This thesis discusses the progress made towards a formal total synthesis of triptolide, a naturally occurring diterpenoid triepoxide molecule. Isolated from a Chinese vine, triptolide features some interesting structural characteristics and has demonstrated a broad range of interesting medicinal effects. It has demonstrated remarkable cytotoxicity against a number of cancer cell lines, immunosuppressive activity, and reversible male sterility. This biological activity has made it a target of a number of total syntheses spanning from 1980 to 2010. Gold-catalyzed transformations are an emerging field in synthetic organic chemistry, but their efficacy and potential uses are gaining much recognition among the synthetic organic community. Our research group is extremely interested in the applications of such gold-catalyzed organic transformations in natural product synthesis. Here, we discuss our investigations towards accessing the tetracyclic core of triptolide using a gold-catalyzed cyclization cascade reaction. We explored a number of synthetic routes towards a common linear precursor, and our successes and failures are discussed herein. We also report numerous unsuccessful efforts towards an oxidative gold-catalyzed cyclization cascade to form the tetracyclic core of triptolide. Finally, we investigated the use of a photocatalytic radical cyclization cascade to access the desired core. We report some promising preliminary results, and this study is ongoing in the Barriault group.

Gold catalysis has become an important tool to achieve highly chemoselective p-acid activation. Exceptional reactivity and selectivity are often encountered under mild reaction conditions. These properties have made gold(I) complexes suitable catalysts for tremendous applications in the total synthesis of natural products. The first chapter will highlight a number of total syntheses using gold catalysis as a key step. The second chapter will cover our application of the gold(I)-catalyzed 6-endo-dig carbocyclization for the synthesis of bridgehead-substituted scaffolds and its use toward the synthesis of PPAP natural products. This research has opened our eyes to the utility of biphenylphosphine ligands, particularly JohnPhos, in gold(I)-catalysis. The reactivity and selectivity exhibited by gold(I) complexes is modulated by the nature of the ancillary ligand. Recent research rationalizes the impact of these ligands on the divergent reactivity observed between cationic and carbenoid intermediates. Our desire to favor the 6-endo-dig pathway has led us toward the discovery of another example of the diagonal reactivity that NHC carbene and biphenylphosphine ligands can bring to gold(I)-catalysis. Chapter three will explain the development of a selective gold-catalyzed synthesis of fused carbocycles . Our selective divergent synthesis of fused carbocycles, combined with the Diels–Alder reaction, has brought new synthetic opportunities. Chapter four will describe our approach toward the synthesis of various polycyclic diterpene-related frameworks. Starting with a unique linear precursor, we have developed a new “one-pot” process for the synthesis of three different polycyclic compounds related to the terpenoid family. The facile modulation of the linear precursor and the use of different dienophiles during the Diels–Alder reaction could enable the synthesis of diverse polycyclic analogues based on three principal frameworks. The gold(I)-catalyzed synthesis of fused carbocycles reached some limitations during our study. Regioselective control was found to be substantially more challenging, with terminal alkynes or alkynes bearing a sterically and electronically neutral methyl substituent. In chapter five, we will discuss how the complementarity of silver(I) catalysis to gold(I) catalysis enabled the selective divergent synthesis of three different fused carbocycles from a unique precursor. Moreover, copper(I) catalysis has given access to the 6-endo-dig pathway on terminal alkynes without the formation of a vinylidene intermediate.

