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With the advent of photoredox catalysis, new synthetic paradigms have been established with increasing numbers of novel transformations being achieved. Nevertheless, modern photoredox chemistry has several drawbacks in efficiency, scalability, and light penetration. In this dissertation, we document developments in photoredox catalysis that harvest red light (600- 800 nm) and demonstrate its applications in polymer science and chemical biology. First, a method towards the red-light activation and control of olefin metathesis will be discussed. This system employs a mixed, bis-N-heterocyclic carbene coordinated ruthenium indenylidene complex in conjunction with an osmium(II) complex under red light irradiation. Mechanistic investigation suggests a reduction of a cationic Ru species, to lead to the active metathesis species. Expectedly, polymerization through barriers is achieved with red light only. Material penetration, including mammalian tissue, and limited photocytotoxicity brings red light photoredox catalysis in the forefront of biological applications such as photoproximity labeling. This proceeds through the photocatalytic generation of reactive intermediates, the lifetimes of which dictate the spatial resolution of labeling. We thus describe a method to activate aryl(trifluoromethyl) diazos using an osmium(II) catalyst and red light, providing highly reactive, short-lived carbenes. The short lifetime of the carbene is highlighted by its ability to map small molecules to target proteins, a feat even nitrenes cannot achieve. Finally, efforts towards the synthesis of a wash-free fluorogenic photocatalyst with applications for intracellular red light photoproximity labeling will be described.

We investigated the electronic structure of the two nematic materials Sr₃Ru₂O₇ and Ca(Fe₀.₉₇Co₀.₀₃As)₂ using spectroscopic – imaging scanning tunneling microscopy (SI-STM) and angle resolved photoemission spectroscopy (ARPES). – – – Sr₃Ru₂O₇ is an itinerant metamagnet that shows a putative quantum critical endpoint at 8 Tesla, submersed by the formation of a nematic electronic phase. Using ARPES, we identified at least 5 Fermi pockets in agreement with quantum oscillation measurements. Surprisingly, we found Fermi velocities up to an order of magnitude lower than in single layer Sr₂RuO₄ and up to 35 times lower than predicted by ab initio calculations. Many bands are confined in an energy range of only ∼10 meV below the Fermi level. This, as well as distinct peak-dip-hump shapes of the spectra with a characteristic energy of around ∼5 meV indicate strong correlations and a possible nontrivial mechanism that is absent in single layer Sr₂RuO₄ and connected to the nematicity. The quasiparticle interference of one of the bands was detected by SI-STM, which was also used to measure subatomic features with the symmetries of the relevant Ru d orbitals. – – – In the second mate- rial, the iron-based high-temperature superconductor Ca(Fe[subscript(1-x)]Co[subscript(x)]As)₂, we discovered electronic nematic nano-pattern in its under-doped ‘parent’ state. We spectroscopically imaged this state in real space over large areas and across domain boundaries that change the directionality of the nano-pattern by 90°. We propose that oriented, dimer-shaped electronic nematogens are responsible for this pattern, in striking contrast to what has been expected and observed in electronic nematic materials. The dimers consist of two Gaussian conductance peaks separated by about 8 a[subscript(FeFe)]. Unidirectionality also shows in the quasiparticle interference pattern of the delocalized electrons. The dispersion is in agreement with scattering from the α₂ band discovered by ARPES but has distinct C₂ symmetry, not inconsistent with a C₄-symmetric band scattered by the proposed dimers.

This thesis describes the development of the [RuCl₂(P N N)L] catalytic system for asymmetric hydrogenation. It has been demonstrated that the current system is efficient in preparing a range of bulky chiral alcohols in good enantioselectivity, many of which are likely to be inaccessible using the more classic [RuCl₂(P P)N N)] system developed by Noyori and coworkers. It has been shown that the current system is tolerant of a range of substrate electronic effects as well as the presence of heteroaromatic functionality, thus showing its applicability in synthesis. This has been extended to prepare a number of bulky derivatives of synthetically important molecules. The demonstration of this is significant as in drug design, for example, studies that aim to extend lipophilicity or steric bulk make the ability to prepare alcohols across the full range of steric properties important. We have shown that chiral alcohols with adjacent gem-dimethyl groups can be prepared in high enantioselectivity and their conversion into other valuable molecules, such as chiral lactones has been demonstrated. Detailed mechanistic studies have been undertaken for the present system in order to aid rational design of new, more active and selective catalysts. A number of achiral variants of the original system have been prepared and the key features of ligand structure for efficient catalysis have been identified. This was accomplished by rigorous kinetic analysis of each complex, using specialist gas-uptake monitoring equipment. The key features of catalyst structure and optimal reaction conditions for efficient asymmetric hydrogenation have been identified. Our greater understanding of the present system allowed us to rationally design new catalysts of for enantioselective hydrogenation. Our aim was to be able to tune the catalyst structure to carry out hydrogenation of a greater variety of ketone substrate with high activity and selectivity. We have successfully prepared second generation catalysts that show enhanced enantioselectivity for a variety of substrates, many of which were problematic with the Noyori system.

