Orientador: Fernando Broetto / Banca: Roberto Lyra Villa Boas / Banca: Luis Antonio Gallo / Resumo: A cultura da berinjela vem se destacando muito, principalmente na Europa, Estados Unidos e também no Brasil, com aumento da demanda por hortaliças. Dentre os fertilizantes potássios mais utilizados no Brasil, o cloreto de potássio, é responsável por 95% do consumo. Entre os fatores que afetam a resposta à adubação potássica, destacam-se salinidade e acidez do solo. O experimento foi divido em duas fases, sendo a primeira desenvolvida no Departamento de Produção Vegetal - Horticultura - UNESP, Campus de Botucatu, São Paulo. A segunda fase, compreendendo as análises bioquímicas, foram conduzidas no Departamento de Química e Bioquímica do Instituto de Biociências - UNESP, Campus de Botucatu, São Paulo. Utilizou-se a variedade de berinjela denominada de Embu, adotando-se delineamento em blocos casualizados, em esquema fatorial 2 x 4, com cinco repetições, com duas fontes de potássio (cloreto e sulfato de potássio) e quatro doses crescentes dos fertilizantes (250, 500, 750 e 1000 kg K2O ha-1) Observou-se que as plantas cultivadas com doses elevadas de ambas as fontes potássicas, induziram maior atividade das enzimas superoxido dismutase e catalase, além do aumento da concentração de L-prolina. Estas alterações indicam que estes parâmetros podem ser adotados como indicadores de estresse mineral na cultura da berinjela. Além dos fatores bioquímicos, observou-se que as variações das fontes potássicas influenciaram nos parâmetros biométricos e agronômicos da berinjela, notadamente quando aplicados em excesso. Avaliando-se os resultados do experimento, concluiu-se que a fonte KCl apresentou efeito salino superior, quando comparado com a fonte K2SO4 baseado no efeito mais pronunciado deste adubo, os parâmetros avaliados. Para ambas as fontes potássicas aplicadas, observou-se que o excesso de potássio afetou os parâmetros biométricos, produção e atividade enzimática das plantas. / Abstract: Eggplant cultivation has extensively developed, mainly in Europe, United States and Brazil due to the increase in the demand for vegetables. Of the potassium fertilizers most frequently used in Brazil, potassium chloride satisfies 95% of the needs. Among the factors affecting the response to potassium fertilization are soil salinity and acidity. This experiment was divided into two steps: the first was conducted in the facilities of the Department of Plant Production, Horticulture, São Paulo State University - UNESP, Botucatu Campus, São Paulo State, Brazil. The second step which consisted of biochemical analyses was carried out in the Department of Chemistry and Biochemistry, Institute of Biosciences, UNESP, Botucatu Campus. The eggplant variety Embu was used, and the experimental design was in randomized blocks, 2 x 4 factorial arrangement, with five replicates, including 2 potassium sources (potassium chloride and sulfate) and four increasing doses of the fertilizers (250, 500, 750, and 1000 kg K2O ha-1). Elevated doses of both potassium sources led to higher activity of the enzymes superoxide dismutase and catalase in plants, as well as to an increasing L-proline concentration. Based on such alterations, those parameters can be used as indicators of mineral stress in eggplant culture. Besides biochemical factors, biometric and agronomical parameters were also influenced by variations in the potassium sources, mainly when applied in excess. The present experiment demonstrated that KCl source had higher saline effect, compared with K2SO4 source, considering the higher effect of the former on the evaluated parameters. As regards both potassium sources, the excess of potassium affected biometric parameters, yield and enzymatic activity. / Mestre

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / No cultivo de plantas medicinais as condiÃÃes de salinidade e de luz podem exercer influÃncia no rendimento e qualidade final da produÃÃo de fitomassa. Este trabalho foi desenvolvido no NÃcleo de Ensino e Pesquisa em Agricultura Urbana (NEPAU) da Universidade Federal do Cearà â UFC, em Fortaleza â CE, com o objetivo de avaliar o efeito de diferentes nÃveis luminosidades e de salinidade na Ãgua de irrigaÃÃo no crescimento e respostas fisiolÃgicas de trÃs espÃcies medicinais do gÃnero Plectranthus. Utilizou-se o delineamento experimental em parcelas subsubdivididas, com cinco repetiÃÃes, sendo as parcelas referentes ao fator ambiente (pleno sol e telado), as subparcelas referentes aos nÃveis de salinidade na