No description available.

Paclitaxel was isolated from the bark of <i>Taxus brevifolia</i> in the late 1960s. It exerts its biological effect by promoting tubulin polymerization and stabilizing the resulting microtubules. Paclitaxel has become one of the most important current drugs for the treatment of breast and ovarian cancers. Studies aimed at understanding the biologically active conformation of paclitaxel bound on β–tubulin are described. In this work, the synthesis of isotopically labeled taxol analogs is described and the REDOR studies of this compound complexed to tubulin agrees with the hypothesis that palictaxel adopts T-taxol conformation. Based on T-taxol conformation, macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. The results show a direct evidence to support T-taxol conformation. (+) Discodermolide is a polyketide isolated from the Caribbean deep sea sponge <i>Discodermia dissoluta</i> in 1990. Similar to paclitaxel, discodermolide interacts with tubulin and stabilizes the microtubule <i>in vivo</i>. Studies aimed at understanding the biologically active conformation of discodermolide bound on β–tubulin are described. In this work, the synthesis of fluorescent labeled discodermolide analogs is described and their biological activities were evaluated. Synthetic approaches to fluorescent labeled and isotopically labeled discodermolide analogs discodermolide are also described. / Ph. D.

Thesis advisor: Amir Hoveyda / Chapter 1: E- and Z-, Di- and Trisubstituted Alkenyl Nitriles through Catalytic Cross MetathesisWe have described the development of several catalytic cross-metathesis strategies, which can deliver a considerable range of Z- or E-disubstituted alkenyl nitriles and their corresponding trisubstituted variants. Through careful examination of the steric and electronic attributes of the starting materials, a Mo-based monoaryloxide pyrrolide or chloride complex may be the optimal choice depending on the reaction type. In the event, equimolar amounts of the two substrates are necessary to maximize reaction efficiency; a pyridine ligand is more desirable than a phosphine ligand, as a stabilizing ligand for a Mo-based complex, for improving reaction stereoselectivity. We also highlighted the utility of this approach with the synthesis of several biologically active compounds, such as LR5182 (Cocaine abuse treatment), alliarinoside (anti-feedant), perhydrohistrionicotoxin (natural product), CC-5079 (anti-cancer) and indatraline (anti-depressant). Chapter 2: Traceless Protection for More Broadly Applicable Olefin Metathesis We have devised an operationally simple in-situ protection/deprotection strategy that significantly expands the scope of kinetically controlled catalytic olefin metathesis. Pretreatment of an olefin containing a protic group with commercially available HB(pin) or HB(trip)2 is sufficient for generating the desired product efficiently through the catalytic cross-metathesis reaction. A wide range of stereochemically defined Z- and E-alkenyl halides and boronates as well as Z-trifluoromethyl-substituted alkenes with a hydroxy or carboxylic acid group were prepared. We also discovered that a small amount of HB(pin) may be used for the removal of residual water and impurities, significantly enhancing the efficiency of a multigram-scale olefin metathesis transformation. Chapter 3: E- and Z-Macrocyclic Trisubstituted Alkenes for Natural Product Synthesis and Skeletal Editing We have introduced a reliable catalytic strategy for the synthesis of a variety of macrocyclic trisubstituted olefins in either stereoisomeric form. This was achieved by overcoming the unexpected difficulties through careful mechanistic studies, including addressing complications arising from pre-metathesis alkene isomerization. Macrocyclic ring-closing metathesis can be performed with a commercially available Mo-based complex and an easily accessible linear diene precursor. Accordingly, we can synthesize a skeletally diverse array of otherwise difficult-to-access macrocyclic alkenes, a critical set of compounds in drug discovery, in either isomeric form. The utility of the method is highlighted in two instances. The first is the near complete reversal of substrate-controlled selectivity in the generation of the macrolactam intermediate, in the total synthesis of the anti-fungal agent Fluvirucin B1. The second is an exceptionally stereoselective late-stage formation of a 24-membered macrocyclic E-trisubstituted alkene, enabling the completion of the total synthesis of a cytotoxic natural product dolabelide C, which is seven times more efficient than that reported previously. Chapter 4: Stereodefined Alkenes with a Fluoro-Chloro Terminus as a Uniquely Enabling Compound Class We have offered a practical solution for the