Dissertations / Theses on the topic 'Lignans Lignans'

An introduction to lignans, including classification, occurrrence, biological activity, the role of lignans and their biosynthesis, is described in chapter 1. Chapter 2 presents a review of the conjugate addition reaction, with particular emphasis on chiral conjugate additions. This chapter also reviews the synthesis of lignans via conjugate additions to both chiral and achiral acceptors. Chapter 3 describes an attempt to synthesize lignans via tandem conjugate additions to a chiral crotonate ester. The project was, however, unsuccessful, due to problems associated with the synthesis of the chiral ester. A number of protected derivatives of ethyl 4-hydroxycrotonate were, however synthesized, as were various mono-protected derivatives of (Z)-1,4-dihydroxybut-2-ene. Chapter 4 describes the synthesis of lignans via tandem conjugate addition to chiral (-)-5-(1-menthyloxy)furan-2(5H)-one. Conjugate addition utilizing diphenyl thioacetals as acyl anion equivalents, followed by in situ trapping with aromatic aldehydes or acid chlorides afforded the adducts in good yields. Desulphurisation and dementhylation yielded (-)-epipodorhizol, which on oxidation afforded (-)-podorhizon. This was successfully cyclised to (-)-γ-apopicropodophyllin, thereby constituting a formal total synthesis of chiral deoxypodophyllotoxin. Chapter 5 describes the use of O-tert-butyldimethysilyl protected cyanohydrins as acyl anion equivalents in the conjugate addition to the chiral butenolide. It has been shown that conjugate additions proceed to afford a single isomer, while tandem conjugate additions afford the adduct as a mixture of two isomers. Ketone regeneration from the cyanohydrin causes isomerisation to occur, to afford a single isomer. A novel dementhylation reaction utilizing sodium borohydride, which occurs with concurrent stereoselective reduction of ther benzylic ketone, is discussed. This methodology has realised the chiral synthesis of a member of the retrolignan series, and the potential for the synthesis of chiral 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane lignans is discussed.

Made available in DSpace on 2014-06-11T19:29:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-08-17Bitstream added on 2014-06-13T20:38:31Z : No. of bitstreams: 1 pereira_mdp_me_araiq_parcial.pdf: 203577 bytes, checksum: ca9c116bb7cb586faf5887975ac7eb5b (MD5) Bitstreams deleted on 2014-11-14T12:17:01Z: pereira_mdp_me_araiq_parcial.pdf,Bitstream added on 2014-11-14T12:17:46Z : No. of bitstreams: 1 000718773.pdf: 4442978 bytes, checksum: 32aaf6f2d0d8b0678b1e8f805a2bd0b1 (MD5)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Holostylis reniformis sintetiza uma variedade de compostos, incluindo seco lignanas e sesquiterpenos. Em busca de potenciais compostos antimaláricos, novos estudos fitoquímicos dos extratos de raízes foram realizados. Este trabalho descreve o isolamento de quatorze compostos por meio de técnicas cromatográficas, principalmente por CCD e CC, e CLAE. Estes compostos foram caracterizados por métodos espectrométricos, especialmente por experimentos de RMN e medidas de rotação óptica específica. A partir dos extratos de raízes de H. reniformis três sesquiterpenos novos, 4,5-seco-guaiano (7-epi-11-hidroxichabrolidiona A, XIV), uma lactona de nove membros (holostilactona, XV), e uma megastigmana [(6S,9S,7E)- 6,9-di-hidroxi-10-(2'-hidroxietoxi)-4,7-megastigmadien-3-ona, XVI], juntamente com uma nova lignana [(7R, 7'R,8S,8'S)-8,8'-dimetil-4-hidroxi-3',4',5,7-tetrametil-2,7'- ciclolignana, VIII] foram isoladas. Além disso, os compostos conhecidos sitosterol (I), alantoína (XI), e a lignana furânica futokadsurin C (IX) foram obtidos. Visando estudos posteriores sobre estrutura e atividade antimalárica, o composto (7'R,8S,8'S)-8,8'-dimetil-3',4',4,5-tetrametil-2,7'-ciclolignan-7-ona foi submetido a transformações químicas gerando dois derivados.
Holostylis reniformis can synthesize a variety of seco compounds including lignans and sesquiterpenes. In search of potential antimalarial compounds further phytochemical studies on the root extracts were carried out. This work describes the isolation of 14 compounds by chromatographic techniques, mainly by TLC, CC, and HPLC. These compounds were characterized by spectrometric methods, particularly by NMR experiments and optical rotation measurements. From the root extracts of H. reniformis three new sesquiterpenes, 4,5-seco-guaiane (7-epi-11- hydroxychabrolidione A, XIV), a nine-membered lactone (holostylactone, XV), and a megastigmane [(6S,7E,9S)-6,9-dihydroxy-10-(2'-hydroxyethoxy)-4,7-megastigmadien -3-one, XVI], together with a new lignan [(7R,7′R,8S,8′S)-8,8′-dimethyl-4-hydroxy- 3′,4′,5,7-tetramethoxy-2,7′-cyclolignan, VIII] were isolated. In addition, the known compounds sitosterol (I), allantoin (XI), and a tetrahydrofuran lignans futokadsurin C (IX) were obtained. (7′R,8S,8′S)-8,8′-dimethyl-3′,4′,4,5-tetramethoxy-2,7′-cyclolignan-7-one was subjected to chemical transformations into two derivatives for further structure and antimalarial activity studies

Orientador: Lucia Maria Xavier Lopes
Banca: André Luiz Meleiro Porto
Banca: Monica Tallarico Pupo
Resumo: Holostylis reniformis sintetiza uma variedade de compostos, incluindo seco lignanas e sesquiterpenos. Em busca de potenciais compostos antimaláricos, novos estudos fitoquímicos dos extratos de raízes foram realizados. Este trabalho descreve o isolamento de quatorze compostos por meio de técnicas cromatográficas, principalmente por CCD e CC, e CLAE. Estes compostos foram caracterizados por métodos espectrométricos, especialmente por experimentos de RMN e medidas de rotação óptica específica. A partir dos extratos de raízes de H. reniformis três sesquiterpenos novos, 4,5-seco-guaiano (7-epi-11-hidroxichabrolidiona A, XIV), uma lactona de nove membros (holostilactona, XV), e uma megastigmana [(6S,9S,7E)- 6,9-di-hidroxi-10-(2'-hidroxietoxi)-4,7-megastigmadien-3-ona, XVI], juntamente com uma nova lignana [(7R, 7'R,8S,8'S)-8,8'-dimetil-4-hidroxi-3',4',5,7-tetrametil-2,7'- ciclolignana, VIII] foram isoladas. Além disso, os compostos conhecidos sitosterol (I), alantoína (XI), e a lignana furânica futokadsurin C (IX) foram obtidos. Visando estudos posteriores sobre estrutura e atividade antimalárica, o composto (7'R,8S,8'S)-8,8'-dimetil-3',4',4,5-tetrametil-2,7'-ciclolignan-7-ona foi submetido a transformações químicas gerando dois derivados.
Abstract: Holostylis reniformis can synthesize a variety of seco compounds including lignans and sesquiterpenes. In search of potential antimalarial compounds further phytochemical studies on the root extracts were carried out. This work describes the isolation of 14 compounds by chromatographic techniques, mainly by TLC, CC, and HPLC. These compounds were characterized by spectrometric methods, particularly by NMR experiments and optical rotation measurements. From the root extracts of H. reniformis three new sesquiterpenes, 4,5-seco-guaiane (7-epi-11- hydroxychabrolidione A, XIV), a nine-membered lactone (holostylactone, XV), and a megastigmane [(6S,7E,9S)-6,9-dihydroxy-10-(2'-hydroxyethoxy)-4,7-megastigmadien -3-one, XVI], together with a new lignan [(7R,7′R,8S,8′S)-8,8′-dimethyl-4-hydroxy- 3′,4′,5,7-tetramethoxy-2,7′-cyclolignan, VIII] were isolated. In addition, the known compounds sitosterol (I), allantoin (XI), and a tetrahydrofuran lignans futokadsurin C (IX) were obtained. (7′R,8S,8′S)-8,8′-dimethyl-3′,4′,4,5-tetramethoxy-2,7′-cyclolignan-7-one was subjected to chemical transformations into two derivatives for further structure and antimalarial activity studies
Mestre