Ãgua de irrigaÃÃo - CEa (0,7; 1,9; 3,1; 4,3 e 5,5 dS m-1), e as subsubparcelas Ãs trÃs espÃcies do gÃnero Plectranthus (P. amboinicus, P. barbatus e P. grandis). O experimento teve a duraÃÃo de 60 dias, apÃs o transplantio, sendo realizadas as seguintes avaliaÃÃes: Ãrea foliar, produÃÃo massa seca da parte aÃrea, massa seca das raÃzes, trocas gasosas, teores de clorofila e acÃmulo de solutos orgÃnicos e inorgÃnicos. O estresse salino induziu reduÃÃes significativas no crescimento e nas trocas gasosas das trÃs espÃcies avaliadas, com as maiores reduÃÃes sendo verificadas nas plantas expostas a pleno sol. A resposta à salinidade da espÃcie P. grandis foi menos influenciada pelo ambiente de cultivo do que nas duas outras espÃcies estudadas. A salinidade afetou a partiÃÃo de matÃria seca, sendo as raÃzes mais afetadas do que a parte aÃrea. Em relaÃÃo a produÃÃo de matÃria seca total, verifica-se que as trÃs espÃcies estudadas se mostraram tolerantes ou moderadamente tolerantes à salinidade de atà 3,1 dS m-1, porÃm na salinidade de 5,5 dS m-1 todas se mostraram sensÃveis ao excesso de sais na Ãgua de irrigaÃÃo. Considerando-se o grau de reduÃÃo na produÃÃo de massa seca da parte aÃrea (parte de interesse comercial), poderia-se recomendar o cultivo da espÃcie P. grandis quando se dispÃe de Ãgua de irrigaÃÃo com CEa de atà 3,1 dS m-1. Verificou-se aumento expressivo na acumulaÃÃo de Na+ e Cl-, e reduÃÃes no teor de potÃssio, tanto nas hastes quanto nas folhas. Em decorrÃncia do maior acÃmulo de sÃdio nas hastes, a relaÃÃo dos Ãons Na+/K+ nesta parte da planta atingiu valor de 1,6 na CEa de 5,5 dS m-1, indicando um possÃvel desequilÃbrio nutricional e toxicidade de Ãons. Para os solutos orgÃnicos, o teor de carboidratos nÃo foi alterado com o aumento da CEa, porÃm os teores de prolina e N-aminossolÃveis aumentaram em resposta ao estresse, sendo que no caso da prolina os aumentos foram maiores na espÃcie P. grandis cultivada em pleno sol. / Growing medicinal plants in the conditions of salinity and light can exert influence on yield and final quality of the biomass production. This work was developed at the Center for Teaching and Research in Urban Agriculture (NEPAU), Federal University of Cearà - UFC, Fortaleza - CE, with the objective of evaluating the effect of different luminosities and salinity levels in irrigation water on growth and physiological responses of three medicinal species of the genus Plectranthus. It was used the completely randomized split plots with five repetitions, the plots had corresponded to the environmental factor (mesh with 50% luminosity and full sunlight) and the split plots for five levels of salt stress in irrigation water â CEw (0.7, 1.9, 3.1, 4.3 and 5.5 dS m-1 ) and the subsubplots the medicinal species (P. amboinicus, P. barbatus and P. grandis). The experiment lasted for 60 days after transplanting, being determined by the following: leaf area, dry mass production of shoot, root dry mass, gas exchange, chlorophyll content and accumulation of organic and inorganic solutes. Salt stress induced significant reductions in the growth and gas exchange of the three species evaluated, with the largest reductions being observed in plants exposed to full sunlight. The response to the salinity of the species P. grandis was less influenced by growth environment than in the other two species. Salinity affected the dry matter partitioning, the roots being more affected than the shoot. Considering the total dry matter production, it is found that all three species studied were moderately tolerant or salinity tolerance of up to 3.1 dS m-1 but on the salinity of 5.5 dS m-1 all were sensitive to excess salts in the irrigation water. Considering the degree of reduction in the production of raw party area (part of commercial interest), one could recommend the cultivation of the species P. grandis when it has irrigation water with ECw up to 3.1 dS m-1 . There was significant increase in the accumulation of Na+ and Cl- , and reductions in potassium content, both on the stems as the leaves. Due to the higher accumulation of sodium in the stems, the ratio of Na+ /K+ in this part of the plant reached a value of 1.5 in CEa of 5.5 dS m-1 , indicating a possible nutritional imbalance and ion toxicity. For the organic solutes, the carbohydrate content was not changed with increasing salinity but the concentrations of proline and N-aminosoluble increased in response to stress and in the case of proline elevations were higher in the species P. grandis grown in full sunlight.