synthesis of trisubstituted alkenyl fluorides by unveiling a widely applicable strategy for stereodivergent synthesis of olefins bearing a fluoro and chloro terminus. The core transformation is unprecedented: cross-metathesis between two trisubstituted olefins, one of which is a commercially available but scarcely utilized trihalo alkene. Alkenes bearing a fluoro,chloro-terminus are versatile substrates for the generation of otherwise difficult-to-access trisubstituted alkenyl fluorides, through stereospecific catalytic cross-coupling reactions. We also highlighted the utility of the method throguh synthesis of, among others, a fluoro-nematic liquid crystal component, peptide analogs bearing an E- or a Z-amide bond mimic, and all four stereoisomers of difluoro-rumenic ester (anti-cancer). / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Furanoeliangolidos são produtos naturais bioativos com peculiar estrutura macrocíclica. A síntese orgânica destes compostos tem despertado grande interesse por parte de vários pesquisadores. Particularmente, há alguns anos, o nosso grupo de pesquisa vem se dedicando, entre outras atividades, ao estudo de métodos sintéticos para a preparação do esqueleto estrutural dos furanoeliangolidos, mais especificamente do goiazensolido. A estrutura simplificada deste produto natural corresponde a um sistema 7-oxabiciclo[6.2.1]undecano. Este produto natural possui as seguintes atividades biológicas: esquistossomicida, citotóxica e antiinflamatória. Nossa metodologia utiliza, como etapa chave, a reação de Diels-Alder. Após a preparação do sistema policíclico, a clivagem da ligação interna dos anéis poderia fornecer o macrociclo desejado. Neste trabalho, foram estudadas três rotas sintéticas para preparação do núcleo básico dos furanoeliangolidos. Na proposta sintética inicial, a reação de Diels-Alder realizada entre o 2-metil-furano e o 3-bromopropiolato de metila, apresentou um aspecto surpreendente, uma alta regiosselevidade. A reação de anelação para formação do sistema policíclico foi investigada com três compostos diferentes. Todavia, nenhuma destas reações forneceu o produto desejado, mas sim resultaram em misturas complexas de produtos. Estes resultados revelaram a dificuldade em se realizar reações de anelação em compostos deste tipo. Outros substratos poderiam ser usados, mas considerando esses resultados insatisfatórios, nós preferimos iniciar o estudo de uma nova rota sintética. Na segunda rota, tentamos introduzir um grupo contendo três carbonos para formar o anel de seis membros, a partir de modificação na parte ?superior? da molécula (éster metílico). O aldeído intermediário pôde ser obtido com bom rendimento, mas o produto resultante da condensação aldólica deste composto com a acetona, é muito instável. A hidrólise de cetais deste tipo, conforme verificamos em experimentos com um cetal mais simples, requer tratamento com ácido forte. O produto obtido da reação aldólica, portanto não poderia resistir a essas condições, então abandonamos a rota. Na terceira rota sintética, a metodologia consistiu na construção do sistema policíclico através de duas reações de Diels-Alder e utilizando uma reação de ozonólise para clivar a dupla ligação central. A estereoquímica do aduto obtido na segunda reação de Diels-Alder foi confirmada por estudos de RMN. A ozonólise deste composto deu origem ao macrociclo desejado, contendo o núcleo estrutural dos furanoeliangolidos. Como o grupo imida presente neste macrociclo é muito resistente à hidrólise e outras reações, nós também desenvolvemos uma modificação que produz um produto mais tratável. O dieno utilizado nesta segunda reação de Diels-Alder não fornece aduto com anidrido maleico, mas ele reage bem com o acetilenodicarboxilato de dimetila dando o aduto correspondente. As duas duplas ligações deste composto são suficientemente diferentes uma da outra para permitir a ozonólise seletiva da dupla ligação central, mais nucleofílica. Nesta última rota sintética, dois macrociclos foram preparados em sete etapas, envolvendo duas reações de Diels-Alder, com rendimento total de 36,3% e 42,1%, respectivamente. / Furanoheliangolides are bioactive natural products containing a peculiar macrocyclic structure. The synthesis of these compounds has been a matter of considerable interest to several researchers. In the last few years, our research group has dedicated some efforts to develop synthetic methods for the preparation of the core structure of the furanoheliangolides, particularly goyazensolide. The core structure of this natural product corresponds to the 7- oxabicyclo[6.2.1]undecane system. This natural product has several biological activities, such as schistosomicidal, cytotoxic and anti-inflammatory. Our methodology uses, as a key step, the Diels-Alder reaction. After