An optimized microwave-assisted extraction (MAE) method is proposed, in conjunction with high performance liquid chromatography (HPLC) analysis, for the general quantification of lignans in flaxseed materials and other plant foods. The method involves hydrolyzing 0.5 – 1.6 g samples with 50 ml of 0.5 M NaOH at 156 W (power level estimated using calorimetric calibration) for 3 min, using intermittent microwave power application (30 s on/off). The final temperature of the extracts is 67°C. The MAE method extracts the lignan from the plant matrix completely, accurately (97.5 % recovery), efficiently (yields 21.4 and 26.6 % higher than those obtained with reference methods), and precisely (coefficients of variation < 4.03 % for repeated determinations). An enzymatic hydrolysis (EH) method, complementary to the MAE method, was developed for the general determination of lignan aglycones in plant samples. The EH method involves hydrolyzing microwave-assisted extracts containing 100 mg sample in 3 ml of sodium acetate buffer (0.01 M, pH 5), with crude solutions of β-glucuronidase using ≥ 40 U of enzyme/mg sample (depending on the hydrolysing capacity of various batches of enzyme) by incubation at 37°C for 48 h. The lignan glucosides are hydrolysed in proportion of 95.6 %. The EH method is recommended for building databases of lignan contents in foods, useful for nutritionists and medical researchers who seek to assess the effects of dietary lignan intake on human health. Artificial neural network (ANN) and partial least squares (PLS) regression models, which are complementary to the MAE method, were calibrated for the general quantification of lignans in a variety of flaxseed materials. The lignan values predicted with the ANN and PLS models were in the range of ± 0.67 to 4.85 % of the reference lignan values. Using the ANN and PLS models requires measuring the UV-Vis light absorption of microwave-assisted flaxseed extracts at 289, 298, 343, and 765 nm, following the Folin-Ciocalteu's assay; the models are useful to the flaxseed processing industry for rapidly and accurately determining the lignan contents of various flaxseed raw materials. A non-automated, affordable and accurate solid phase extraction (SPE) method was developed for purifying microwave-assisted flaxseed extracts. The method requires the preparation of extracts prior to SPE by adjusting the pH of extracts in two stages, 1st to pH 3 with sulphuric acid for removing the water soluble proteins and carbohydrates by precipitation, and 2nd to pH 5 with sodium hydroxide for improving the retention of lignan by the packed SPE phase in order to reduce the lignan losses in the wash-water eluate. Microwave-assisted extracts from 0.6 and 1.5 g defatted flaxseed meal can be purified by SPE in order to recover in the 10, 20 and 30 % ethanol pooled eluates 71.2 % and 60.6 %, respectively, of the amount of lignan subjected to purification. SPE purified extracts can be used for further experiments, such as testing the antioxidant activity and the stability of the lignan extracts during various storage conditions.
Une méthode optimisée d'extraction assistée par micro-ondes (EAMO), en conjonction avec l'analyse par chromatographie liquide de haute performance, est proposée pour la quantification de lignanes, de façon généralisée, dans des échantillons des graines de lin et des aliments d'origine végétale. La méthode nécessite l'hydrolyse des échantillons de 0.5 - 1.6 g avec 50 ml de NaOH 0.5 M en appliquant 156 W (niveau de puissance estimé par calibration calorimétrique) de façon intermittente (30 s marche/arrêt) pour 3 min. La température finale des extraits était de 67°C. La méthode EAMO extrait les lignanes des matrices végétales complètement, avec exactitude (récupération de 97.5 %), avec efficacité (rendements de 21.4 et 26.6 % plus hauts que ceux obtenus avec des méthodes conventionnelles), et avec précision (coefficients de variation pour analyses répétées < 4.03 %).Une méthode d'hydrolyse enzymatique (HE), complémentaire pour la méthode EAMO, a été développée pour la quantification généralisée des lignanes aglycones dans des échantillons végétaux. La méthode HE nécessite l'hydrolyse des extraits, obtenus par EAMO, qui contient 100 mg d'échantillons dans 3 ml de solution tampon d'acétate de sodium (0.01 M, pH 5), avec des solutions d'enzyme β-glucuronidase en concentrations de ≥ 40 U d'enzyme/mg échantillon dépendant de la capacité d'hydrolyse des différents lots d'enzymes), par incubation a 37°C pour 48 h. Les lignanes glucosides sont hydrolysés en proportion de 95.6 %. La méthode HE est recommandée pour construire des bases des données des contenus en lignanes des aliments, qui sont utiles aux chercheurs en santé et nutrition qui cherchent à évaluer les effets des apports nutritionnels des lignanes sur la santé humaine. Des modèles de réseaux de neurones artificiels (RNA) et de régression par les moindres carrés partiels (MCP), qui sont complémentaires pour la méthode EAMO, ont été calibrés pour la quantification généralisée des lignanes dans une variété d'échantillons de graines de lin. Les valeurs des lignanes estimées avec les modèles RNA et MCP ont été dans des écarts de ± 0.67 jusqu'à 4.85 % des valeurs de référence des lignanes. L'utilisation de modèles RNA et MCP nécessite d'effectuer des tests de Folin-Ciocalteu afin de mesurer l'absorption de la lumière UV-Vis des extraits a 289, 298, 343, et 765 nm. Ces modèles sont utiles aux industries de transformations des graines de lin pour quantifier avec rapidité et précision les niveaux de lignanes dans les différentes sources de matières premières à base de graines de lin.Une méthode non-automatisée, abordable et précise d'extraction sur phase solide (EPS) a été développée afin de purifier des extraits de graines de lin produits par EAMO. La méthode nécessite la préparation des extraits avant la EPS par ajustement du pH à deux reprises; premièrement au pH 3 avec de l'acide sulfurique pour enlever, par précipitation, les protéines et les hydrates de carbone qui sont solubles dans l'eau; et, deuxièmement au pH 5 avec de l'hydroxyde de soude pour améliorer la rétention des lignanes en phase solide par l'entonnoir EPS afin de réduire les pertes de lignanes dans l'eau de lavage. Des extraits produits par EAMO à partir de 0.6 et 1.5 g de farine de graines de lin dégraissée peuvent être purifiés par EPS afin de récupérer 71.2 et 60.6 %, respectivement, de la quantité des lignanes utilisée pour la purification, dans les liquides d'élution des10, 20 et 30 % d'éthanol mis en commun. Des extraits purifiés par EPS peuvent être utilisés pour tester la capacité antioxydante et la stabilité des extraits des lignanes durant leur entreposage dans des conditions variées.