Copper interconnect requires liner materials that function as a diffusion barrier, a seed layer for electroplating, and an adhesion promoting layer. Ruthenium has been considered as a promising liner material, however it has been reported that Ru itself is not an effective Cu diffusion barrier due to its microstructure, which is polycrystalline with columnar grains. The screening study of Ru precursors revealed that all Ru films were polycrystalline with columnar structure, and, due to its strong 3D growth mode, a conformal and ultrathin Ru film was difficult to form, especially on high aspect ratio features. The microstructure of Ru films can be modified by incorporating P. Amorphous Ru(P) films are formed by chemical vapor deposition at 575 K using a single source precursor, cis-RuH₂(P(CH₃)₃)₄, or dual sources, Ru₃(CO)₁₂ and P(CH₃)₃ or P(C6H5)₃ The films contain Ru and P, which are in zero-valent states, and C as an impurity. Phosphorus dominantly affects the film microstructure, and incorporating > 13% P resulted in amorphous Ru(P) films. Metastable Ru(P) remains amorphous after annealing at 675 K for 3 hr, and starts recrystallization at ~775 K. The density of states analysis of the amorphous Ru(P) alloy illustrates metallic character of the films, and hybridization between Ru 4d and P 3p orbitals, which contributes to stabilizing the amorphous structure. Co-dosing P(CH)₃ with Ru₃(CO)₁₂ improves film step coverage, and the most conformal Ru(P) film is obtained with cis-RuH2(P(CH₃)₃)₄; a fully continuous 5 nm Ru(P) film is formed within 1 µm deep, 8:1 aspect ratio trenches. First principles density functional theory calculations illustrate degraded Cu/Ru adhesion by the presence of P at the interface, however, due to the strong Ru-Cu bonds, amorphous Ru(P) forms a stronger interface with Cu than Ta and TaN do. Cu diffusion studies at 575 K suggests improved barrier property of amorphous Ru(P) films over polycrystalline PVD Ru.

N-heterocyclic carbenes (NHCs) have become a very popular class of ligands, which has found uses in numerous catalytic applications. The use of such compounds in combination with phosphorus-based ligands within metal complexes has enabled the design of very active yet robust catalytic systems. The following chapters will describe the design of novel well-defined palladium- and ruthenium-based pre-catalysts featuring a NHC and a phosphorus-based ligand, referred at as mixed ligand systems. Such species were employed in catalysis where their properties appeared highly beneficial, uses at low catalysts loading and under harsh conditions were then envisioned. The preparation of a series of well-defined palladium mixed NHC/phosphine species is presented in chapter 2. Their catalytic activity in the aqueous Suzuki-Miyaura reaction of aryl chlorides and boronic acids, using low catalyst loadings, is described. The observation of catalytic activity of the latter systems in the hydration of nitriles prompted us to further investigate this reactivity. This reaction appeared to be operative in the absence of palladium species and could be performed under base-catalysed conditions, which was studied in detail and depicted in chapter 3. The combination of a NHC and a phosphite ligand in ruthenium olefin metathesis pre-catalysts has been underexplored. Preliminary results showed that such species could be readily prepared and presented an unusual geometry and a high catalytic activity. Variations in phosphite-containing ruthenium olefin metathesis pre-catalysts are presented. Chapter 4 describes the investigation of various Schrock carbene moieties in such architectures, as well as their implications in structure and catalysis. Chapter 5 depicts attempts to design olefin metathesis Z-selective pre-catalysts by inserting a chelating NHC moiety within phosphite-containing ruthenium species. This dissertation concludes on the potential of such mixed species in catalysis, and armed with the new knowledge provided by this work, proposes potential developments of such chemistry in the design of always more robust and active catalytic systems.

No description available.