the preparation of the polycyclic system, the cleavage of the internal bond of the rings should furnish the desired macrocycle. In this work, three synthetic routes to the preparation of the core structure of the furanoheliangolides were studied. In the first route, the Diels-Alder reaction between 2-methylfuran and methyl 3-bromopropiolate, occurred with unusually high regioselectivity The cyclization reaction for the formation of the polycyclic system was investigated with three different compounds. However, none of these reactions furnished the desired product, but resulted instead in complex mixtures of products. These results showed the difficulty to perform cyclization reactions in compounds of this type. Other substrates could have been used, but considering these discouraging initial results, we preferred to start the studies of a new synthetic route. In the second route we were still attempting to introduce a three-carbon group to form the new six-membered ring; the main modification was that we would now start from the other side of the molecule. The aldehyde could be obtained in good yield, but the aldol reaction product of this aldehyde with the ketone is very unstable. As we have found in experiments with a simple ketal, the hydrolysis of ketals of this type require rather strong acidic treatment. Therefore, the aldol product would not withstand these conditions, so we abandoned these studies. In the third synthetic route, the methodology consisted of building the polycyclic system through two Diels-Alder reactions followed by an ozonolysis reaction to cleave the central double bond. The stereochemistry of the addut obtained in the second Diels-Alder reaction was confirmed by NMR studies. The ozonolysis of this product produced the desired core of the furanoheliangolides. As the imide group of this macrocycle is very resistant to hydrolysis and other reactions, we have also developed a modification that produces a more treatable product. The diene used in this second Diels-Alder reaction does not give Diels-Alder adduct with maleic anhydride, but it reacts well with dimethyl acetylenedicarboxylate to give correspondent addut. The two double bonds of this addut are sufficiently different from each other to permit the selective ozonolysis of the more nucleophilic central bond. In this last synthetic route, two macrocycles were prepared in seven steps, involving two Diels-Alder reactions, with overall yields of 36.3% and 42.1%, respectively.

A Baccharis coridifolia é uma planta tóxica da família Compositae, gênero Baccharis L., conhecida popularmente como \"mio-mio\", a qual é encontrada no sul do Brasil e também em algumas regiões do Estado de São Paulo. Em bovinos, a intoxicação provoca lesões necróticas no trato gastrintestinal e nos tecidos linfóides sólidos em geral, com exceção do timo. Já em camundongos, a B. coridifolia promove, além das lesões em órgãos linfóides, lesões necróticas também no timo. Os princípios ativos da B. coridifolia foram isolados e identificados como sendo os tricotecenos macrocíclicos: roridinas A, D e E; verrucarinas A e J e miotoxina A. Em relação ao mecanismo de ação, trabalhos recentes in vitro demonstraram que as roridinas e as verrucarinas, promovem apoptose em tecido linfóide. Deste modo, considerando a toxicidade desta planta aos tecidos linfóides, o objetivo do presente estudo foi investigar se linfócitos tumorais (linfoma) seriam mais sensíveis aos efeitos tóxicos da B. coridifolia que linfócitos normais. Para tal, fez-se um experimento in vitro com culturas de linfócitos provenientes do baço e timo de camundongos hígidos, bem como células do linfoma murino A20 e carcinoma mamário de Ehrlich tratadas com o Resíduo Hexânico (RH) obtido do extrato etanólico de B. coridifolia por 24 horas. A viabilidade celular foi verificada pela técnica MTT, na qual se evidenciou diminuição da viabilidade das duas linhagens tumorais tratadas, linfoma A20 e carcinoma de Ehrlich, sem alteração na viabilidade dos linfócitos normais. Para melhor caracterizar este efeito tóxico do RH em linfócitos tumorais, camundongos nude (NMRI-nu/nu) foram inoculados com células A20, sendo posteriormente tratados por via oral, durante sete dias, com RH, associado ou não a uma aplicação intraperitoneal do quimioterápico ciclofosfamida no primeiro dia de tratamento. Resultados mostraram que os animais tratados com RH foram menos afetados com a ocorrência de metástase do linfoma primário para outros órgãos e que as involuções tumorais foram mais expressivas no grupo submetido à associação deste tratamento com uma aplicação de ciclofosfamida. Estes resultados permitem sugerir que linfócitos tumorais são mais suscetíveis aos efeitos tóxicos da B. coridifolia. / Baccharis coridifolia is a toxic plant from Compositae