No presente trabalho desenvolveu-se uma rota sintética em fase sólida para obter de forma rápida o esqueleto da hiacintacina 110 utilizando-se L-Boc-prolina 101 como bloco de construção. Não há relatos na literatura, até o momento, do uso da Lprolina como material de partida para a síntese de núcleos pirrolizidínicos, entretanto o estudo desta rota é uma alternativa interessante porque possibilita a síntese destes biciclos em apenas 4 etapas. A síntese iniciou com o acoplamento entre a L-Bocprolina 101 e a resina Merifield 41 em condições clássicas. Após a retirada do grupamento protetor com ácido cloridríco por 40 minutos em temperatura ambiente, procedeu-se à adição de Michael do produto 103 ao propiolato de etila 116 gerando o enaminodiéster 104. Na última etapa usou-se DBU sob irradição de microondas por 10 minutos, obtendo-se o azabiciclo 110 com redimento de 37%. Em solução, através da adição de Michael entre a L-prolina O-protegida 95 e alcinos e alceno ativados obtevese adutos cuja estereoquímica das olefinas foi sempre E, com bons rendimentos (60- 95%). Os enaminodiésteres 97 e 118 foram facilmente convertidos nos seus correspondentes aminodiésteres 124 e 126 com NaBH(OAc)3 com redimento de 65%. Na etapa da ciclização de Dieckmann obteve-se sucesso utilizando Na/THF/3h sob refluxo gerando o azabiciclo[3.3.0]octano desejado com rendimento de 50-60%. Os análogos das hiacintacinas foram sintetizados a partir da redução dos produtos 109, 132 e 133 com LiAlH4/THF e rendimentos de 52%. Os produtos 109, 132, 133, 135, 136 e 137 foram testados para atividades antiparasitárias e apresentaram bons resultados para a ação carrapaticida com doses até 0,625μg/ml em ovos e 1,25μg/ml em larvas. / We present here an original solid-phase approach to synthesize rapidly the hyacinthacine core 110 using L-proline N-Boc 101 as building block. There is no reference in the literature wich uses L-proline as building block to synthesize this pirrolizidine skeleton. The study of this possibility would be extremely interesting because it could be used to prepare structural systems related to hyacinthacine in only four steps. The synthesis initiates with the coupling of L-Boc-proline 101 to Merrifield resin 41 under classical conditions. The protection group was removed with hidrogen chloride and the Michael addition was proveeded with adduct 103 and ethyl propiolate 116, afording 104 in satisfactory yields. At least, the azabicycle 110 was obtained by reacting 98 using DBU as catalyst at MW irradiation for 10 min, in good yields (37 %). In solution, we have proceed to Michael addition of L-proline O-protected 95 to activated alkynoates/alkenes conducing to aducts where the stereochemistry of the olefins was always E, with excellent yield (60-95%). Enaminoesters 97 and 118 could be easily converted into the corresponding aminodiesters 124 and 126 by NaBH(OAc)3 in 65% yield. In the step of the Diekmann cyclization of aminodiesters the sistem Na/THF/3h at reflux afforded the derived azabicyclo[3.3.0]octanes in 50- 60% yield. The analogs of the hyacinthacines were synthesized with reduction of 109, 132 and 133 with LiAlH4/THF in 52% yield with the stereochemistry to be determined. The products 109, 132, 133, 135, 136 and 137 were tested for parasitic activity and showed good results. Compounds 109, 132, 135 and 136 killed 100% of the larvae at the concentrations of 5 μg/ml and 2.5 μg/ml being not toxic at the lower concentrations. Compounds 133 and 137 were more toxic being lethal to the larvae at concentrations of 1.25 μg/ml but did not case death at the lower concentrations.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Cassava (Manihot esculenta Crantz) belongs to the family Euphorbiceae, Manihot genus, which consists of 98 species Manihot esculenta being the only commercially produced. It is usually propagated vegetatively, but several factors such as the process of soil salination can cause serious damage to crops, decreasing the production of cassava. For the maintenance of physiological processes in adverse conditions such as salt stress, plants accumulate amino acids compatible to the cytosol, such as proline, which assists in maintaining the osmotic pressure, keeping the water absorption. micropropagation in