An approach to the synthesis of 2,6-diaryl-8-oxo-3,7-dioxabicyclo [3,3,0] octane lignan lactones is presented and then used in the synthesis of the natural products aptosimon and styraxin. The structure of aptosimon has now been confirmed as having a 2,6-diaryl structure rather than the 2,4-diaryl structure which has been postulated in the literature. A germination inhibitor MEL, isolated from Aegilops ovata, has also been synthesised. A key ring closing reaction in this strategy was a Lewis acid catalysed directed aldol reaction between a silyl enol ether and an acetal. A review of similar ring closures in the literature is presented. The use of alpha-arylidene lactones as intermediates in lignin synthesis has also been investigated. The stereochemistry of products from reactions used in this strategy was determined and as a result it was possible to successfully design a stereochemically controlled synthesis of dihydrosesamin.

Orientador: Fernando Antonio Santos Coelho
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química
Made available in DSpace on 2018-08-11T20:25:29Z (GMT). No. of bitstreams: 1 Trazzi_Giordano_D.pdf: 4999245 bytes, checksum: f94ecef7fd826cf4fd4109674ac33860 (MD5) Previous issue date: 2008
Resumo: Lignanas são produtos naturais produzidos por plantas, cuja diversidade estrutural e pronunciada atividade biológica têm atraído o interesse acadêmico e industrial há mais de um século, a exemplo do fármaco antitumoral Etoposide® (Sandoz), derivado semi-sintético da podofilotoxina, uma lignana natural até hoje comercialmente obtida por extração vegetal. Dentre as rotas de síntese de lignanas, as mais eficazes empregam uma b-benzil-g-butirolactona como intermediário-chave da estratégia. Nesse contexto, propusemos o emprego da reação de Morita-Baylis-Hillman (MBH) para o preparo de a-(aril-hidroximetil)- acrilatos (adutos de MBH) e sua utilização como materiais de partida para a síntese de b-(aril-silaniloximetil)-g-butirolactonas, novos intermediários-chave para a síntese de lignanas. Partindo paralelamente do piperonal, do 6-bromo-piperonal e da vanilina, empregamos a reação de MBH para preparar os a-(aril-hidroximetil)- acrilatos correspondentes, e então os utilizamos na preparação de suas respectivas b-(aril-silaniloximetil)-g-butirolactonas, de forma diastereosseletiva e com rendimentos globais de 56% a 69%, em 4 etapas a partir dos adutos de MBH. A b-(piperonil-silaniloximetil)-g-butirolactona foi empregada com alta eficiência na síntese total das lignanas naturais (±)-yateína, (±)-podorrizol e (±)-epi-podorrizol. A b-(6-bromo-piperonil-silaniloximetil)-g-butirolactona permitiu a preparação de um intermediário avançado para uma nova proposta sintética para a (±)- podofilotoxina. A b-(guaiacil-silaniloximetil)-g-butirolactona, obtida a partir da vanilina, e um intermediário chave para a síntese racemica da porção aglicona do medusasídeo A, uma nova lignana da classe dos dibenzilbutanodiois, cuja síntese ainda não foi descrita
Abstract: Lignans are plant-produced natural products, which structural diversity and pronounced biological activity has being attracting the interest of academy and industry through the entire last century, taking as example the antineoplasic drug Etoposide® (Sandoz), a semi-synthetic derivative of podophyllotoxin, a natural lignan which is, up to date, commercially obtained only by vegetal extraction. Among the routes of synthesis to lignans, the most efficient ones uses a b-benzyl- g-butyrolactone as the key intermediate. In this scenario, we have envisaged the use of the Morita-Baylis-Hillman reaction to synthetize a-(aryl-hydroxymethyl)- acrylates (MBH adducts) and it¿s use as starting materials to the synthesis of b-(aryl-silanyloxymethyl)-g-butyrolactones, new key intermediates to the synthesis of lignans. Starting alongside from piperonal, b-bromo-piperonal and vanillin, we used the MBH reaction to prepare the corresponding a-(aryl-hydroxymethyl)-acrylates (MBH adducts), and used it in the preparation of it¿s corresponding b-(arylsilanyloxymethyl)- g-butyrolactones, in a diastereoselective way and with global yields from 56% to 69% in four steps. The b-(piperonyl-silanyloxymethyl)-g- butirolactone obtained was used with high efficiency in the synthesis of natural lignans (±)-yatein, (±)-podorrizol and (±)-epi-podorrizol. The b-(6-bromo-piperonylsilanyloxymethyl)- g-butirolactone obtained allowed the preperation of an advanced intermediate to a new synthetic strategy to (±)-podophyllotoxyn. The b-(guaiacylsilanyloxymethyl)- g-butirolactone obtained is a key intermediate to the racemic synthesis of medusaside A aglycone, a new dibenzylbutanediol lignan whose synthesis was not described yet
Doutorado
Quimica Organica
Doutor em Ciências

Les lignanes sont des composés polyphénoliques largement distribués dans le monde végétal. Le lin, cultivé pour son huile ou sa fibre, renferme de grandes quantités d'un lignane de type dibenzylbutane : le sécoisolaricirésinol, qui est stocké dans le tégument de la graine sous forme diglucosylée, dans une macromolécule contenant de nombreux composés phénoliques assemblés par des liaisons esters. De nombreuses études s'intéressent aux effets bénéfiques sur la santé des lignanes et du sécoisolaricirésinol en particulier, du fait de propriétés antioxydantes marquées, néanmoins le rôle de ces molécules in planta n'est pas clairement élucidé ; un rôle potentiel dans les mécanismes de réponse aux stress est toutefois proposé. Une enzyme clé de la biosynthèse du sécoisolaricirésinol est la PLR (Pinorésinol Laricirésinol Réductase). Des lins RNAi PLR ont montré l’absence d'accumulation de SDG dans les graines. Il est donc envisagé dans cette thèse de comparer le contenu en métabolites (semi-)polaires de lins accumulant du SDG ou non, en condition de stress osmotique ou en condition témoin, par des approches métabolomiques en couplant deux méthodes analytiques : la résonance magnétique nucléaire du proton (RMN 1H) et la chromatographie liquide lié à la spectrométrie de masse (LC-MS). Les résultats ont montré que les plantes de lin témoins ainsi que celles transgéniques déficientes en lignanes, ont une réponse métabolique différente après avoir été exposées à des conditions de stress osmotique, cependant, les deux lignées ont montré une capacité d'induire une réponse adaptative au stress osmotique. Ces résultats suggèrent donc l'implication indirecte des lignanes dans la réponse au stress osmotique
Lignans, phenolic plant secondary metabolites, are derived from the phenylpropanoid biosynthetic pathway. Although, being investigated for their health benefits in terms of antioxydant, antitumor, anti-inflammatory and antiviral properties, the role of these molecules in planta remains not completely elucidated; a potential role in stress response mechanisms has been however proposed. In this study, a non-targeted metabolomic analysis of the roots, stems and leaves of wild type and PLR1-RNAi transgenic flax, devoid of (+) Secoisolariciresinol diglucoside ((+) SDG) – the main flaxseed lignan, was performed using 1H-NMR and LC-MS, in order to obtain further insight into the involvement of lignan in the response of plant to osmotic stress. Results showed that wild type and lignan deficient flax plants have a different metabolic response after being exposed to osmotic stress conditions, but they both showed the capacity to induce an adaptative response to osmotic stress. These findings suggest the indirect involvement of lignans in osmotic stress response