family, genus Baccharis L., known as \"mio-mio\". It is found in the south of Brazil, as well as in some regions of São Paulo state. In bovines, its intoxication leads to necrotic injuries to gastrointestinal tract and linfoid tissues. In mice, B. coridifolia leads, apart from linfoid solids in general to necrotic injuries in thymus. B. coridifolia\'s active principles were isolated and identified as being macrocyclic tricotecenes: roridines A, D and E; verrucarines A and J and miotoxine A. Related to action pathway, recent research (in vitro) has shown that roridines and verrucarines, B. coridifolia\'s active principles, lead to apoptosis in linfoid tissues. Therefore, considering this plant\'s toxicity to linfoid tissues, this work aimed the study of whether tumoral lymphocytes (lymphoma) would be more sensitive to B. coridifolia\'s effects than regular lymphocytes. In this sense, an experiment was carried out (in vitro) using healthy mice\'s lymphocytes from spleens and thymus, as well as cells from murine A20 lymphoma and Ehrlich breast carcinoma treated with a residue (RH, hexane obtained) from a B. coridifolia\'s ethanol effusion (24 hours). The cell viability was tested using MTT technique, where a decrease in viability was found for treated tumoral cells lineages, A 20 lymphoma and Ehrlich carcinoma, with no changes in normal lymphocytes viability. To find a better characterization to RH\'s toxic effect in tumoral lymphocytes, nude mice (NMRI-nu/nu) were inoculated with A 20 cells and then were orally treated, during 7 days, with RH, and, in some cases, with intraperitonial injection of cyclophosphamide, during the first day of treatment. Results showed that RH treated animals were less affected to primary lymphoma metastasis in other organs and tumoral involutions were more prominent in the group treated with cyclophosphamide concomitantly. These results suggest that tumoral lymphocytes are more susceptible to B. coridifolia\'s toxic effects.

The recently discovered cucurbit[n]uril are a range of macrocyclic hosts which have enormous potential in industrial, medical and academic applications. Cucurbit[n]uril have a rigid repeating structure of methylene bridged glycouril, which give cucurbit[n]uril their gourd like shape of a cavity with two carbonyl fringed portals. In this thesis the host-guest binding abilities of three cucurbit[n]uril (n = 6, 7, 8) have been examined for a range of potential guests. These guests ranged from simple alkyl amines through globular alkyl and carboranyl amines to bipyridyl systems. In total 45 guest molecules where examined. Most of the guests examined where either cationically charged, capable of hydrogen binding, contained a substantial molecular dipole, or a combination of these. Furthermore, all of the potential guests examined had some solubility in an acidified aqueous sodium sulfate solution within which the host-guest properties were examined. It was generally found that the larger guests did have selectivity for the larger hosts. However, when the host became too large weaker complexes would form and for the range of materials examined here cucurbit[7]uril was found to be the 'best' host system. In one example, p-xylene diamine, a 2:1 complex with cucurbit[8]uril was observed. While not the focus of this work a new rapid purification method was developed for the cucurbit[n]uril using different metal ions to either solubilise or precipitate the different cucurbit[n]uril. In the second part of this work these same guest molecules where used as potential templates in the synthesis of cucurbit[n]uril. Surprisingly the guests that bound strongly to an individual host did not seem to template the cucurbit[n]uril synthesis at all. Rather these strong binders inhibited the reaction such that little or no cucurbit[n]uril formed under the reaction conditions studied. However, several examples provided excellent template results. Indeed the results indicate that guests which bound with intermediate rates of exchange are the best templates and using templates under these conditions we have been able to produce cucurbit[7]uril as 46% by mass of the total cucurbit[n]uril product. This is the highest yield ever recorded for cucurbit[7]uril and it is the first example of cucurbit[7]uril being the major product of this condensation reaction. In an another example cucurbit[8]uril formed 18% of the product an increase of 150% over the standard reaction conditions. While studying both the template reactions and the host-guest binding properties of the cucurbit[n]uril a new supramolecular form, an 'inverse rotaxane' was discovered. Inverse rotaxanes are not held in place by large blocking groups, rather the molecular structure encapsulated by the cucurbit[n]uril host prevents decomplexation of the axle.