Made available in DSpace on 2015-07-22T20:50:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-11-25 / O melanoma é a forma mais agressiva de câncer de pele em virtude do elevado grau de proliferação, invasão e metástase das células tumorais. Menos de 10% dos pacientes com melanoma metastático sobrevivem por 5 anos. Quimioterapias com um único composto são bem toleradas, mas associadas a baixas taxas de resposta terapêutica. Associações de quimioterápicos já aprovados para uso humano também foram relacionadas a baixas taxas de resposta, sem redução da toxicidade. Logo, a identificação de novos agentes antitumorais é crítica para o tratamento do melanoma, e este trabalho buscou avaliar a atividade antitumoral de novos quimioterápicos derivados de paládio e rutênio no modelo pré-clínico de melanoma murino B16F10-Nex2. Um composto ciclopaladado, [Pd2(S(-)C2, N-dmpa)2 (μ-dppe)Cl2], denominado C7A, avaliado anteriormente pelo nosso grupo, demonstrou elevada atividade antitumoral e baixa toxicidade in vivo, porém, seu mecanismo de ação ainda não estava determinado. Neste trabalho demonstramos que este composto interage com grupos tiol presentes em proteínas da membrana mitocondrial, induzindo uma abrupta redução na acidificação extracelular, colapso do potencial de membrana mitocondrial e translocação da proteína Bax para o interior dessa organela. Evidenciamos também um aumento nas concentrações intracelulares de cálcio, proveniente de organelas celulares e do meio extracelular. Estes efeitos iniciais causaram ativação de caspases efetoras, condensação nuclear, degradação do DNA e dramáticas alterações morfológicas nessas células. Esses dados sugerem que C7A provoca uma morte celular por apoptose induzindo a via intrínseca em células de melanoma murino B16F10-Nex2. Observou-se que células tumorais humanas são sensíveis ao C7A, e o mecanismo de ação do composto nessas células parece ser idêntico ao observado em células murinas. O ciclopaladado 7A reduziu significativamente o número de nódulos pulmonares sem toxicidade aparente, indicando sua eficiência também contra tumores metastáticos. A atividade antitumoral de diversos compostos nitrosil-tetraamina-rutênio (trans-[RuII(NH3)4(L)NO+], onde L corresponde a diferentes ligantes de estabilização, e que são doadores de óxido nítrico (NO) em meios biológicos foi avaliada. Todos os compostos testados foram citotóxicos in vitro para células tumorais murinas e humanas. Alguns compostos foram selecionados e avaliados in vivo, mostrando uma elevada toxicidade em paralelo a uma atividade antitumoral. No entanto, observou-se que os compostos onde o NO havia sido substituído por um radical sulfato, utilizados como controles dos compostos doadores de NO, apresentaram elevada atividade antitumoral e baixa toxicidade in vivo, retardando o desenvolvimento do tumor subcutâneo e prolongando a sobrevida dos animais tratados. Os compostos sulfatados também apresentaram baixa toxicidade ao reduzir o número de nódulos metastáticos dos animais tratados. Esses compostos também foram citotóxicos in vitro para células tumorais humanas, e as alterações morfológicas, externalização de fosfatidilserina, condensação nuclear e degradação de DNA observados sugerem que os compostos tetraamina rutênio sulfatados levam a célula tumoral à morte por apoptose. Ambos os quimioterápicos testados abrem novas possibilidades para o tratamento do melanoma maligno. / Melanoma is the most aggressive form of skin cancer mainly because of the high degree of tumor cell proliferation, invasion and metastasis. Less than 10% of metastatic melanoma patients show 5 years survival. Single drug chemotherapy is well tolerated but associated with low response rates. Associations of chemotherapeutic agents approved for human use are related to low response rates, without improvement on side effects. Therefore, the identification of new antitumor agents is critical to melanoma treatment, and this study aimed to evaluate the antitumor effect of novel palladium and rutheniun derived chemotherapeutic drugs in the preclinical model of murine melanoma B16F10-Nex2. A cyclopalladated compound, [Pd2(S(-)C2, N-dmpa)2 (μ-dppe)Cl2], named C7A was previously evaluated by our group. The complex showed high antitumor and low toxicity in vivo, however, the targets for this compound in tumor cells were not determined yet. In this work we demonstrated that C7A interacts with thiol proteins present in the mitochondrial membrane, leading to an abrupt reduction of extracellular acidification, collapse of mitochondrial membrane potential and Bax translocation to the interior of this organelle. It was also observed an increase in intracellular calcium concentrations, originated