Οι κυκλινοεξαρτώμενες κινάσες (Cdks) είναι μια κατηγορία των πρωτεϊνικών κινασών, οι οποίες ενεργοποιούνται μέσω σύνδεσης με την κατάλληλη κυκλίνη και εμπλέκονται στη ρύθμιση του κυτταρικού κύκλου. Η ενεργοποίηση συγκεκριμένων συμπλόκων Cdks-κυκλινών επιτρέπει την ομαλή μετάβαση από την μία στην επόμενη φάση του κύκλου. Ωστόσο, η υπερλειτουργία των Cdks οδηγεί σε ανεξέλεγκτο κυτταρικό πολλαπλασιασμό, με αποτέλεσμα την εμφάνιση διαφόρων ασθενειών, όπως είναι ο καρκίνος, η νόσος του Alzheimer και ο διαβήτης. Λόγω αυτού, οι Cdks αποτελούν υποψήφιους μοριακούς στόχους για την θεραπευτική αντιμετώπιση αυτών των ασθενειών. Πολλά μικρά χημικά μόρια έχουν αποδειχθεί αναστολείς των CDKs. Κάποιοι από αυτούς έχουν προχωρήσει σε κλινικές δοκιμές φάσης Ι και ΙΙ, ωστόσο κανένας δεν έχει λάβει έγκριση για κυκλοφορία. Πρόσφατα, ο Cdk αναστολέας Dinaciclib εισήλθε σε κλινικές δοκιμές φάσης ΙΙΙ. Τα θαλάσσια σφουγγάρια αποτελούν πλούσια πηγή φυσικών προϊόντων με ανασταλτική δράση έναντι πλήθους κινασών. Η Hymenialdisine (HMD) είναι ένα φυσικό προϊόν, το οποίο έχει απομονωθεί από διάφορα είδη θαλάσσιων σφουγγαριών και εμφανίζει ανασταλτική δράση έναντι πολλών πρωτεϊνικών κινασών, μεταξύ των οποίων και οι CDKs. Στα πλαίσια της παρούσας μελέτης σχεδιάσθηκαν και συντέθηκαν νέα σπειρανικά ανάλογα της HMD με σκοπό να εμφανίσουν ισχυρότερη και εκλεκτικότερη ανασταλτική δράση από αυτήν έναντι πρωτεϊνικών κινασών. Οι νέες ενώσεις φέρουν δομικά χαρακτηριστικά της HMD, όπως έναν πυρρολο[2,3-c]αζεπινονικό δακτύλιο που έχει αποδειχθεί κρίσιμος για την ανάπτυξη δεσμών υδρογόνου με τη θέση πρόσδεσης του ATP. Ωστόσο, ο γλυκοκυαμιδινικός δακτύλιος της HMD έχει αντικατασταθεί στα νέα ανάλογα από έναν εξαμελή λακταμικό σπειρανικό δακτύλιο. Η συνθετική προσέγγιση που ακολουθήθηκε για την σύνθεση των νέων ενώσεων περιελάμβανε αρχικά την ανοικοδόμηση του πυρρολο[2,3-c]αζεπινο-4,8-διονικού δακτυλίου και στην συνέχεια την μετατροπή της 4-κετο-ομάδας αυτού σε ένα αμινο-υποκατεστημένο στερεογονικό κέντρο. Για τον σκοπό αυτό, χρησιμοποιήθηκε μια κλασσική μεθοδολογία, η οποία περιελάμβανε συμπύκνωση του παραπάνω δακτυλίου με χειρόμορφα t-βουτυλοσουλφινυλαμίδια και νουκλεόφιλη προσβολή των ενδιάμεσων σουλφινυλιμινών που προέκυψαν με οργανομεταλλικά αντιδραστήρια Grignard. Η συνθετική προσέγγιση που ακολουθήθηκε επέτρεψε την σύνθεση εναντιομερών σπειρανικών αναλόγων της HMD. Η αποτίμηση της βιολογικής δράσης των νέων ενώσεων αναμένεται σύντομα. / Cyclin-dependent kinases (Cdks) are protein kinases and their enzymatic activity requires the binding of a regulatory cyclin subunit. Cdks are implicated in the regulation of the cell cycle. The activation of different Cdks-cyclin complexes drives the transition of cell through the distinct phases of the cell cycle. However, overactivation of Cdks results in uncontrolled cell proliferation and hence, in many diseases such as cancer, Alzheimer’s disease and diabetes. Cdks represent candidate molecular targets for the treatment of these diseases. Many small molecules have been proved potent Cdks inhibitors. Many of them, are in phase I or II of clinical trials. Recently, Dinaciclib became the first Cdk inhibitor which entered in phase III of clinical trials. The sea sponges are a rich source of natural products which present inhibitory activities against protein kinases. Hymenialdisine (HMD) is a natural product, which has been isolated from many sea sponges and inhibits many kinases, such as Cdks. In this research work, new spiro analogues of HMD were designed and synthesized, aimining at the discovery of new compounds with enhanced inhibitory activity and selectivity against to protein kinases. These new compounds bear structural characteristics of HMD, like a pyrrolo[2,3-c]azepinone ring, which is crucial for the binding of HMD to the ATP-binding site of the enzyme. The glycocyamidine ring of the HMD has been replaced by a six-membered lactam spiro-ring. The synthetis of new compounds involves the formation of the pyrrolo[2,3-c]azepino-4,8-dione and subsequently the introduction of a new amino-substituted stereogenic center. Key-step to this approach is the substitution of the intermediate chiral t-butanesulfinylimines by organometallic reagents. The synthetic approach provides access to different stereoisomers. The biological evaluation of the new compound is in progress.