In this thesis the pH dependency of the coordination modes of lanthanide complexes with macrocyclic ligands based on 1,4,7,10-tetraazacyclododecane skeleton was studied. The cyclen-based ligand structures in this work contained three acetate and one aminoethyl group with a N-alkyl-N-methylphosphonate substituent, DO3AN(R)P, where R is an alkyle substituent on the nitrogen atom of the pendant arm (R = methyl, benzyl). Lanthanide complexes of a previously studied prototype ligand DO3ANP with secondary amino group (R = H) have shown interesting properties in the field of 31 P NMR imaging because of their various coordination properties, which allow in situ pH measurement. These complexes can also be used for monitoring the kinetics of the chemical exchange of the amino group proton in 1 H NMR imaging using the chemical exchange saturation transfer (CEST NMR). In this thesis, two new derivatives DO3ANMeP and DO3ANBnP were prepared in order to better understand the coordination modes changes in this ligand series. Also, their coordination behaviour with selected lanthanide ions was studied (Eu3+ , Gd3+ , Dy3+ , Yb3+ ). Based on a series of NMR and luminescence measurements, it was found out, that in acidic conditions the complexes containing DO3ANP motif bind a water molecule in their coordination...

Furanoeliangolidos são produtos naturais bioativos com peculiar estrutura macrocíclica. A síntese orgânica destes compostos tem despertado grande interesse por parte de vários pesquisadores. Particularmente, há alguns anos, o nosso grupo de pesquisa vem se dedicando, entre outras atividades, ao estudo de métodos sintéticos para a preparação do esqueleto estrutural dos furanoeliangolidos, mais especificamente do goiazensolido. A estrutura simplificada deste produto natural corresponde a um sistema 7-oxabiciclo[6.2.1]undecano. Este produto natural possui as seguintes atividades biológicas: esquistossomicida, citotóxica e antiinflamatória. Nossa metodologia utiliza, como etapa chave, a reação de Diels-Alder. Após a preparação do sistema policíclico, a clivagem da ligação interna dos anéis poderia fornecer o macrociclo desejado. Neste trabalho, foram estudadas três rotas sintéticas para preparação do núcleo básico dos furanoeliangolidos. Na proposta sintética inicial, a reação de Diels-Alder realizada entre o 2-metil-furano e o 3-bromopropiolato de metila, apresentou um aspecto surpreendente, uma alta regiosselevidade. A reação de anelação para formação do sistema policíclico foi investigada com três compostos diferentes. Todavia, nenhuma destas reações forneceu o produto desejado, mas sim resultaram em misturas complexas de produtos. Estes resultados revelaram a dificuldade em se realizar reações de anelação em compostos deste tipo. Outros substratos poderiam ser usados, mas considerando esses resultados insatisfatórios, nós preferimos iniciar o estudo de uma nova rota sintética. Na segunda rota, tentamos introduzir um grupo contendo três carbonos para formar o anel de seis membros, a partir de modificação na parte ?superior? da molécula (éster metílico). O aldeído intermediário pôde ser obtido com bom rendimento, mas o produto resultante da condensação aldólica deste composto com a acetona, é muito instável. A hidrólise de cetais deste tipo, conforme verificamos em experimentos com um cetal mais simples, requer tratamento com ácido forte. O produto obtido da reação aldólica, portanto não poderia resistir a essas condições, então abandonamos a rota. Na terceira rota sintética, a metodologia consistiu na construção do sistema policíclico através de duas reações de Diels-Alder e utilizando uma reação de ozonólise para clivar a dupla ligação central. A estereoquímica do aduto obtido na segunda reação de Diels-Alder foi confirmada por estudos de RMN. A ozonólise deste composto deu origem ao macrociclo desejado, contendo o núcleo estrutural