vitro seedlings require a number of requirements, such as growth room with artificial light and carbon source, which together with the low survival rate in the acclimatization, more expensive the final product. The use of natural light even in vitro rooting phase, called photoautotrophy, and the decrease in sucrose concentration appears as potential possibilities to improve the acclimatization of plants, helping reduce costs and enabling trade. In Chapter 1, six genotypes were used in the ex vitro salinity experiment: Sergipe, Lagoão, BRS Verdinha, BRSTapioqueira, BRS Kiriris and BRS Formosa. During acclimatization, the seedlings were watered weekly with MS liquid solution, with or without added 4 or 8 g.L-1 NaCl, making three treatments. After 90 days it was found that the cultivars BRS Formosa and BRS Kiriris had higher salt tolerance and proline accumulation was intensified in all varieties from the addition of salt to the substrate. In Chapter 2, the treatments were applied in vitro rooting phase, and with different concentrations of sucrose (10, 20, 30 and 40 g.L-1) for Tapioqueira and Lagoão for 45 days and transferred to the greenhouse. After 60 days were assessed: root number, leaf number, number of tubercle, shoot length, root length, number of buds, shoot dry weight, root dry weight and survival rate. The two genotypes developed better at higher sucrose concentrations. In a second experiment, the treatments sucrose (10, 20 and 30 g.L-1) and light (natural and artificial growth area) were applied at the same stage, and the BRS Formosa, BRS Verdinha and Lagoão. After 45 days under natural light or artificial light, the explants were transferred to the greenhouse. After 60 days, the BRS Formosa and Lagoão performed better under natural light and high sucrose concentrations, as BRS Verdinha had better development under natural light, but with lower carbohydrate concentration. In Chapter 3, explants of Lagoão, BRS Tapioqueira and BRS Verdinha were inoculated in MS medium without growth regulators and with different salt concentrations (0, 25, 50, 75 and 100 mM). After 90 days, BRS Verdinha and BRS Tapioqueira had higher salt tolerance and BRS Tapioqueira showed greater potential to osmoregulation due to its high proline production. / A mandioca (Manihot esculenta Crantz) pertence à família Euphorbiceae, gênero Manihot, que é composto por 98 espécies, sendo a Manihot esculenta a única comercialmente produzida. Geralmente é propagada vegetativamente, porém, vários fatores como o processo de salinização do solo podem ocasionar danos graves às plantações, diminuindo a produção da mandiocultura. Para a manutenção dos processos fisiológicos em situações adversas como estresse salino, as plantas acumulam aminoácidos compatíveis ao citossol, como a prolina, que auxilia na manutenção da pressão osmótica, mantendo a absorção de água. Mudas micropropagadas in vitro demandam uma série de requisitos, como sala de crescimento com luz artificial e fonte de carbono, o que juntamente com a baixa taxa de sobrevivência na aclimatização, encarecem o produto final. O uso de luz natural ainda na fase de enraizamento in vitro, denominado fotoautotrofia, e a diminuição na concentração de sacarose surgem como possibilidades potenciais para melhorar a aclimatização de plantas, auxiliando na redução de custos e viabilizando o comércio. No capítulo 1, seis genótipos foram utilizados no experimento de salinidade ex vitro: Sergipe, Lagoão, BRS Verdinha, BRS Tapioqueira, BRS Kiriris e BRS Formosa. Durante a aclimatização, as mudas foram regadas semanalmente com solução MS líquido, adicionado de 0, 4 e 8 g.L-1 de NaCl, perfazendo três tratamentos. Após 90 dias constatou-se que as cultivares BRS Formosa e BRS Kiriris apresentaram maior tolerância ao estresse salino e o acúmulo de prolina foi intensificado em todos os genótipos a partir da adição de sal ao substrato. No capítulo 2, os tratamentos foram aplicados na fase de enraizamento in vitro, e com diferentes concentrações de sacarose (10; 20; 30 e 40 g.L-1) para BRS Tapioqueira e Lagoão por 45 dias e transferidas para casa de vegetação, onde permaneceram por 60 dias. Foram avaliados o número de raiz, número de folha, número de tubérculo, comprimento da parte aérea, comprimento