Les motifs polyènes constituent une fonction importante parmi les composés organiques et sont présents dans de nombreux composés naturels sous la forme de diènes 1,3-conjugués. Il est donc essentiel de mettre au point des méthodes permettant d’accéder à ces diènes tout en portant un regard attentif à l’impact environnemental. Au cours de ces travaux, nous avons pu synthétiser un composé naturel ayant une incidence sur le diabète de type II : l’acide abscissique. L’étape clef conduisant au succès de cette synthèse est la réaction de Heck. A partir de ces résultats, nous avons mis au point une méthode robuste et efficace pour obtenir divers composés diéniques (E,Z) et triéniques (E,E,Z) en s’affranchissant d’utiliser des ligands ou un solvant. Les composés ainsi obtenus sont envisagés comme potentiels analogues de l’acide abscissique et sont engagés dans diverses réactions afin d’essayer d’obtenir l’acide carboxylique correspondant ou un bioisostère de ce dernier. En parallèle, nous avons mis au point une voie d’accès à des composés de type benzo[d]thiazole substitués en position 2 par un groupement N-aryle ou N-alkyle. Cette méthodologie de synthèse s’inscrit dans un contexte d’écocompatibilité par l’utilisation d’une catalyse au diiode. / Polyene units constitute an important function from organic compounds and are present in many natural products in the form of 1,3-conjugated dienes. It is therefore essential to develop methods to access these dienes while wearing a careful look at the environmental impact. During this work, we were able to synthesize a natural compound which has activity on type II diabetes: the abscisic acid. The key step leading to the success of this synthesis is the Heck reaction. From these results, we have developed a robust and efficient method to obtain various diene compounds (E, Z) and trienes (E, E, Z) without ligand or solvent. The compounds thus obtained are considered as potential analogues of the abscisic acid and are involved in various reactions in order to obtain the corresponding carboxylic acid or its bioisostere. In parallel with this synthesis application, we have developed a pathway to obtain benzo[d]thiazole compounds substituted in position 2 with an N-aryl or N-alkyl. This synthetic methodology is part of a context of environmental compatibility by using iodine catalyst.

Made available in DSpace on 2014-06-11T19:32:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-11-26Bitstream added on 2014-06-13T18:43:57Z : No. of bitstreams: 1 lopes_fcm_dr_arafcf.pdf: 1909059 bytes, checksum: 974b3ea32c4f5b47c9236b3e9490981c (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Universidade Estadual Paulista (UNESP) / Produtos naturais têm contribuído intensamente para o desenvolvimento da terapêutica moderna. As plantas produzem um vasto número de substâncias, que em estado natural ou após sofrerem transformações químicas, possuem diversas atividades farmacológicas. Fungos endofíticos, organismos que vivem no interior das plantas, também podem representar novas fontes de produtos biologicamente ativos. Atualmente, a relação causal entre inflamação, imunidade inata e câncer é largamente aceita. O envolvimento de mediadores inflamatórios, como óxido nítrico (NO) e citocinas, gerados por macrófagos ativados, na patogênese das doenças inflamatórias já está bem estabelecido. Além disso, a inibição da angiogênese tem sido reconhecida como uma promissora abordagem terapêutica para o controle do crescimento tumoral, das metástases e das doenças inflamatórias crônicas. Alchornea glandulosa Poepp & Endl. (Euphorbiaceae) é uma planta com conhecida atividade antiinflamatória que está distribuída do sudeste ao sul do Brasil, principalmente na Mata Atlântica e no Cerrado. O potencial antiinflamatório, antitumoral e antiangiogênico dos compostos obtidos a partir da planta (fração acetato de etila e os compostos puros isoquercitrina, afzelina, ácido gálico, pteroginina e pteroginidina) e de fungos endofíticos presentes no interior das suas folhas (extratos acetato de etila ALG-A, ALG-02 e ALG-03) foram estudados por meio de experimentos utilizando-se culturas de macrófagos murinos, linhagens tumorais murinas de