The work described in this thesis outlines the achiral synthesis of lignans and their oxidation. Chapter one classifies lignans and examines their natural occurrence and biological activities. The biosynthesis and synthesis of lignans is also reviewed. Chapter two describes the selective synthesis of trans-dibenzylbutyrolactone lignans. Tandem conjugate addition to 2(5H)-furanone utilising diphenyl thioacteals as acyl anion equivalents, followed by in situ trapping with aromatic benzyl bromides, afforded the adducts in good yields. Desulfurisation yielded the trans-dibenzylbutyrolactone lignans, including enterolactone and matairesinol. The biological activity of some trans-dibenzylbutyrolactone lignans is also discussed. Chapter three describes the non-selective synthesis of cis-dibenzylbutyrolactone lignans. An Aldol reaction with a substituted aromatic aldehyde, followed by acetylation and treatment with NaH, afforded the corresponding α,β-unsaturated lactones in good yields. Subsequent catalytic hydrogenation yielded with cis-dibenzylbutyrolactone lignans as the major product. Chapter four describes the selective oxidative cyclisation of trans-dibenzylbutyrolactone lignans using RUTFA, PIFA and DDQ to afford dibenzocyclooctadiene lignans. The non-selective oxidative cyclisation of cis-dibenzylbutyrolactone lignans was also carried out using the same reagents. It was also shown that cyclisation of para-hydroxy-dibenzylbutyrolactone lignans occurs via a spirodienone intermediate with PIFA is employed. Chapter five describes the selective oxidative cyclisation of trans-dibenzyltetrahydrofuran lignans. Reduction of the trans-dibenzylbutyrolactone lignans, and subsequent dehydration of the resultant dibenzylbutanediols, afforded the dibenzyltetrahydrofurans in good yields. These were successfully cyclised to dibenzocyclooctadiene lignans using RUTFA and PIFA. It was also shown that cyclisation of para-hydroxy-dibenzyltetrahydrofuran lignans occurs via a spirodienone intermediate with PIFA.

The work described in my thesis outlines the achiral and chiral synthesis of lignans by cyclisation reactions via oxidation of phenols. The synthesis of achiral lignans via oxidation of the phenolic tandem conjugate addition products to but-2-en-4-olide utilizing diphenyl thioacetals as acyl anion equivalents, followed by in situ trapping with aromatic aldehyde or benzyl halide afforded the adducts in good yields. Desulphurisation yielded dibenzylbutyrolactones among which were arctigenin and prestegane A. These were successfully cyclised to spirodienone and dibenzocyclooctadiene lignans stereoselectively by the oxidation of the phenolic dibenzylbutyrolactones with bis(trifluoroacetoxy)iodobenzene. The stereochemistry was defined by detailed ¹H and ¹³C nmr studies and confirmed by X-ray analysis. These reactions provide the first synthesis of spirodienones which have been proposed as intermediates in both the synthesis and biosynthesis of the dibenzocyclooctadiene series. The reactions also provide an alternative biomimetic route to compounds of the steganacin and schizandrin type. The asymmetric synthesis of lignans demonstrates the formation and use of (-)-(4R)-4-menthoxybutenolide and benzyl bromide also in tandem conjugate addition reactions. Desulphurisation led to the homochiral menthoxy substituted phenolic dibenzylbutyrolactone which was cyclised successfully via oxidation of the phenol with bis(trifluoroacetoxy)iodobenzene to give a menthoxy substituted dibenzocyclooctadiene which was dementhylated to give the chiral dibenzocyclooctadiene plus a dibenzocyclooctadienediol as a side product. Also dementhylation of the menthoxy substituted dibenzylbutyrolactone gave a dibenzylbutanediol as a side product plus the target dibenzylbutyrolactone. The latter was cyclised via oxidation of the phenol with bis(trifluoroacetoxy)iodobenzene and then gave the chiral dibenzocyclooctadiene lignan.

A lignin epoxide resin was synthesized and characterized. The epoxidation reaction was studied by reacting hydroxypropylated guaiacol (a lignin-like model compound) and epichlorohydrin using a catalyst system of potassium hydroxide and a phase transfer catalyst in toluene. The parameters studied were different epichlorohydrin level and temperature. The reaction was followed by HPLC and the structure of the product was identified with IR, ¹H and ¹³C NMR spectroscopy. The lignin epoxide was synthesized by reacting hydroxyalkylated (hydroxypropyl and hydroxybutyl) lignin with epichlorohydrin using the reaction conditions defined by the model compound studies. The reaction was studied at different epichlorohydrin level and at elevated and room temperature. The epoxy content of the lignin epoxide was determined by titration with HBr and its structure was identified with IR, ¹H and ¹³C NMR spectroscopy. Lignin epoxides were cured by crosslinking with a diamine and with phthalic anhydride. An amine-terminated rubber was added as toughening agent. Sol fraction and swelling behavior, stress-strain behavior and dynamic mechanical behavior of the cured lignin epoxides were studied in relation to cure conditions.
M.S.

Guaiacol and hydroxypropyl-guaiacol were taken as model compounds for lignins and hydroxypropyl lignins to study their vinylation and copolymerization behaviors. Lignin model compounds and lignin were subjected to reaction with isocyanatoethyl methacrylate (IEM) using dibutyltin dilaurate as catalyst. The acrylate derivatives were characterized by elemental analysis, UV, IR, ¹H-NMR, and ¹³C-NMR spectroscopy. The acrylated lignin model compounds, guaiacol-IEM urethane (GIU) and hydroxypropyl-guaiacol-IEM urethane (HPGIU), were copolymerized with methyl methacrylate (MMA) and styrene (St) through free radical mechanism. Solution copolymerizations in 1,2-dichloroethane: ethanol were initiated by benzoyl peroxide. The monomer reactivity ratios were investigated for these copolymerization combinations. The copolymer compositions were analyzed by UV for GIU-co-MMA and HPGIU-co-MMA, while methoxyl content determination by HI-GC was used to determine compositions of styrene-based copolymers. The copolymers were characterized by gel permeation chromatography (GPC), and by IR and NMR spectroscopy. The reactivity ratios were computed by use of the Fineman-Ross linearization method, by the KelenTudos equation and by the Yezrielev-Brokhina-Roskin (YBR) numerical method. A comprehensive analysis with respect to the methods used to derive the ratios has shown that the Kelen-Tudos method and the YBR method produce diagnostic reactivity ratios. A great copolymerization tendency of lignins and hydroxypropylated lignins is predicted from the reactivity ratios of the lignin models. A statistical treatment of the model reactivity ratios lead to prediction for chain sequence length distribution of the copolymers formed. Hydroxybutyl lignin IEM urethanes (HBLIU's) were copolymerized with a vinyl-terminated poly(butadiene-acrylonitrile) macromer and MMA to study the copolymerization behaviors of macromolecular lignin acrylate derivatives. The crosslinked films with desired properties were cast from methylene chloride, with benzoyl peroxide as an initiator. The copolymerized network polymers were characterized by sol fraction measurements, differential scanning calorimetry (DSC), dynamic mechanical thermal analysis (DMTA), and by scanning electron microscopy (SEM). The influences of vinyl content in lignin acrylate derivatives and the ratio of lignin derivatives to vinyl monomer or macromer were studied with respect to structure-property relationship in the copolymers.
M.S.