de raiz, número de gemas, massa seca da parte aérea, massa seca de raiz e taxa de sobrevivência. Os dois genótipos apresentaram melhor desempenho em concentrações mais altas de sacarose. Num segundo experimento, os tratamentos sacarose (10; 20 e 30 g.L-1) e luz (natural e artificial da sala de crescimento) foram aplicados na mesma fase, e para os genótipos BRS Formosa, BRS Verdinha e Lagoão. Após 45 dias sob luz natural ou luz artificial, os explantes foram transferidos para casa de vegetação. Após 60 dias, a BRS Formosa e Lagoão obtiveram melhores resultados sob luz natural e altas concentrações de sacarose e a BRS Verdinha o melhor desenvolvimento sob luz natural, porem na menor concentração. No Capítulo 3, explantes dos genótipos Lagoão, BRS Tapioqueira e BRS Verdinha foram inoculados em meio MS, sem reguladores de crescimento e com diferentes concentrações salinas (0; 25; 50; 75 e 100 mM). Após 90 dias, BRS Tapioqueira e BRS Verdinha apresentaram maior tolerância ao estresse salino, bem como BRS Tapioqueira maior potencial de osmorregulação devido a sua alta produção de prolina.

A cana-de-açúcar é uma das principais culturas agrícolas no cenário econômico e social brasileiro. Na cultura de cana-de-açúcar o estresse hídrico é o principal fator limitante para o aumento de produtividade, sendo responsável por alterações fisiológicas, bioquímicas e moleculares nas plantas, que podem deflagrar perturbações metabólicas que ativam a morte celular programada (MCP). Sabendo-se que o gene BI-1 apresenta o potencial de reduzir os efeitos da MCP desencadeado por estresses bióticos e abióticos em plantas, este trabalho teve como objetivo analisar plantas transgênicas de cana-de-açúcar que expressam o gene BI-1 de Arabidopsis thaliana (AtBI-1) em condições de estresse hídrico. Também, plantas transgênicas e controle foram inoculadas com o fungo Puccinia melanocephala demonstrando que o processo de transformação genética com o gene AtBI-1 alterou as características pré existentes de resistência a ferrugem marrom nas plantas transgênicas. Os estudos de tolerância ao défict hídrico foram realizados em dois experimentos, o experimento 1 com plantas transgênicas e controles de 90 dias e o experimento 2 com plantas de 60 dias. Plantas do experimento 1 foram analisadas quanto características morfológicas como número de estômatos e tricomas, altura e circunferência do colmo e após ficarem 24 dias sem água foram analisadas quanto a taxa fotossintética, comportamento estomático e conteúdo relativo de água nas folhas, enquanto no experimento 2 as plantas foram analisadas quanto aos teores de prolina, atividades das enzimas guaiacol peroxidase (GPOX), ascorbato peroxidase (APX) e catalase (CAT) após as plantas ficarem 17 dias sob déficit hídrico. Estas enzimas estão envolvidas em processos de desativação de elementos ativos de oxigênio. Os resultados demonstraram que as plantas transgênicas expressando o gene AtBI-1 possuem fenótipo de menor altura, e maior taxa fotossintética, maior comportamento estomático e maior conteúdo relativo de água nas folhas, e assim apresentam maior tolerância ao déficit hídrico que plantas controle. Contudo, houve baixo acúmulo de prolina, baixa atividade da GPOX, APX e CAT nas plantas transgênicas durante o estresse hídrico comparada com as plantas controle do mesmo tratamento. Porém foi observado alta atividade constitutiva da catalase nas plantas transgênicas. A atividade da catalase nestas plantas transgênicas sugere a possibilidade da interação entre AtBI-1 e calmudolinas. Futuros estudos podem contribuir para elucidar se a proteína BI-1 é essencial para a ativação das catalases por calmudolinas. / Sugarcane is one of the main agricultural crops in the Brazilian social and economic scenario. Water stress in the culture of sugarcane is the main limiting factor for increasing productivity accounting for physiological, biochemical and molecular plants that can trigger metabolic disturbances activating programmed cell death (MCP). Knowing that the BI-1 gene has the potential to reduce the effects of MCP triggered by biotic and abiotic stresses in plants, this study aimed to analyze transgenic sugarcane that express the BI-1 gene of Arabidopsis thaliana (AtBI-1) under water stress. Also, transgenic