from cellular organelles as well as from extracellular medium. These initial effects caused activation of effector caspases, nuclear condensation, DNA degradation and dramatic morphological changes in these cells. All these data suggests that the cyclopalladated 7A induces the intrinsic pathway apoptotic cell death on B16F10-Nex2 murine melanoma cells. Human tumor cells are sensitive to this compound and mitochondria also seem to be the target for C7A on these cells. Cyclopalladated 7A significantly reduced the number of pulmonary nodules with no apparent toxicity, indicating that this compound is also active against metastatic melanoma lesions. Antitumor activity of several nitrosyl tetraammine ruthenium compounds with general formula (trans-[RuII(NH3)4(L)NO+], where L corresponds to different stabilization ligands, were evaluated. These compounds are nitric oxide (NO) donors in biological media. All tested compounds were cytotoxic in vitro to human and murine tumor cells. Some compounds were selected and evaluated in vivo, showing numerous side effects in association with the antitumor effect. However, it was found that the compounds where the NO was replaced by a sulfate group, used regularly as a negative control for NO-donor ruthenium complexes, showed a pronounced antitumor activity and low toxicity in vivo, delaying subcutaneous tumor development and extending survival of treated animals. Sulfate compounds also reduced the number of metastatic lung nodules with no apparent toxicity. These compounds were also cytotoxic for human tumor cells in vitro, and the morphological alterations, phosphatidylserine externalization, nuclear condensation and DNA degradation observed after cell treatment suggested that sulfate tetraamine compounds induced an apoptotic cell death. Both evaluated chemotherapeutic drugs open new possibilities for malignant melanoma treatment. / TEDE / BV UNIFESP: Teses e dissertações

This thesis explores the design, synthesis and optoelectronic properties of supramolecular photoactive materials based on chiral iridium(III) and ruthenium(II) metalloligands. Our design strategies aim to create a high concentration of chromophoric units that, when self-assembled in well-defined geometrical arrangements, exhibit emergent photophysical properties.

Submitted by Cláudia Bueno (claudiamoura18@gmail.com) on 2016-01-15T13:24:17Z No. of bitstreams: 2 Tese - Patrícia Ferreira da Silva Castro - 2015.pdf: 4272048 bytes, checksum: bb8709720dbc4fb91db81ca23004d59d (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-01-18T08:44:08Z (GMT) No. of bitstreams: 2 Tese - Patrícia Ferreira da Silva Castro - 2015.pdf: 4272048 bytes, checksum: bb8709720dbc4fb91db81ca23004d59d (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-01-18T08:44:08Z (GMT). No. of bitstreams: 2 Tese - Patrícia Ferreira da Silva Castro - 2015.pdf: 4272048 bytes, checksum: bb8709720dbc4fb91db81ca23004d59d (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-03-26 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / Nitric oxide is a potent bronchodilator and compounds capable of increasing its supply have demonstrated clinical interest in the treatment of obstructive airways diseases. This study evaluated and compared the mechanisms of relaxation of two nitric oxide donors, ruthenium complex [Ru(terpy)(bdq)NO+]3+ (TERPY) and sodium nitroprusside (SNP) in healthy isolated trachea, Sham group, or experimental model of asthma induced by ovalbumin in rats, OVA group. The isolated trachea was sectioned into rings and contracted with carbachol in an organ chamber for studying relaxation. The relaxing effect of TERPY and SNP was evaluated at increasing concentrations from 10 nM to 100 μM. Thus, we verified the contribution of the different types of K+ channels, the importance of sGC/cGMP pathway, the inhibition of PDEs (for IBMX, amrinone, rolipram and dypiridamole), the influence of the extra and intracellular Ca2+ sources (for cyclopiazonic acid) and the influence of the store and voltage operated calcium channels. Besides inhibition of COX (diclofenac), antagonism of leukotriene receptor (montelukast) and superoxide anion scavenger (TIRON). Analyses were performed under light microscopy for evidence of inflammatory infiltration and bronchoditation by TERPY in slices bronchioles of asthmatic animals. The results verified that sensitization with ovalbumin led to intense inflammatory process and hyperresponsives to carbachol in compared Sham group. TERPY and SNP led to the relaxation of tracheal smooth muscle preparations in a dependent-concentration mode in both groups. However, the maximum effect induced by TERPY was higher than the effect of SNP in Sham