The 2,6-diaryl-3,7-dioxabicyclo[3,3,0]octanes (or furofurans) belong to the lignan family of natural products. Lignans represent very attractive synthetic targets owing to their large range of biological properties including anticancer, antiviral and immunosuppressant activities. There is considerable structural variation in this series in both the nature and the stereochemistry of the aryl substituents. Since activity is dependent on stereochemistry, synthetic routes, which can provide controlled but tuneable access to one particular class, are very attractive. In this respect, we have been interested in developing efficient ways to synthesise the furofuran skeleton. Based on previous work in our group, the first synthesis of a natural endo-endo furofuran, Epiasarinin, has been achieved via a five step strategy. It included a Darzens condensation followed by a thermal rearrangement of vinyl epoxide to cis dihydrofuran, a Lewis acid promoted cyclisation of a dihydrofuryl alcohol and a reduction of a glycosidic bond. Variations of this methodology afforded the selective the thermal rearrangement has been explored and improvement of this step via different activation methods considered. Another aim of this thesis was to extend this existing method to generate aza analogues. Two strategies have been explored. Generation of furopyrroles can be achieved via the thermal rearrangement of vinyl aziridines or via the acid catalysed cyclisation of dihydrofuryl amines. In conclusion, this short and selective synthetic route leads to a large range of natural or unnatural furofurans and the extension to their aza analogues was also explored.

Made available in DSpace on 2014-06-11T19:35:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-03-29Bitstream added on 2014-06-13T19:24:28Z : No. of bitstreams: 1 messiano_gb_dr_araiq.pdf: 977133 bytes, checksum: 74ff4709db2848a47b1ce05ae6c31e31 (MD5)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
As espécies brasileiras do gênero Aristolochia possuem similaridade morfológica. Sendo assim, foi desenvolvido um método para a classificação e identificação destas espécies baseado no estudo dos óleos essenciais por CG-EM e quimiometria. Foi também realizado um estudo fitoquímico de duas espécies de Aristolochiaceae, ricas em terpenos e lignanas, e um estudo sintético de lignanas ariltetralônicas e derivados, já que estas lignanas mostraram in vitro uma alta atividade antiplasmódica. Uma das rotas sintéticas estudada foi regiosseletiva, e em quatro etapas dois pares enantioméricos de lignanas ariltetralônicas foram produzidos. As misturas enantioméricas foram testadas in vitro e os resultados mostraram que os pares enantioméricos possuem menor atividade que as lignanas naturais, o que sugere que a atividade antiplasmódica depende das configurações relativa e absoluta dos compostos. A segunda síntese proposta para obtenção de lignanas ariltetralônicas envolveu duas reações de acilação de Friedel-Crafts, e não produziu lignanas, mas seis produtos, incluindo benzofuranos e isocoumarinas. Além disso, lignanas ariltetralônicas foram também alvo de transformações químicas e biotransformações com os fungos Cunninghamella echinulata e Beauveria bassiana, e foram obtidas duas lignanas ariltetralônicas e uma nova lignana ariltetralina [(7'R,8S,8'S)-8,8'-dimetil-3',4',4,5-tetrametoxi-2,7'-ciclolignan-8-ol]. Esta tese também descreve os estudos das investigações de Aristolochia malmeana e Holostylis reniformis. Os compostos foram isolados por técnicas cromatográficas, principalmente CC e CCDP, e foram caracterizados por métodos espectrométricos, particularmente estudos de RMN e medidas de atividade óptica. De H. reniformis foram isoladas quatro lignanas ariltetralônicas, incluindo a inédita ariltetralólica...
The Brazilian Aristolochia species have strong morphological similarities. Thus, a method to classify and identify these species based on analyses of their essential oils by GC-MS and chemometry was developed. Phytochemical study of two Aristolochiaceae species, rich in terpenes and lignans, and syntheses of aryltetralone lignans and derivatives were performed, as these lignans have shown high in vitro antiplasmodial activity. A regioselective synthetic route led to two pairs of enantiomeric aryltetralone lignans in four steps. The antiplasmodial activity of these enantiomeric pairs was evaluated in vitro, and the activity was lower than that of the natural lignans, which suggests that the antiplasmodial activity depends on the relative and absolute configuration of the compounds. A second synthetic route proposed for obtaining the A-B ring portion of aryltetralone lignans, involving two Friedel-Crafts acylation reactions of 1-(3',4'-dimethoxyphenyl)-2-propanol, did not produce the expected aryltetralone lignans, but six products, including benzofurans and isocoumarins. Moreover, chemistry transformations and biotransformations of lignans by fungus (Cunninghamella echinulata and Beauveria bassiana) were studied, from which two aryltetralone lignans and a new aryltetralin lignan [(7'R,8S,8'S)-8,8'-dimethyl-3',4',4,5-tetrametoxy-2,7'-ciclolignan-8-ol] were obtained by the biotransformations. This thesis also describes the results of the investigations of Aristolochia malmeana and Holostylis reniformis. The compounds were isolated by chromatographic techniques, mainly by TLC and CC, and were characterized by spectrometric methods, particularly by NMR experiments and optical rotation measurements. From H. reniformis four lignans were isolated, including a new aryltetralol lignan [rel. (7R,7'R,8S,8'S)-4-hydroxy-3',4',5-trimetoxy-2,7'-cyclolignan-7- ol]. In addition, Anticarsia gemmatalis... (Complete abstract click electronic access below)