and control plants were inoculated with Puccinia melanocephala fungus demonstrating that the genetic transformation process with the AtBI-1 gene altered the pre-existing characteristics of brown rust resistance in transgenic plants. Studies of tolerance to water deficit were performed in two experiments, the experiment 1 was prepared with transgenic and control plants with 90 days and the experiment 2 used plants with 60 days. Plants from experiment 1 were analyzed as for morphological characteristics such as number of stomata and trichomes, height and diameter of stem after plants being under water for 24 days as were analyzed photosynthetic rate, stomatal behavior, relative water content in leaves while in the experiment 2, plants were analyzed for the levels of proline, enzyme activities of guaiacol peroxidase (GPOX), ascorbate peroxidase (APX) and catalase (CAT) under water deficit for 17 days. These enzymes are involved in deactivation of active elements oxygen. The results demonstrated that the transgenic plants expressing the AtBI-1 gene presented the phenotype of lower height, higher index of leaf area, higher photosynthetic rate, higher stomatal behavior and higher relative water content in leaves than control plants increasing tolerance to drought stress. However, there were low levels of proline, low activity of GPOX activity, APX and CAT in transgenic plants during drought stress compared to control plants of the same treatment, but the observed high constitutive activity of catalase in transgenic plants. Catalase activity in these transgenic plants suggests the possibility of interaction between AtBI-1 and calmudolinas. Future studies may contribute to understand whether the BI-1protein is essential for the activation of catalase by calmudolinas.

In der vorliegenden Dissertation geht es um die Synthese und Charakterisierung chiraler, redoxaktiver (Raumtemperatur-)Ionischer Flüssigkeiten basierend auf Ferrocen und der natürlich vorkommenden Aminosäure S-Prolin. Diese Baueinheiten sind entweder über eine Ether- oder über eine Esterverbrückung verknüpft. Auch der Anionenaustausch vom I– - zum CF3SO3– - sowie (CF3SO2)2N– -Salz (kurz NTf2–) wird dargelegt und der Einfluss des Anions auf den Schmelzpunkt der Verbindungen untersucht und diskutiert. Die Redoxaktivität wird durch das im Ferrocen enthaltene Fe II eingebracht, das reversibel zu Fe III oxidiert werden kann. Aufgrund des Pyrrolidin-Rings sind die dargestellten Verbindungen stets chiral und bilden nach der Quaternisierung mit Halogenalkanen Diastereomere, soweit die Alkylkette größer als Methyl ist. Das Diastereomerenverhältnis wurde mittels 1H-NMR-Spektroskopie und in einem Fall anhand von Röntgenpulverdiffraktogrammen durch Rietveld-Verfeinerung analysiert. Die Verbindungen wurden thermisch anhand simultaner thermischer Analysenund Tieftemperaturversuchen untersucht, die belegen, dass die Synthese von insgesamt sechs neuen Raumtemperatur-Ionischen Flüssigkeiten gelang. Davon basiert eine Verbindung, (1S2S)- und (1R2S)-2-[(Ferrocenylcarbonyl)oxy]methylen-N-methyl-N-pentylpyrrolidin-1-iumiodid, auf I– und fünf Verbindungen enthalten NTf2– als Gegenion. Das Diastereomerengemisch der Verbindungen (1S2S)- und (1R2S)-N-Butyl-2-[(ferrocenylcarbonyl)oxy]methylen-N-methylpyrrolidin-1-ium NTf2– besitzt den größten Flüssigkeitsbereich von -25 bis +263 °C und auch die höchste Zersetzungstemperatur aller hier dargestellten Verbindungen. Insgesamt werden in dieser Arbeit elf Einkristallstrukturanalysen vorgestellt, wobei es sich um drei Verbindungen des Typs FcCH2N(CH3)2(CnH2n+1)I (Fc = Ferrocenyl, n = 1,2,3), Ferrocenmonocarbonsäurechlorid, zwei ether- sowie fünf esterverbrückte Verbindungen handelt. Mikrokristalline Proben wurden mittels Röntgenpulverdiffraktometrie charakterisiert. Ergänzende Analysen wurden mittels UV-Vis- und IR-Spektroskopie sowie Massenspektrometrie und Elementaranalyse durchgeführt. Ein wichtiger Aspekt bei Ferrocenverbindungen ist das Redoxpotential, welches mittels Cyclovoltammetrie bestimmt wurde. Hierbei liegt das Formalpotential des Fe II /Fe III -Redoxpaars der etherverbrückten Verbindungen bei +0,05 V und bei den esterverbrückten Verbindungen unabhängig vom Anion bei +0,28 V vs. Ferrocen/Ferrocenium in