dos furanoeliangolidos. Como o grupo imida presente neste macrociclo é muito resistente à hidrólise e outras reações, nós também desenvolvemos uma modificação que produz um produto mais tratável. O dieno utilizado nesta segunda reação de Diels-Alder não fornece aduto com anidrido maleico, mas ele reage bem com o acetilenodicarboxilato de dimetila dando o aduto correspondente. As duas duplas ligações deste composto são suficientemente diferentes uma da outra para permitir a ozonólise seletiva da dupla ligação central, mais nucleofílica. Nesta última rota sintética, dois macrociclos foram preparados em sete etapas, envolvendo duas reações de Diels-Alder, com rendimento total de 36,3% e 42,1%, respectivamente. / Furanoheliangolides are bioactive natural products containing a peculiar macrocyclic structure. The synthesis of these compounds has been a matter of considerable interest to several researchers. In the last few years, our research group has dedicated some efforts to develop synthetic methods for the preparation of the core structure of the furanoheliangolides, particularly goyazensolide. The core structure of this natural product corresponds to the 7- oxabicyclo[6.2.1]undecane system. This natural product has several biological activities, such as schistosomicidal, cytotoxic and anti-inflammatory. Our methodology uses, as a key step, the Diels-Alder reaction. After the preparation of the polycyclic system, the cleavage of the internal bond of the rings should furnish the desired macrocycle. In this work, three synthetic routes to the preparation of the core structure of the furanoheliangolides were studied. In the first route, the Diels-Alder reaction between 2-methylfuran and methyl 3-bromopropiolate, occurred with unusually high regioselectivity The cyclization reaction for the formation of the polycyclic system was investigated with three different compounds. However, none of these reactions furnished the desired product, but resulted instead in complex mixtures of products. These results showed the difficulty to perform cyclization reactions in compounds of this type. Other substrates could have been used, but considering these discouraging initial results, we preferred to start the studies of a new synthetic route. In the second route we were still attempting to introduce a three-carbon group to form the new six-membered ring; the main modification was that we would now start from the other side of the molecule. The aldehyde could be obtained in good yield, but the aldol reaction product of this aldehyde with the ketone is very unstable. As we have found in experiments with a simple ketal, the hydrolysis of ketals of this type require rather strong acidic treatment. Therefore, the aldol product would not withstand these conditions, so we abandoned these studies. In the third synthetic route, the methodology consisted of building the polycyclic system through two Diels-Alder reactions followed by an ozonolysis reaction to cleave the central double bond. The stereochemistry of the addut obtained in the second Diels-Alder reaction was confirmed by NMR studies. The ozonolysis of this product produced the desired core of the furanoheliangolides. As the imide group of this macrocycle is very resistant to hydrolysis and other reactions, we have also developed a modification that produces a more treatable product. The diene used in this second Diels-Alder reaction does not give Diels-Alder adduct with maleic anhydride, but it reacts well with dimethyl acetylenedicarboxylate to give correspondent addut. The two double bonds of this addut are sufficiently different from each other to permit the selective ozonolysis of the more nucleophilic central bond. In this last synthetic route, two macrocycles were prepared in seven steps, involving two Diels-Alder reactions, with overall yields of 36.3% and 42.1%, respectively.