As lignanas naturais possuem vários tipos de estruturas que exibem uma vasta gama de atividades biológicas. As lignano-lactonas naturais, tais como a arctigenina (1) e os derivados da podofilotoxina (2), representadas nas estruturas abaixo, são conhecidas por apresentarem atividades citotóxicas e, há várias décadas, vêm despertando enorme interesse em virtude de suas propriedades anti-cancerígenas e anti-HIV. Apesar de haver numerosos tipos de síntese racêmica e vários exemplos de síntese assimétrica desses compostos, os métodos sintéticos tradicionais geralmente empregados não são convenientes para a preparação em larga escala desses compostos opticamente puros, em virtude da necessidade de utilizar quantidades estequiométricas de fontes quirais e/ou grande seqüência de etapas sintéticas. Em vista disso, um método mais eficiente para realizar a síntese enantiosseletiva desses produtos naturais é através da catálise assimétrica utilizando materiais de partida proquirais. Trabalhos anteriores realizados em nosso laboratório serviram para testar alguns métodos sintéticos descritos na literatura. Entretanto, como esses métodos são relativamente longos e produzem baixos rendimentos, optamos por testar um método alternativo para a obtenção de lignano-lactonas naturais biologicamente ativas, tais como a parabenzlactona (51) e a oxoparabenzlactona (52), cujas estruturas são mostradas a seguir. Esses dois compostos, além de apresentarem propriedades biológicas úteis, podem ser transformados em outros produtos naturais de interesse, tais como as lignanas do tipo dibenzilbutirolactonas, ariltetralinas e furofurânicas. Os materiais de partida utilizados nessa nova metodologia sintética foram os derivados protegidos de 3-hidroximetil--butirolactona (50), os quais, neste trabalho, foram sintetizados através da hidrogenação enantiosseletiva de derivados insaturados produzidos a partir do ácido 3,3-dimetilacrílico (81). Os estudos de hidrogenação enantiosseletiva foram realizados utilizando catalisadores quirais de ródio e rutênio. Diversos derivados de butenolidas foram estudados com intuito de se obter o intermediário 50 de maneira enantiosseletiva e com rendimentos satisfatórios. Os resultados obtidos nas reações de hidrogenação catalítica dessas butenolidas com complexos quirais de ródio e rutênio mostraram que a quelação do substrato com o centro metálico do catalisador assimétrico é fortemente afetada pelo tipo de substituinte ligado no esqueleto da butenolida. De maneira geral, os produtos de hidrogenação foram obtidos com larga faixa de pureza óptica (2-100% ee) dependendo do tipo de substituinte. Esses resultados indicam uma importante influência dos grupos protetores da função hidroxila alilíca nas reações de hidrogenação assimétrica dos derivados das butenolidas estudados. A fim de se investigar o mecanismo de complexação dos substratos com os catalisadores quirais, simulações computacionais foram realizadas com o catalisador quiral cloreto de [(S)-(?)-2,2?-bis-(difenilfosfino)-1,1-binaftil]cloro(p-cimeno) rutênio e os substratos derivados da 3-hidroximetilbutenolida. Os resultados dos estudos computacionais realizados até o momento mostraram que a ocorrência de mais de um ponto de complexação entre o substrato e o centro metálico do catalisador quiral diminui a energia de ativação do intermediário-chave, aumentando a atividade catalítica e resultando em alta estereosseletividade. Uma vez concluídos os estudos de hidrogenação enantiosseletiva, prosseguiu-se os estudos para a obtenção dos produtos naturais de interesse, a partir de um dos intermediários racêmicos derivados da 3-hidroximetilbutenolida, contendo o metoximetil-éter como grupo protetor. O aldeído intermediário 87, obtido em baixo rendimento, deverá ser transformado nos diversos produtos naturais de interesse. Por causa de sua grande instabilidade, já descrita na literatura, novas metodologias estão sendo testadas para a obtenção do aldeído 87 com melhor rendimento. As lignanas naturais possuem vários tipos de estruturas que exibem uma vasta gama de atividades biológicas. As lignano-lactonas naturais, tais como a arctigenina (1) e os derivados da podofilotoxina (2), representadas nas estruturas abaixo, são conhecidas por apresentarem atividades citotóxicas e, há várias décadas, vêm despertando enorme interesse em virtude de suas propriedades anti-cancerígenas e anti-HIV. Apesar de haver numerosos tipos de síntese racêmica e vários exemplos de síntese assimétrica desses compostos, os métodos sintéticos tradicionais geralmente empregados não são convenientes para a preparação em larga escala desses compostos opticamente puros, em virtude da necessidade de utilizar quantidades estequiométricas de fontes quirais e/ou grande seqüência de etapas sintéticas. Em vista disso, um método mais eficiente para realizar a síntese enantiosseletiva desses produtos naturais é através da catálise assimétrica utilizando materiais de partida proquirais. Trabalhos anteriores realizados em nosso laboratório serviram para testar alguns métodos sintéticos descritos na literatura. Entretanto, como esses métodos são relativamente longos e produzem baixos rendimentos, optamos por testar um método alternativo para a obtenção de lignano-lactonas naturais biologicamente ativas, tais como a parabenzlactona (51) e a oxoparabenzlactona (52), cujas estruturas são mostradas a seguir. Esses dois compostos, além de apresentarem propriedades biológicas úteis, podem ser transformados em outros produtos naturais de interesse, tais como as lignanas do tipo dibenzilbutirolactonas, ariltetralinas e furofurânicas. Os materiais de partida utilizados nessa nova metodologia sintética foram os derivados protegidos de 3-hidroximetil-?-butirolactona (50), os quais, neste trabalho, foram sintetizados através da hidrogenação enantiosseletiva de derivados insaturados produzidos a partir do ácido 3,3-dimetilacrílico (81). Os estudos de hidrogenação enantiosseletiva foram realizados utilizando catalisadores quirais de ródio e rutênio. Diversos derivados de butenolidas foram estudados com intuito de se obter o intermediário 50 de maneira enantiosseletiva e com rendimentos satisfatórios. Os resultados obtidos nas reações de hidrogenação catalítica dessas butenolidas com complexos quirais de ródio e rutênio mostraram que a quelação do substrato com o centro metálico do catalisador assimétrico é fortemente afetada pelo tipo de substituinte ligado no esqueleto da butenolida. De maneira geral, os produtos de hidrogenação foram obtidos com larga faixa de pureza óptica (2-100% ee) dependendo do tipo de substituinte. Esses resultados indicam uma importante influência dos grupos protetores da função hidroxila alilíca nas reações de hidrogenação assimétrica dos derivados das butenolidas estudados. A fim de se investigar o mecanismo de complexação dos substratos com os catalisadores quirais, simulações computacionais foram realizadas com o catalisador quiral cloreto de [(S)-(?)-2,2?-bis-(difenilfosfino)-1,1?-binaftil]cloro(p-cimeno) rutênio e os substratos derivados da 3-hidroximetilbutenolida. Os resultados dos estudos computacionais realizados até o momento mostraram que a ocorrência de mais de um ponto de complexação entre o substrato e o centro metálico do catalisador quiral diminui a energia de ativação do intermediário-chave, aumentando a atividade catalítica e resultando em alta estereosseletividade. Uma vez concluídos os estudos de hidrogenação enantiosseletiva, prosseguiu-se os estudos para a obtenção dos produtos naturais de interesse, a partir de um dos intermediários racêmicos derivados da 3-hidroximetilbutenolida, contendo o metoximetil-éter como grupo protetor. O aldeído intermediário 87, obtido em baixo rendimento, deverá ser transformado nos diversos produtos naturais de interesse. Por causa de sua grande instabilidade, já descrita na literatura, novas metodologias estão sendo testadas para a obtenção do aldeído 87 com melhor rendimento. Estudos sobre a síntese enantiosseletiva de lignano-lactonas naturais contendo importantes atividades biológicas. Os estudos foram realizados utilizando catalisadores quirais de ródio e rutênio e foram avaliados a influência de grupos protetores da função hidroxila da butenolida estudada, frente ao catalisador analisado.
Natural lignans have several types of structures exhibiting a wide variety of biological activities. Natural lignan-lactones, such as arctigenin (1) and the podofilotoxin derivatives (2), are well known for their cytotoxic activities, and both their anti-cancer and anti-HIV properties have attracted much research interest in the last decades. Although numerous racemic syntheses and several examples of the asymmetric synthesis of these compounds have been largely employed, they are not useful for the large-scale preparation of optically pure compounds because stoichiometric amounts of chiral sources and/or la long sequence of synthetic reaction steps are necessary for their accomplishment. A more efficient method for the enantioselective synthesis of these natural products uses asymmetric catalysis with prochiral substances as starting materials. Previous works developed at our laboratory have employed some synthetic methods described in the literature to investigate the synthesis of some natural products. However, these methods involve several synthetic steps and lead to low yields. These facts have thus stimulated us to develop an alternative method for the obtention of biologically active natural lignan-lactones such as parabenzlactone (51) and oxo-parabenzlactone (52). Besides their useful biological properties, these compounds can also be transformed into other interesting natural products, such as aryltetralin, dibenzylbutyrolactone, and furofuran lignans. Protected derivatives of 3-hydroxymethyl-?-butyrolactone (50) were used as the starting materials of this new methodology. These derivatives were synthesized using the enantioselective hydrogenation of the unsaturated material produced from 3,3-dimethylacrylic acid (81). Enantioselective hydrogenation studies were performed using rhodium and ruthenium chiral catalysts Several butenolides derivatives were studied aiming at the obtention of a satisfactory yield of the enantioselective intermediate (50). The catalytic hydrogenation of these butenolide derivatives with rhodium and ruthenium chiral complexes showed that chelation of the substrate with the metallic center of the asymmetric catalyst strongly depends on the substituent attached to the butenolide skeleton. The hydrogenation products were obtained with a large range of optical purity (2-100% ee), depending on the substituent type. These results indicate that the presence of protective groups in the allylic hydroxyl function has a strong effect on the asymmetric hydrogenation reaction of the studied butenolides. Some computer simulations were performed in order to investigate the mechanism of substrate complexation with the chiral catalyst. [(S)-(?)-2,2?-bis-(diphenylphosphino)-1,1?-binaphtyl]chloro(p-cymene) chloride ruthenium was the chiral catalyst and 3-hydroxymethylbutenolide derivatives were used as substrates. The computer simulation results obtained to date have shown that when there is more than one point of complexation between the metallic center of the chiral catalyst and the unsaturated substrate, the activation energy of the key intermediate is lowered, thus enhancing the catalytic activity and resulting in high stereoselectivity. Once the enantioselective hydrogenation studies were concluded, we pursued the synthesis of natural products from one of the racemic derivatives, the one containing a methoxymethylether as protective group. Once the intermediate aldehyde 87 is obtained, a large number of interesting natural products could be synthesized. New methodologies are now under investigation in order to obtain aldehyde 87, which is difficult to achieve due to its low stability, as described in the literature.