Acetonitril. Bei den iodidhaltigen Verbindungen zeigt das I– -Ion ebenfalls eine Redoxaktivität bei E(0,f,Fc) = -0,18 V und 0,22V. Die Diffusionskoeffizienten der esterverbrückten Triflat- und NTf2– -Verbindungen liegen in der Größenordnung von 7·10−6 cm2/s und die heterogenen Geschwindigkeitskonstanten bei 0,01 cm/s. / The present dissertation deals with the synthesis and characterization of chiral, redoxactive room temperature ionic liquids (RTILs) based on ferrocene and the naturally occurring amino acid S-proline. These building blocks are coupled either via an ether- or an ester-bridge. The anion exchange from I– to CF3SO3– and (CF3SO2)2N– salts (abbreviated as NTf2–) is presented. The influence of the anion on the melting point of the compound is investigated and discussed. The redox activity is introduced into the molecule via the Fe II -containing ferrocenyl groups, which can be oxidized reversibly to Fe III . The synthesized compounds based on the pyrrolidine ring are chiral. After quaternization with alkyl halides, they form diastereomers in case of alkyl chains longer than methyl. The ratio of the different diastereomers was analyzed by 1H NMR spectroscopy and, in one case, by Rietveld refinement of the X-ray powder diffraction pattern. The thermal behavior of the compounds was studied by simultaneous thermal analysis and low temperature experiments. The results show the successful synthesis of six new RTILs. One of them is based on iodide ((1S2S)- and (1R2S)-2-[(ferrocenylcarbonyl)oxy]methylene-N-methyl- N-pentylpyrrolidine-1-ium iodide) and six RTILs contain NTf2– as counter ion. The diastereomeric mixture of compounds (1S2S)- and (1R2S)-N-butyl-2-[(ferrocenylcarbonyl)oxy]methylene-N-methylpyrrolidine-1-ium NTf2– exhibits the widest liquid range from -25 to +263 °C and the highest decomposition temperature of all compounds presented herein. Eleven single crystal structure analyses are presented. Three of them belong to compounds FcCH2N(CH3)2(CnH2n+1)I (with Fc = ferrocenyl and n = 1,2,3), then ferrocene monocarboxylic acid chloride, two of ether- as well as five ester-bridged compounds. Microcrystalline samples were characterized by X-ray powder diffractometry. Supplementary analyses by UV/Vis and IR spectroscopy as well as mass spectrometry and elemental analyses have been carried out. An important feature of ferrocene containing compounds is their redox potential which is determined with cyclic voltammetry. The formal potential of the Fe II /Fe III redox couple in the ether-bridged compounds is at +0.05 V and in the ester-bridged compounds independent from the type of anion at +0.28 V vs. ferro- cene/ferrocenium in acetonitrile. The I– anion shows as well redox activity with formal potentials at E(0,f,Fc) = -0.18 V and 0.22 V. The diffusion coefficients of the ester-bridged triflate and NTf2– compounds are in the order of 7·10−6 cm2/s, the heterogeneous rate constants in the order of 0.01 cm/s.

The clinically used antibiotic lincomycin consists of an amino-sugar and an amino-acid moiety. The incorporated amino-acid 4-propyl-L-prolin (PPL) is very important for the linomycin bioactivity, as evidenced by the lower activity of the related antibiotic celesticetin, which incorporates proteinogenic L-prolin instead. Gene clusters for the biosynthesis of both lincosamides are published and reflect a common basis - biosynthesis of amino-sugar precursor and condensation reactions. Additionally, in the biosynthetic gene cluster for lincomycin there is a sub-cluster of genes encoding the biosynthesis of PPL, the alkylated proline derivative (APD). PPL has a common biosynthetic origin with other APDs that are part of the structures of antitumor pyrrolobenzodiazepines and the signal molecule hormaomycin, which is also reflected in the presence of homologous genes in their gene clusters. The acquired knowledge on PPL biosynthesis thus can be applied to a larger group of natural products. The first overall concept of APD biosynthesis was published forty years ago. The milestone was the year 1995 when the gene cluster for lincomycin biosynthesis was published and specific gene products have been proposed for individual biosynthetic steps. The functional proof of proteins has been performed so far just...