câncer de mama (LM2) e pulmão (LP07) e culturas de células endoteliais de veia umbilical humana (HUVEC). Ensaios de determinação de óxido nítrico (reagente de Griess), citocinas pró-inflamatórias TNF-α, IL-1β, IL-6 e IL-12 (ELISA), atividade citotóxica (MTT) e avaliação da taxa de inibição do crescimento de tumores tratados com injeção... / Natural products have contributed enormously to the development of important therapeutic drugs used currently in modern medicine. Plants produce a vast number of compounds that, either directly or after chemical modifications, exert pharmacological activities. Endophytic fungi, organisms which live in plants, are also being recognized as new sources of biological active substances. Nowadays, the relationship among inflammation, innate immunity and cancer are widely accepted. Inflammatory mediators as nitric oxide (NO) and cytokines produced by activated macrophages are involved in the pathogenesis of inflammatory diseases. Besides that, angiogenesis inhibition has been accepted as a promising therapy for the control of tumor growth, metastasis and also chronic inflammatory conditions. Alchornea glandulosa Poepp & Endl. (Euphorbiaceae) is a plant that demonstrates anti-inflammatory activity. It can be found in Brazil, distributed from southeast to south, mainly in the Atlantic Forest and Cerrado. The anti-inflammatory, antitumor and antiangiogenic potential of the compounds obtained from this plant (ethyl acetate fraction and the pure compounds isoquercitrin, afzelin, gallic acid, pterogynine and pterogynidine) and from the endophytic fungi present in its leaves (ALG-A, ALG-02 and ALG-03 ethyl acetate extracts) were studied using macrophage cultures, tumor cell lines (LM2 and LP07) and human umbilical vein endothelial cells (HUVEC). To evaluate anti-inflammatory and antitumor activity, in vitro assays were utilized to determine NO (Griess reagent), TNF-α, IL-1β, IL-6 and IL-12 proinflammatory cytokines (ELISA) and cytotoxicity (MTT). Tumor growth inhibition rate was also studied in vivo. Apoptosis (TUNEL assay), proliferation (bromodeoxiuridine – BrdU), invasion (double-chamber assay), capillary-like structures formation (matrigel) and NFκB activity (ELISA) were realized to study... (Complete abstract click electronic access below)

Submitted by Regina Correa (rehecorrea@gmail.com) on 2016-10-03T20:53:43Z No. of bitstreams: 1 TeseACBMM.pdf: 12490231 bytes, checksum: 097b90957f143d8d696733602a92d242 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2016-10-05T13:41:11Z (GMT) No. of bitstreams: 1 TeseACBMM.pdf: 12490231 bytes, checksum: 097b90957f143d8d696733602a92d242 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2016-10-05T13:41:20Z (GMT) No. of bitstreams: 1 TeseACBMM.pdf: 12490231 bytes, checksum: 097b90957f143d8d696733602a92d242 (MD5) / Made available in DSpace on 2016-10-05T13:48:36Z (GMT). No. of bitstreams: 1 TeseACBMM.pdf: 12490231 bytes, checksum: 097b90957f143d8d696733602a92d242 (MD5) Previous issue date: 2015-03-20 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Breast cancer is the leading cause of death in Brazil and worldwide, between the types of cancer, triple negative TNBC (Triple Negative Breast Cancer), which do not express hormone receptors, represents 20% of the cases and presents relapses within 3 years. However, the major cause of death in cancer is due the formation of metastasis. The TNBC has a greater propensity to form lung and brain metastasis. Furthermore, currently few treatments are available. Search for new target treatments, with fewer side effects is very important to treat this disease. Natural products are rich sources of molecules with antitumoral activity; among them are the gingerols, from ginger and resveratrol, from grapes. Nevertheless, not much is known about antitumor activity of [10]-gingerol (10G). Therefore, the aim of this work was to investigate the potential use of 10G as an antimetastatic molecule in in vitro and in vivo experiments. In this work, 10G had antiproliferative activity on several breast cancer cell lines (4T1BM2, 4T1BM2 shRNAβ3, 4T1Br4, MDA-MB-231, MDA-MB-231 BrM) and on a normal cell line, bEnd.3. The natural compounds affected tumor cell morphology and RSVT was able to inhibit cell migration and adhesion through vitronectin. 