Orientador: Rosangela da Silva de Laurentiz
Resumo: As lignanas apresentam grande variedade estrutural e diversidade de propriedades biológicas, desta forma ocupam um papel de destaque na busca por moléculas bioativas. A introdução de nitrogênio no esqueleto químicos de lignanas ariltetralínicas e arilnaftalênicas fornece compostos azo-heterocíclicos que contém o núcleo quinolínico e o anel lactônico e, portanto, são lactonas dihidroquinolinicas e quinolínicas. Essas estruturas podem ser potenciais alvos na pesquisa por novas moléculas para o desenvolvimento de fármacos para uma série de enfermidades. Desta forma, o objetivo deste trabalho foi sintetizar azo-análogos de lignanas ariltetralínicas, de estruturas conhecidas e inéditas, a fim de determinar suas propriedades leishmanicida, esquistossomicida, antimicrobiana e citotóxica contra células tumorais. A síntese dos azo-ariltetralinicos foi realizada a partir da reação multicomponente assistida por micro-ondas entre ácido tetrônico, anilinas substituídas e aldeídos aromáticos. O uso de reação multicomponente assistida por micro-ondas tem a finalidade a obtenção desses compostos de uma forma mais rápida e eficiente em relação às metodologias tradicionais de síntese. Foram obtidos 39 derivados azo-ariltetralínicos, pela variação dos substituintes dos aldeídos e anilinas, em rendimentos que variaram de 70 a 94%. Dentre os ensaios biológicos aos quais esses compostos foram submetidos, deve-se destacar a atividade leishmanicida e atividade antimicrobiana com valores de CI50, par... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Lignans have a great variety of structure and diversity of biological properties, thus they play a prominent role in the search for new bioactive molecules. The introduction of nitrogen into the chemical skeleton of aryltetralin and arylnaphthalene lignans provides azo-heterocyclic compounds containing the quinolinic nucleus and the lactonic ring and thus are dihydroquinolinic and quinolinic lactones. These structures may be potential targets in the search for novel molecules for the development of drugs for a range of diseases. Thus, the aim of this work was to synthesize azo-analogues of aryltetralin lignans of known and novel structures in order to determine their leishmanicidal, schistosomicidal, antimicrobial and cytotoxic properties against tumor cells. The synthesis of azo-aryltetralinics was carried out from the microwave-assisted multicomponent reaction between tetronic acid, substituted anilines and aromatic aldehydes. The use of microwave-assisted multicomponent reaction has the purpose of obtaining these compounds more quickly and efficiently than traditional synthetic methodologies. Thirty-nine azo-aryltetralin derivatives were obtained by varying the aldehyde and aniline substituents in yields ranging from 70 to 94%. Among the biological assays to which these compounds were submitted, the leishmanicidal activity and antimicrobial activity with IC50 values varying of 1.07-3.57 μg/mL and 12.5-100 μg/mL, respectively, for the most active compounds, should be highli... (Complete abstract click electronic access below)
Doutor

Les lignanes sont des métabolites secondaires végétaux, dont la fonction biologique reste aujourd’hui inconnue in planta, mais qui présentent un intérêt en santé humaine. Cette étude vise à progresser dans la connaissance de la fonction des lignanes dans la plante en étudiant la régulation de la biosynthèse de ces molécules. Cette étude a été menée chez des lins : Linum usitatissimum (espèce cultivée) et Linum flavum (espèce sauvage). Chez Linum usitatissimum, la régulation spatio-temporelle de la biosynthèse des lignanes a été établie et il a été démontré que l’acide abscissique régulait la biosynthèse des lignanes dans la graine. Chez Linum flavum, un gène clé dans la production de lignanes a été isolé et la régulation spatiotemporelle de la biosynthèse des lignanes a été établie. Un protocole amélioré d’extraction de sécoisolaricirésinol utilisant une cellulase a été mis au point à partir de téguments de graines de Linum usitatissimum. Enfin de nouvelles sources de lignanes cytotoxiques parmi les Juniperus et Callitris ont été identifiées, et l’extraction de ces composés à partir de feuilles a été optimisée
Lignans are plant secondary metabolites whose in planta biological function is still unknown but are of interest for human health. This work aims at understanding the function of plant lignans through the study of the lignans biosynthesis regulation. This study was conducted in flax: Linum usitatissimum (cultivated species) and Linum flavum (wild species). In Linum usitatissimum, spatial and temporal regulation of lignans biosynthesis has been established and it has been shown that abscisic acid regulates the lignan biosynthesis in seed coats. In Linum flavum, a key gene of lignans production has been isolated, spatial and temporal regulation of lignans biosynthesis has been established. An improved protocol for secoisolariciresinol extraction from Linum usitatissimum seed teguments involving the use of a cellulase was developed. Finally new sources of cytotoxic lignans were identified among Juniperus and Callitris species and extraction from leaves was optimized

