculated from the fitted model. Atomic charges given by the monopole parameters have been compared with those obtained by integration of the atomic basins and theoretical molecular calculations.

Les travaux présentés dans cette thèse s’inscrivent dans une thématique de modification de surfaces par le biais de monocouches auto-assemblées post-fonctionnalisables. L’objectif principal consiste à élaborer une méthode générique de modification de monocouches par des motifs moléculaires variés. Pour cela, les travaux se concentrent sur la mise au point d’une plateforme générique facilement fonctionnalisable par un motif d’intérêt et greffable sur électrode modifiée. La voie retenue consiste à utiliser deux réactions de "click chemistry" de type "CuAAC". La première réaction de CuAAC s’effectue en solution et permet de solidariser plateforme et motifs d’intérêt (principalement des dérivés ferrocényles). Les ligands ainsi obtenus ont été utilisés pour la complexation d’ions métalliques (Cu2+, Zn2+). Les ligands et les complexes ont été étudiés en solution par électrochimie ainsi que par spectroscopies UV-Visibles et RPE. La seconde réaction de CuAAC permet l’immobilisation des différents complexes de cuivre sur des électrodes pré-modifiées par des fonctions azoture, généralement à l’aide de monocouches auto-assemblées. Ce greffage s’effectue selon le mode opératoire de l’"électroclick auto-induite", c'est-à-dire que le complexe de cuivre à immobiliser est également catalyseur de la réaction de CuAAC. Les systèmes ainsi immobilisés (mono-, bi- ou tri-métalliques) ont pu être étudiés en terme de cinétique d’immobilisation, de cinétique de transfert d’électrons et en réactivité. Ce dernier point a par ailleurs fait l’objet d’une attention particulière pour le cas de la réduction électro-catalytique des ions nitrite par les complexes de cuivre (I), en solution et sur surface. / This work depends on functionalized surface theme using modification of selfassembled monolayers (SAMs). The main objective consists to elaborate a new general pathway to modify monolayers with miscellaneous objects of interest. For this, we decide to focus our work to synthesize a versatile platform handling two ethynyl arms. These functions are available to operate two CuAAC reactions. The first one is use for linking platform with object of interest (in general ferrocenyl derivatives). Ligands obtained by that way were used for complexation of Cu2+ and Zn2+ ions. Electrochemical and spectroscopic (UV-Visible and EPR) studies were performed on these compounds. The second CuAAC reaction is used to immobilize copper complexes on azide modified electrode (azide derivatives SAMs on gold and ITO or direct functionnalization of glassy carbon surface). The grafting is operating through “self-induced electroclick” method; this means the CuAAC reaction is catalysed by the copper complex which is immobilized. Functionalized electrodes were characterized by cyclic voltammetry. It appears that similar complexes have closed grafting kinetic. These studies also demonstrate the both influence of copper and spacer on a second electroactive site (ferrocene moieties). The reactivity of copper centre is evaluated for complexes in solution and immobilized on surface with electrocatalytic reduction of nitrite ions by copper (I) species. The catalytic efficiency strongly depends on potential of copper reduction. Also, similar complexes show a loss of catalytic power with immobilization on surface.