10G induced apoptosis via the extrinsic pathway through the increase of caspase-9, -3 and -7 expression and decrease of Bcl-2 expression, induced cell cycle arrest in G1 and subG0 phase. In in vivo models, 10G inhibited primary tumor growth and lung metastasis, as well as bone and brain metastasis. Therefore, this study was able to provide new data as 10G can be acting in tumor cells and its possible clinical application. / O câncer de mama é o que mais afeta as mulheres no Brasil e no mundo, entre os tipos de câncer de mama, o triplo negativo TNBC (Triple Negative Breast Cancer), que não expressa nenhum receptor hormonal, corresponde a 20% dos casos e apresenta recidivas em três anos. Entretanto, a maior causa de morte no câncer é devido a formação de metástases. O TNBC possui uma maior propensão a metástases pulmonares e cerebrais. Além disso, atualmente poucos tratamentos estão disponíveis. Buscas para novos medicamentos alvo para o TNBC e com menos efeitos colaterais são de grande importância para o tratamento dessa doença. Produtos naturais são fontes ricas em moléculas com atividades antitumorais, dentre elas os gingeróis, presentes no gengibre e o resveratrol (RSVT), presente nas uvas. Entretanto, pouco se sabe da atividade antitumoral do [10]-gingerol (10G). Este trabalho teve como objetivo investigar o potencial uso do 10G como molécula antimetastática em experimentos in vitro e in vivo. Neste trabalho verificou-se a atividade antiproliferativa do 10G e do RSVT em diversas linhagens de câncer de mama (4T1BM2, 4T1BM2 shRNAβ3, 4T1Br4, MDA-MB- 231, MDA-MB-231 BrM) e um controle de célula normal, a bEnd.3. Os produtos naturais (PNs) usados afetam a morfologia celular nas células tumorais e o RSVT é capaz de inibir a adesão e migração via vitronectina. O 10G induziu apoptose da linhagem 4T1Br4 através da via extrínseca, com o aumento da expressão de casspase-9, -3 e -7; induziu a parada do ciclo celular nas fases G1 e sub G0. Em modelos de metástase in vivo o 10G inibiu o crescimento do tumor primário e de metástases pulmonares, além de inibir metástases ósseas e cerebrais. Portanto, este trabalho foi capaz de fornecer dados de como o 10G atua nas células tumorais e sua possível aplicação clínica.

Resumo: Dentre os fatores que podem afetar a produtividade de feijão caupi detaca-se o ataque de Bemisia tabaci (Gennadius, 1889) biótipo B. Dessa forma, o objetivo desse trabalho foi avaliar a resistência de feijão caupi associado a doses de nim no desenvolvimento e oviposição de mosca branca. Os experimentos foram conduzidos em casa de vegetação no Departamento de Fitossanidade da Faculdade de Ciências Agrárias e Veterinárias, UNESP/Câmpus de Jaboticabal-SP, no período de outubro de 2009 a agosto 2010. Foram realizados testes para oviposição, com e sem chance de escolha, antibiose e ação ovicida. Para identificar os tipos de resistência avaliou-se sete genótipos de Vigna unguiculata L. (Walp.), BRS Milênio, BR17 Gurguéia, BR3 Tracuateua, BRS Novaera, Sempre Verde, BRS Urubuquara e IPA-206. De acordo com os dados obtidos pode-se concluir que os genótipos BRS Urubuquara, IPA-206 e BR17 Gurgueia apresentaram resistência do tipo não preferência para oviposição de B. tabaci biótipo B; o genótipo BRS Urubuquara apresenta resistência do tipo não preferência para alimentação e/ou antibiose; o genótipo Sempre Verde foi o mais suscetível; e, B. tabaci biótipo B prefere ovipositar na face abaxial das folhas na posição superior das plantas de caupi. Posteriormente, foram selecionados dois genótipos resistentes e um suscetível ao ataque de mosca branca, os quais foram associados a diferentes doses de produto natural a base de óleo de nim, sendo realizados testes de não preferência para oviposição, antiobiose e ação ovicida. De acordo com os dados obtidos pode-se concluir o genótipo BRS Urubuquara e IPA-206 associados ou não ao óleo de nim foram os menos ovipositados por B. tabaci biótipo B; a associação do óleo de nim com o genótipo Sempre Verde reduziu a oviposição do inseto; a posição superior das folhas na planta é a mais ovipositada pela praga... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Amongst the factors that can affect the cowpea productivity, the Bemisia tabaci (Gennadius, 1889) biotype B stands out. The objective of this study was to evaluate the cowpea resistance associated to neem dosages at the whitefly development and oviposition. The experiments were conducted at a greenhouse at the Departamento de Fitossanidade of the Faculdade de Ciências Agrárias e Veterinárias, UNESP/Câmpus de Jaboticabal-SP, between october 2009 and August 2010, oviposition (chance and non-chance), antibiosis and neem oil ovicide action tests were performed. To identify the resistance types, seven Vigna unguiculata genotypes: BRS Milênio, BR17 Gurguéia, BR3 Tracuateua, BRS Novaera, Sempre Verde, BRS Urubuquara and IPA-206, were evaluated. According to obtained data, it can be concluded that the BRS Urubuquara, IPA-206 and BR17 Gurgueia presented non-preference for oviposition of B. tabaci biotype B resistance; the BRS Urubuquara genotype presented non-preference resistance for feeding and/or antibiosis; the Sempre Verde genotype was the more susceptible to infestation; and the B. tabaci biotype B prefers to ovipositate at the leaves abaxial faces of the upper cowpea plant position. After that, two resistant and one susceptible to whitefly infestation genotypes were selected. Those were then associated to a natural product with different neem oil dosages and non-preference for oviposition, antibiosis and ovicide action tests were then performed. According to obtained data it can be concluded that the BRS Urubuquara and IPA-206, associated or not to neem oil, were the less ovipositated by the B. tabaci biotype B; association between neem oil with the Sempre Verde genotype reduced the oviposition; the abaxial leaves faces of the upper cowpea plant position were the most affected by infestation at the Sempre Verde and IPA-206 genotypes; the neem oil provided... (Complete abstract click electronic access below) / Orientador: Arlindo Leal Boiça Júnior / Coorientador: Paulo Roberto da Silva Farias / Banca: Antonio Carlos Busoli / Banca: Marcelo Francisco Arantes Pereira / Mestre

Pond management in the Czech Republic uses semi-intensive methods to produce market carp in fishing ponds. Natural food complemented with cereals play an important role in this economical and environment-friendly method of fish breeding. The system makes it possible to increase weight gains of carps in comparison with natural production. At this level of production the market carp maintains high quality meat and therefore it is highly valued also on markets abroad. Every year approximately one half of the market carp production is exported from the Czech Republic and the rest is sold in this country. The purpose of my work is to assess the existing technology of additional feeding of market carp in Fishery Chlum u Třeboně, where I have monitored the stock, spring and , losses, individual weights, weight increases, used feed and feed coefficients. I have also cooperated on monitoring of pilot plant tests in the system of Humlenské ponds where the carps were fed with various cereals

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Atualmente hà um aumento no interesse em desenvolver novos agentes terapÃuticos a partir de molÃculas biologicamente ativas presentes em fontes naturais, e os organismos marinhos tem-se destacado. Dentro deste contexto, as algas marinhas vermelhas tÃm recebido muita atenÃÃo por apresentar propriedades biolÃgicas e farmacolÃgicas ativas, como: antibacteriana, antioxidante, antiviral, antitumoral, antitrombÃtica, prÃ-trombÃtica, antinociceptiva, antinflamatÃria, anticoagulante e anticancerÃgena. Pesquisas recentes mostram que muitos bioativos obtidos de origem marinha apresentam grande potencial para aplicaÃÃes neurofarmacolÃgicas. Assim o objetivo desta dissertaÃÃo foi avaliar os efeitos dos polissacarÃdeos sulfatados totais (PST) obtidos da alga marinha vermelha Gracilaria cornea no Sistema Nervoso Central, em modelos clÃssicos de animais (labirinto em cruz elevada (LCE), campo aberto, Placa perfurada, rota rod, nado forÃado e suspensÃo de cauda) para screening de drogas com