and OVA groups. The relaxation mechanism of TERPY in boht groups showed differences. In Sham group, TERPY relaxation by the activation of Kv, Kir, KCa and KATP channels, cGMP-independent mechanisms and by reduction of calcium influx by blocking the store and voltage operated calcium channels. In OVA group, TERPY acts through activation K+ channels, NO/GCs/GMP way and blocking the store and voltage operated calcium channels. The relaxing effect induced by SNP in OVA group was dependent of NO/GCs/GMP pathway, Kv, KCa and BKCa channels and blocking the store and voltage operated calcium channels. However, the activation of the enzyme sGC seems to be reduced in inflamed smooth muscle, as well as the role of the sarcoplasmic reticulum calcium pump. Diclofenac, montelukast and TIRON improved relaxation of the TERPY and SNP in OVA group. The TERPY is able to reverse the contraction of carbachol in asthmatic bronchioles. In conclusion, TERPY and SNP have their mechanisms of relaxation modified by the inflammatory process. However, this modification was not able to alter the pharmacological parameters potency and efficacy to TERPY. Since SNP has less efficacy effect in asthmatic tracheas. This may result from the lower participation of the enzyme sGC and reticular calcium pump, making TERPY a promising drug to reverse the narrowing of the airways. / O óxido nítrico é um potente broncodilatador e compostos capazes de aumentar a sua oferta têm demonstrado interesse clínico no tratamento das doenças obstrutivas das vias aéreas. Estee trabalho avaliou comparativamente os mecanismos de relaxamento de dois doadores de óxido nítrico, o complexo de rutênio [Ru(terpy)(bdq)NO+]3+ (TERPY) e o nitroprussiato de sódio (SNP) em traqueias isoladas de ratos saudáveis, grupo Sham, e com asma experimental induzida por ovalbumina, grupo OVA. As traqueias isoladas foram cortadas em anéis, montadas em banho para órgãos isolados e contraída com carbacol para estudo do relaxamento. O efeito relaxante do TERPY e do SNP foi avaliado em concentrações crescentes e cumulativas (10 nM a 100 μM). Foi verificada a participação dos diferentes tipos de canais de K+, a participação da via GCs/GMPc, inibição das PDEs (pelo IBMX, amrinona, rolipram e dipiridamol), a participação dos estoques internos de Ca2+ (pelo ácido ciclopiazônico), assim como a participação do influxo deste íon pelos canais de cálcio controlados por estoque e por voltagem, além da inibição da COX (pelo diclofenaco), do antagonismo dos receptores de leucotrienos (pelo montelucaste) e do sequestro dos íons superóxidos (pelo TIRON). Foram realizadas análises em microscopia de luz para comprovação da presença de infiltrado inflamatório e da broncodilatação exercida pelo TERPY em cortes de bronquíolos de animais asmáticos. Como resultados, verificou-se que a sensibilização com ovalbumina levou a um intenso processo inflamatório com migração celular e hiperreatividade ao carbacol. Evidenciou-se que o TERPY e o SNP relaxaram o músculo liso traqueal de forma concentração-dependente em ambos os grupos. Entretanto, o efeito máximo induzido pelo TERPY foi maior do que o do SNP tanto no grupo Sham quanto no OVA. O mecanismo de relaxamento do TERPY mostrou-se diferente entre os grupos. No grupo Sham, o TERPY exerce relaxamento por ativação dos canais Kv, Kir, KCa e KATP independentemente de GMPc e por redução do influxo de cálcio através do bloqueio dos canais de cálcio operados por voltagem e por estoque. No grupo OVA, o TERPY exerce seu efeito através da por ativação dos canais K+, via NO/GCs/GMP e redução do influxo de cálcio por bloqueio dos canais de cálcio operados por voltagem e operados por estoque. O efeito relaxante do SNP no grupo OVA ocorre através da ativação da via NO/GCs/GMPc, dos canais Kv, KCa e SKCa e por redução do influxo de cálcio pelos canais de cálcio operados por voltagem e operados por estoque. Entretanto, a ativação da enzima GCs parece estar reduzida em músculo liso inflamado, assim como o papel da bomba de cálcio do retículo sarcoplasmático. O diclofenaco, o montelucaste e o TIRON melhoraram o perfil de relaxamento tanto do TERPY quanto do SNP no grupo OVA. O TERPY é capaz de reverter a contração do carbacol em bronquíolos asmáticos. Em conclusão, tanto o SNP quanto o TERPY têm seus mecanismos de relaxamento modificados pelo processo inflamatório. Entretanto, esta modificação não foi capaz de alterar os parâmetros farmacológicos de potência e eficácia do TERPY. Já o SNP, tem menor eficácia em traqueias de ratos do grupo OVA e isso pode decorrer da menor participação da enzima GCs e da bomba de cálcio reticular, fazendo do TERPY uma droga promissora para reversão do estreitamento das vias aéreas.