Photodynamic therapy (PDT) is a non-invasive treatment of cancer with an advantage of having localized photo-activation of the drug at the targeted tumor cells leaving the healthy cells unaffected by the photo-toxicity of the PDT agent. Organic molecules and 4d/5d metal complexes have been extensively studied for their DNA cleavage activity and photo-cytotoxicity in UV and/or visible light. The photoactivity of the current PDT drugs is due to reactive singlet oxygen species. To address the hypoxic nature within neoplasia and to get a realistic scenario to build model and potent PDT agents, attempts have been made in this thesis work to design and synthesize new cobalt and copper complexes having a variety of ancillary ligands and planar phenanthroline bases showing efficient visible light-induced anaerobic plasmid DNA cleavage activity. The disulfide and thiol compounds are known to generate thyil radical in anaerobic medium in presence of some electron donating solvent. To exploit this chemistry of the sulfur anion radical as a reactive species damaging DNA under light irradiation, we have prepared copper(II) complexes of bis(2-hydroxybenzylamino-ethyl)disulfide and D-penicillaminedisulfide and characterized. The complexes are moderate binders to calf thymus DNA and exhibit plasmid DNA cleavage activity in red light. Near-IR light-induced double-strand DNA cleavage activity is observed for the complexes having 3,3' -dithiodipropionic acid and phenanthroline bases. These complexes show lethal double strand breaks in SC DNA responsible for the inhibition in DNA repair mechanism in the cells thus becoming potent candidates as transcription inhibitors. The work has been extended to achieve better visible light-induced plasmid DNA cleavage activity and UV light-induced photocytotoxicity using a more bio-compatible metal ion, viz. cobalt(II) with the same ligand system and enhancement in the photocytotoxicity is observed. To investigate the role of the disulfide ancillary ligands, complexes of salicylideneaminothiophenol bound to the copper(II) are prepared and the complexes show significant plasmid DNA cleavage activity in red light. Finally, ternary cobalt(III) phenanthroline base complexes are prepared to study their DNA cleavage activity in red light and photo-cytotoxicity in UV light. The complexes show efficient plasmid DNA cleavage activity in red light, significant cytotoxicity in UV light, low dark cytotoxicity, and protein (BSA, lysozyme) cleavage activity in UV light. The mechanistic aspects of the photo-induced DNA and protein cleavage activity of the complexes have been studied. A dual involvement of the charge transfer and d-d band is observed in the photosensitization process leading to generation of reactive oxygen species. In summary, the thesis work presents cobalt and copper complexes having thiolate and disulfide moieties that are designed and synthesized as new photodynamic therapeutic agents showing anaerobic DNA cleavage activity in red light and photocytotoxicity. The present study opens up new strategies for designing and developing cobalt and copper based photosensitizers for their potential photochemotherapeutic applications under hypoxic reaction conditions. References: Lahiri, D. et al., J Chern. Sci, 2010, 122, 321-333; Inorg. Chern., 2009, 48, 339-349; Dalton Trans. 2010,39,1807-1816; Polyhedron, 2010, 29, 2417-2425.

The synthesis of metal-redox active ligand complexes is described, along with reactivity studies aimed at facilitating novel C-N bond forming reactions. A copper bis(iminosemiquinone) structure is characterized, analyzed and its reduction series are characterized and the reactivity of the Cu(II) bis(amidophenolate) analog is investigated with tosyl azide. The identification of the major reaction product and its characterization is detailed, with reaction sensitivities and heavily distorted x-ray diffraction single crystal structure generating a complex data set. The characterization of the isolated product is ongoing, with EPR studies aimed at identifying the radical nature of the complex. Unusual solvent effects and solubility issues have been noted with these initial EPR studies and more data is necessary before analysis can be properly attempted. An ytterbium bis(amidophenolate) complex was synthesized and its reactivity studied with aryl azides. Initial reactivities generate the first documented lanthanide tetrazenes in-lieu of the targeted ytterbium imido. Reactivities and characterization of these complexes support a stable, heavily ionic tetrazene-metal complex with no observed redox nature, UV light sensitivities, or imido azide-tetrazene equilibrium observed in various tetrazene transition metal complexes. Synthesis of a sterically blocked ytterbium imido was attempted, utilizing DMAP. Initial isolation was achieved with characterization and reactivity studies supporting the imido nature of the complex. The weak coordinating of the DMAP provided instability that proved in opposition to crystallization, however, so the imido could not be confirmed. Initial reactions using alternative steric hinderance from triphenylphosphine oxide and pyridine N-oxide prove promising to increasing the stability of the presumed ytterbium imido. Organic synthesis was performed generating a potential antibacterial agent. The synthesis of cyclopropenes was initiated as antagonists for ETR proteins in fruits and plants. The intermediates proved highly sensitive to harsh chemical conditions, which was overcome utilizing a tin-mediated Barbier allylation. The cyclopropene alcohol synthon was synthesized, though protecting group optimization is necessary.