atividades relacionadas com as desordens neurocomportamentais, como ansiedade e depressÃo. Para a realizaÃÃo dos experimentos foram utilizados camundongos Swiss, machos, pesando de 25-32g, provenientes do biotÃrio da Universidade Federal do CearÃ. Os animais foram tratados agudamente com PST nas doses de 0,1, 1 ou 10 mg/kg, via intraperitoneal. Trinta minutos apÃs o tratamento, os animais foram submetidos aos testes comportamentais de locomoÃÃo (campo aberto e rota rod), ansiedade (LCE e placa perfurada) e depressÃo (nado forÃado e suspensÃo de cauda). Os resultados mostraram que PST, na dose de 10 mg/kg, apresentou efeito ansiolÃtico nos modelos de LCE e placa perfurada, pois aumentou todos os parÃmetros analisados no LCE, assim como o nÃmero de mergulhos nos orifÃcios da placa perfurada. Este efeito està provavelmente relacionado com o sistema gabaÃrgico, pois o flumazenil, antagonistas dos receptores GABAA/ BenzodiazepÃnicos, reverteu o efeito ansiolÃtico dos PST no LCE. No teste de campo aberto a dose de 10 mg/kg aumentou o nÃmero de quadrantes e o nÃmero de rearing, tento uma aÃÃo exitatÃria, jà no teste de rota rod nÃo houve alteraÃÃo, mostrando que a atividade motora dos animais nÃo foi prejudicada. Na avaliaÃÃo da atividade depressiva, os PST nÃo alteraram o tempo de imobilidade nos testes de nado forÃado e de suspensÃo de cauda, embora a dose de 10mg/kg apresentou uma diminuiÃÃo no parÃmetro analisado, porÃm nÃo significativo. ConclusÃo: os polissacarÃdeos sulfatados totais extraÃdos da Gracilaria cornea, na dose de 10 mg/Kg, sugerem uma aÃÃo ansiolÃtica no Sistema Nervoso Central, possivelmente relacionado com o sistema gabaÃrgico, desprovida de aÃÃo antidepressivo. / Currently there is an increased interest in developing new therapeutic agents from biologically active molecules present in natural sources from marine organisms has been posted. Within this context, red marine algae have received much attention for presenting active biological and pharmacological properties such as antibacterial, antioxidant, antiviral, antitumor, antithrombotic, pro-thrombotic, antinociceptive, anti-inflammatory, anticancer and anticoagulant. Recent surveys show that many bioactive obtained from marine sources have great potential for neuropharmacological applications. Thus the aim of this thesis was to evaluate the effects of sulfated polysaccharides total (PST) obtained from the red seaweed Gracilaria cornea in the Central Nervous System in classic animal models elevated plus maze (EPM), open field, hole board, rota rod, forced swim and tail suspension for the screening of drugs with activities related to neurobehavioral disorders such as anxiety and depression. For the experiments Swiss male mice were used, weighing 25-32g, from the vivarium of the Federal University of CearÃ. The animals were treated acutely with PST at doses of 0.1, 1 or 10 mg/kg intraperitoneally. Thirty minutes after treatment, the animals were subjected to behavioral tests of locomotion (open field and rota rod), anxiety (LCE and hole board) and depression (forced swim and tail suspension). The results showed that PST, at a dose of 10 mg/kg, showed anxiolytic effects in models of EPM and hole board, it increased all parameters analyzed in the EPM, as well as the number of dives in the holes of the perforated plate. This effect is probably related to the GABAergic system because flumazenil, antagonists of GABA/Benzodiazepine receptor, reversed the anxiolytic effects of PST in the EPM. In the open field test dose of 10 mg/kg increased the number of quadrants and the number of rearing, try one exitatÃria action already in the route test rod did not change, showing that the motor activity of the animals was not affected. In the assessment of depressive activity, the PST did not alter the immobility time in the forced swim and tail suspension tests, although the dose of 10mg/kg showed a decrease in the parameter analyzed nonsignificant. Conclusion: total sulfated extracted from Gracilaria cornea, at a dose of 10 mg/kg, polysaccharides suggest an anxiolytic action in the central nervous system, possibly associated with the GABAergic system, devoid of antidepressant action.