A Baccharis coridifolia é uma planta tóxica da família Compositae, gênero Baccharis L., conhecida popularmente como \"mio-mio\", a qual é encontrada no sul do Brasil e também em algumas regiões do Estado de São Paulo. Em bovinos, a intoxicação provoca lesões necróticas no trato gastrintestinal e nos tecidos linfóides sólidos em geral, com exceção do timo. Já em camundongos, a B. coridifolia promove, além das lesões em órgãos linfóides, lesões necróticas também no timo. Os princípios ativos da B. coridifolia foram isolados e identificados como sendo os tricotecenos macrocíclicos: roridinas A, D e E; verrucarinas A e J e miotoxina A. Em relação ao mecanismo de ação, trabalhos recentes in vitro demonstraram que as roridinas e as verrucarinas, promovem apoptose em tecido linfóide. Deste modo, considerando a toxicidade desta planta aos tecidos linfóides, o objetivo do presente estudo foi investigar se linfócitos tumorais (linfoma) seriam mais sensíveis aos efeitos tóxicos da B. coridifolia que linfócitos normais. Para tal, fez-se um experimento in vitro com culturas de linfócitos provenientes do baço e timo de camundongos hígidos, bem como células do linfoma murino A20 e carcinoma mamário de Ehrlich tratadas com o Resíduo Hexânico (RH) obtido do extrato etanólico de B. coridifolia por 24 horas. A viabilidade celular foi verificada pela técnica MTT, na qual se evidenciou diminuição da viabilidade das duas linhagens tumorais tratadas, linfoma A20 e carcinoma de Ehrlich, sem alteração na viabilidade dos linfócitos normais. Para melhor caracterizar este efeito tóxico do RH em linfócitos tumorais, camundongos nude (NMRI-nu/nu) foram inoculados com células A20, sendo posteriormente tratados por via oral, durante sete dias, com RH, associado ou não a uma aplicação intraperitoneal do quimioterápico ciclofosfamida no primeiro dia de tratamento. Resultados mostraram que os animais tratados com RH foram menos afetados com a ocorrência de metástase do linfoma primário para outros órgãos e que as involuções tumorais foram mais expressivas no grupo submetido à associação deste tratamento com uma aplicação de ciclofosfamida. Estes resultados permitem sugerir que linfócitos tumorais são mais suscetíveis aos efeitos tóxicos da B. coridifolia. / Baccharis coridifolia is a toxic plant from Compositae family, genus Baccharis L., known as \"mio-mio\". It is found in the south of Brazil, as well as in some regions of São Paulo state. In bovines, its intoxication leads to necrotic injuries to gastrointestinal tract and linfoid tissues. In mice, B. coridifolia leads, apart from linfoid solids in general to necrotic injuries in thymus. B. coridifolia\'s active principles were isolated and identified as being macrocyclic tricotecenes: roridines A, D and E; verrucarines A and J and miotoxine A. Related to action pathway, recent research (in vitro) has shown that roridines and verrucarines, B. coridifolia\'s active principles, lead to apoptosis in linfoid tissues. Therefore, considering this plant\'s toxicity to linfoid tissues, this work aimed the study of whether tumoral lymphocytes (lymphoma) would be more sensitive to B. coridifolia\'s effects than regular lymphocytes. In this sense, an experiment was carried out (in vitro) using healthy mice\'s lymphocytes from spleens and thymus, as well as cells from murine A20 lymphoma and Ehrlich breast carcinoma treated with a residue (RH, hexane obtained) from a B. coridifolia\'s ethanol effusion (24 hours). The cell viability was tested using MTT technique, where a decrease in viability was found for treated tumoral cells lineages, A 20 lymphoma and Ehrlich carcinoma, with no changes in normal lymphocytes viability. To find a better characterization to RH\'s toxic effect in tumoral lymphocytes, nude mice (NMRI-nu/nu) were inoculated with A 20 cells and then were orally treated, during 7 days, with RH, and, in some cases, with intraperitonial injection of cyclophosphamide, during the first day of treatment. Results showed that RH treated animals were less affected to primary lymphoma metastasis in other organs and tumoral involutions were more prominent in the group treated with cyclophosphamide concomitantly. These results suggest that tumoral lymphocytes are more susceptible to B. coridifolia\'s toxic effects.

Taxol™, isolated from the bark of Taxus brevifolia in the late 1960s, and the semisynthetic analog Taxotere™ have proven clinical importance for the treatment of ovarian and breast cancer. Taxol™ exerts its biological effect by binding to polymerized tubulin and stabilizing the resulting microtubules. Studies aimed at understanding the biologically active conformation of taxol and its binding environment on β-tubulin are described. This knowledge is important because it could lead to the design of structurally less complicated drugs with better efficacy and better bioavailability. Moreover, the information can be extended to other natural products that possess microtubule-stabilizing properties similar to Taxol™. In this work, the synthesis of a triply labeled taxol analog is described as well as REDOR studies of this compound complexed to tubulin are in progress. Macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. Chemical modeling of these analogs and their activities agrees with the hypothesis that Taxol™ adopts T-shaped conformation. Difficulties were encountered with the key ring-closing metathesis strategy, suggesting that a more flexible and efficient macrocyclization method will be needed to synthesize additional macrocyclic analogs. / Ph. D.