The designer proline-rich antimicrobial peptide (PrAMP) Chex1-Arg20 amide (ARV-1502) is active against Gram-negative and Gram-positive pathogens in differentmurine infection models when administered parenterally and possesses a wide therapeutic index. Here we studied the pharmacokinetics of ARV-1502 for the first time when administered intramuscularly or intravenously (IV) in Sprague Dawley rats and Beagle dogs. First, a specific and robust quantitation method relying on parallel reaction monitoring (PRM) using a high-resolution hybrid quadrupole-Orbitrap mass spectrometer coupled on-line to reversed-phase uHPLC was established and validated. The limit of detection was 2 ng/mL and the limit of quantitation was 4 ng/mL when spiked to pooled rat and dog plasma. When ARV-1502 was administered IV at doses of 75 and 250 μg/kg in dogs and rats, the plasma concentrations were 0.7 and 3.4μg/mL 2min post-administration, respectively. ARV-1502 plasma concentrations declined exponentially reaching levels between 2 and 4 ng/mL after 2 h. Intramuscular administration of 0.75 mg/kg in dogs and 2.5 mg/kg in rats resulted in a different pharmacokinetics profile. The plasma concentrations peaked at 15min post-injection at 1μg/mL (dogs) and 12μg/mL (rats) and decreased exponentially within 3 h to 4 and 16 ng/mL, respectively. The initial plasma concentrations of ARV-1502 and the decay timing afterwards indicated that the peptide circulated in the blood stream for several hours, at some point above the minimal inhibitory concentration against multidrug-resistant Enterobacteriaceae, with blood concentrations sufficient to suppress bacterial growth and to modulate the immune system.

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Les hétérocycles azotés en chimie médicinale sont une classe très importante de composés présents dans une panoplie de médicaments sur le marché. De ces structures, la pipérazine et ses analogues occupent une place importante en chimie médicinale. Plus particulièrement son similaire, l’acide pipérazine-2-carboxylique permet une plus vaste fonctionnalisation en raison de son groupement acide carboxylique qui peut être fonctionnalisé en ester, en amide, en alcool et en éther pour ne nommer qu’eux. La bioisostérie est un concept important en chimie médicinale permettant de moduler les effets pharmacologiques d’une molécule. Notamment, la tridimensionnalité et la rigidité d’une structure moléculaire par rapport à une autre permet, entre autres, une meilleure affinité dans des sites actifs de récepteurs ou d’enzymes. Alors, nous avons proposé la structure de 4 composés azabicycliques pouvant agir comme bioisostères de l’acide pipérazine-2-carboxylique. Ces structures seraient des bons candidats comme remplacement pour des tests biologique futurs in vitro en les comparant à la molécule mère. Nous avons synthétisé et caractérisé les 4 structures proposées avec de bons rendements et des réactions fiables et robustes. Nous avons utlisé les chiron 4-trans-hydroxy L-proline et L-pyroglutaminol comme produits de départ, qui sont peu dispendieux et très disponibles. / Nitrogen heterocycles in medicinal chemistry are a very important class of compounds present in a wide range of drugs on the market. Of these structures, piperazine and its analogues occupy an important place in medicinal chemistry. More particularly its similar, piperazine-2-carboxylic acid allows a broader functionalization due to its carboxylic acid group which can be functionalized into esters, amide, alcohols and ethers to name a few. Bioisostery is an important concept in medicinal chemistry making it possible to modulate the pharmacological effects of a molecule. In particular, three-dimensionality and rigidity of one molecular structure compared to another allows, among other things, a better affinity in active sites of biological receptors or enzymes. So, we proposed the structure of 4 azabicyclic compounds that could act as bioisosteres of piperazine-2-carboxylic acid. These structures would be good candidates as a replacement for future in vitro biological tests by comparing them to the parent molecule. We have synthesized and characterized the 4 proposed structures with reliable yields and robust reactions. We used chiron 4-trans-hydroxy L-proline and L-pyroglutaminol as starting materials, which are inexpensive and very available.