Submitted by (edna.saturno@ufrpe.br) on 2016-11-24T16:14:21Z No. of bitstreams: 1 Gustavo Neto Bandeira.pdf: 480654 bytes, checksum: e048697a909f44f9284d66f9f557a5c9 (MD5) / Made available in DSpace on 2016-11-24T16:14:22Z (GMT). No. of bitstreams: 1 Gustavo Neto Bandeira.pdf: 480654 bytes, checksum: e048697a909f44f9284d66f9f557a5c9 (MD5) Previous issue date: 2009-07-01 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The family Brassicaceae is one of the most economically important in the world, having as their main pest to Plutella xylostella (L.) (Lepidoptera: Plutellidae), which causes great damage to the crop with up to 100% of yield losses. In order to investigate alternatives to synthetic insecticides, medicinal plants have been in recent years in search of compounds with insecticidal properties, repellent, fumigant or that act directly on the disruption of biological cycles of pests such as P. xylostella. Furthermore, the literature is scarce when it comes to studies with the use of essential oils and organic extracts to verify their potential insecticide. Accordingly, the medicinal plants chosen to carry out the research potential of the insecticide are the following families: Tiliaceae (Muntingia calabura) Piperaceae (Piper marginatum) Rutaceae (Citrus reticulata x Citrus sinensis, C. reticulata Blanco) and Myrtaceae (Melaleuca leucadendron). The bioassays carried out indicated that P. xylostella larvae were susceptible to all selected plant extracts and oils tested. Furthermore the extract etanolic of flowers (MCEFL) achieved 99.5% of larvalmortality and a lethal concentration LC50 estimated of 1.63 mg/mL. In addition the extract MCEFL caused 100% of pupal inviability on treated larvae. The development of larvae increased 1.62 days when being treated with the extract hexanic of fruits (MCHFR) compared to the untreated ones. P. xylostella was susceptible to all essential oils tested. Among the oils the mosttoxic was those prepared from Citrus (LC50 of 0.55ppm for C. reticulata and 0,78ppm for C. sinensis x C. reticulata). Also, the oil from C. reticulata x C. sinensis increased larval development in 2.2 days compared to the other oils and untreated larvae. / A família Brassicaceae é uma das mais economicamente importantes no mundo, tendo como sua principal praga a Plutella xylostella (L.) (Lepidoptera: Plutellidae), que causa grandes danos à cultura chegando a atingir até 100% de perdas na produção. Tendo em vista a investigação de alternativas aos inseticidas sintéticos, as plantas medicinais tem sido alvo nos últimos anos na busca de compostos com propriedades inseticidas, repelentes, fumigante ou que atuem diretamente na interrupção dos ciclos biológicos de pragas, como a P. xylostella. Por outro lado, a literatura é escassa, quando se trata de estudos com o uso de óleos essenciais e extratos orgânicos para verificar seu potencial inseticida. Nesse sentido, as plantas medicinais escolhidas para realização da investigação do potencial inseticida foram: Muntingia calabura; Piper marginatum; Citrus reticulata x Citrus sinensis, C. reticulata Blanco e Melaleuca leucadendra. Os experimentos realizados com extratos e óleos das diferentes plantas selecionadas mostraram que as larvas de P. xylostella foi sensível a todos. Com relação ao extratos, o mais tóxico foi o extrato etanólico da flor, que promoveu 99,5% de mortalidade de larvas e uma CL50 estimada de 1,63 mg/mL. Na duração da fase larval, o extrato hexânico do fruto prolongou essa fase em 1,62 dias em relação ao controle e quanto à mortalidade da fase pupal, o extrato etanólico da flor inviabilizou completamente a emergência de adultos. As larvas de P. xylostella foi sensível atodos os óleos testados. Os mais tóxicos foram os óleos de Citrus (CL50 0,55ppm para C. reticulata e CL50 0,78ppm para C. sinensis x C. reticulata). Quanto a duração da fase larval, o melhor resultado foi observado para o óleo de C. reticulata x C. sinensis, que apresentou um incremento de 2,2 dias com relação ao controle.