Orientador: Raquel Marques Braga
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica
Made available in DSpace on 2018-08-04T22:47:27Z (GMT). No. of bitstreams: 1 Lima_ValeriaBittencourtde_D.pdf: 9598037 bytes, checksum: 83f061fb32519074a309e1975981ace5 (MD5) Previous issue date: 2005
Resumo: Nosso trabalho tem por objetivo o isolamento e a elucidação estrutural dos metabólitos secundários de Himatanthus obovatus (família Apocynaceae, sub-família Rauvolfioideae). Apenas cinco espécies de Himatanthus já foram estudadas do ponto de vista químico. O material de H. obovatus utilizado nesse trabalho foi coletado na Chapada dos Guimarães (MT) e em Casa Branca (SP). Utilizando diferentes metodologias de extração e tratamento dos extratos etanólicos brutos foram isoladas 5 lignanas: pinoresinol, isolariciresinol, hidroxipinoresinol, lariciresinol e olivil; 3 nor-isoprenóides: blumenol C, blumenol A e um nor-isoprenóide inédito; o iridóide plumieride, misturas dos terpenos: acetato de lupeol + acetato de a-amirina + acetato de b-amirina + germanicol e stigmasterol + b-sitosterol + campesteroI a, após a acetilação do extrato etanólico bruto, o glicitol inositol. Os extratos Diclorometânico (CDCb) e Etanólico (CECb) da casca de H. obovatus (Casa Branca (SP) foram submetidos aos testes com Artemia salina Leach. e de atividade antiproliferativa frente à 4 linhagens celulares derivadas de tumores humanos: leucemia (K562), pulmão (NCI460), melanoma (UACC62) e mama (MCF7). Os resultados dos dois testes foram bastante coerentes, já que ambos mostraram resultados promissores para o extrato CDCb. Os testes de bioautografia foram realizados com os extratos da casca de H. obovatus (Casa Branca): CHCb (heptano), CDCb (diclorometano) e CECb (etanol) e com as substâncias isoladas: pinoresinol, isolariciresinol, blumenol C, blumenol A, nor-isoprenóide inédito, hidroxipinoresinol, lariciresinol, plumieride e inositol, frente aos fungos: Alternaria alternata, Aspergillus fumigatus, A. niger, Candida albicans, Cladosporium cladosporioides, Fusarium oxysporium, Penicillium oxalicum, P. funicullosum e Rhizopus orizae. e frente às bactérias: Bacillus subtilis, Escherichia coli, Micrococcus luteus, Salmonella typhimurim, Staphilococcus aureus e Streptococcus mutans. Foram observadas atividades bactericida para as lignanas: isolariciresinol frente à bactéria S. mutans e lariciresinol frente à bactéria S. aureus. Os compostos isolados de H. obovatus permitiram comparar filogeneticamente este gênero aos gêneros Tabernaemontana e Rauvolfia (pertencentes às mesmas família e sub-família), estudados anteriormente em nosso grupo de pesquisas e ricos em alcalóides indólicos.
Abstract: Our objective is the isolation and identification of the compounds from Himatanthus obovatus (family Apocynaceae and sub-family Rauvolfioideae). Five species from genus Himatanthus have been chemically studied. H. obovatus was collected in Chapada dos Guimarães (MT state, Brazil) and in Casa Branca (SP State, Brazil). We used different methodologies for extraction and purification of the extracts, yielding 5 lignans: pinoresinol, isolariciresinol, hydroxypinoresinol, lariciresinol and olivil; 3 nor-isoprenoids: blumenol C, blumenol A and one unknown nor-isoprenoid; the iridoid plumieride, a mixture of terpenes: lupeol acetate + a-amirin acetate + b-amirin acetate + germanicol and stigmasterol + b-sitosterol + campesterol and, after acetylation of the crude ethanolic extract, the glycitol inositol. The diclorometanic (CDCb) and ethanolic (CECb) extracts trom the bark of H. obovatus (Casa Branca - SP) have been tested with Artemia salina Leach. and for antiproliferative activity against 4 carcinoma cell lines derived from human cancer: leukemia (K562), lung (NCI1460), melanoma (UACC62) and breast (MCF7). The good results with the CDCb extract in both tests suggest that this extract is a development candidate. The Bioautography tests were made with the heptanic (CHCb), diclorometanic (CDCb) and ethanolic (CECb) extracts from the bark of H. obovatus (Casa Branca - SP) and with the isolated substances: pinoresinol, isolariciresinel, blumenol C, blumenol A, the unknown nor-isoprenoid, hydroxypinoresinol, lariciresinol, plumieride and inositol against the fungi: Alternaria alternata, Aspergillus fumigatus, A. niger, Candida albicans, Cladosporium cladosporioides, Fusarium oxysporium, Penicillium oxalicum P. funicullosum and Rhizopus orizae and against the bacteria: Bacillus subtilis, Escherichia coli, Micrococcus luteus, Salmonella typhimurim, Staphilococcus aureus and Streptococcus mutans. We observed bactericide activity at the lignans: isolariciresinol against the bacteria S. mutans and lariciresinol against the bacteria S. aureus. The coumpounds isolated from H. obovatus allowed us to phylogenetically compare this genus to the genera Tabernaemontana and Rauvolfia (belonging to the same family and sub-family), previously studied in our group and rich in indolic alkaloids.
Doutorado
Quimica Organica
Doutor em Ciências

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico
Neste trabalho à descrito o isolamento dos constituintes quÃmicos micromoleculares das folhas, talos e raÃzes de Combretum fruticosum (Combretaceae), popularmente conhecida como âescova-de-macaco-alaranjadaâ. O estudo fitoquÃmico da espÃcie, empregando mÃtodos cromatogrÃficos em coluna gravitacional e cromatografia liquida de alta eficiÃncia, permitiu o isolamento de nove constituintes quÃmicos pertencentes a diferentes classes estruturais: trÃs triterpenos de esqueleto oleanano identificados como Ãcido malÃnico, Ãcido oleanÃlico e Ãcido arjunÃlico, duas lignanas denominadas (-) trachelogenina e vladinol F, uma misturas dos esterÃides β-sitosterol e estigmasterol incluindo suas respectivas formas glicosiladas, uma lactona aromÃtica Ãcido 4â-O-Acetil-3â,3,4-tri-O-metilelÃgico e o flavonÃide apigenina 8-C-β-D-glicosÃdeo. A determinaÃÃo estrutural das substÃncias foi realizada atravÃs do uso de tÃcnicas espectromÃtricas como: infravermelho (IV), espectrometria de massa (EM e EM-IES) e ressonÃncia magnÃtica nuclear de hidrogÃnio (RMN 1H) e carbono-13 (RMN 13C), incluindo tÃcnicas bidimensionais (COSY, HSQC e HMBC) e comparaÃÃo com dados descritos na literatura.
This work describe the isolation of the chemical constituents from leaves, stems and roots of Combretum fruticosum (Combretaceae), popularly known as âescova-de-macaco-alaranjadaâ. The phytochemical studies, using chromatographic methods such as gravity column chromatography over silica gel and high performance liquid chromatography (HPLC), allowed the isolation and characterization of nine chemical constituents belonging to different structural class: three oleanane triterpenes identified as malinic acid, oleanolic acid and arjunolic acid; two lignans named (-)-trachelogenin and vladinol, the mixture of β-sitosterol e stigmasterol, including its glucoside forms, a aromatic lactone 4â-O-acetyl-3â,3,4-tri-O-methylelagic and the flavonoid apigenin 8-C-β-D-glucoside. The structural determination was realized by spectrometric techniques such as: infrared (IR), mass spectrometry (EM and EM-IES), and magnetic resonance of hydrogen (1H NMR) and carbon-13 (13C NMR), including bidimensional techniques (COSY, HSQC e HMBC) and comparison with literature

Application of radical reactions in the organic synthesis for the formation of carbon-carbon bond has dramatically increased over the last fifteen years by virtue of their high degree of chemo-, regio- and stereoselectivity. The present thesis entitled "Radical Cyclisation based Approaches to 9-pupukeanone and Lignan Precursors" describes the application of radical reactions in the synthesis of isotwistane carbon framework present in pupukeananes, and b-arylmethylbutyrolactones, established precursors of various types of lignans. For convenience, the results are presented in two chapters, & ( I ) Radical annulation approach to chiral analogues of 9-pupukeanones; (2) Synthesis of (+-)-enterolactone and lignan precursors; and an appendix entitled 'Chiral synthons from (R)- carvone'. In each Chapter the compounds are sequentially numbered (bold and double underlined), and references are marked sequentially as superscripts and listed at the end of the Chapter. All the figures were obtained by direct xerox of the originaltNMR and muss spectra, and in some of them uninformative areas have been cut to save the space.

Orientador: Fernando Antonio Santos Coelho
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica
Made available in DSpace on 2018-08-14T14:24:10Z (GMT). No. of bitstreams: 1 Andre_MarceloFabiano_M.pdf: 7456902 bytes, checksum: 8a8b77c97023eb4ce17c25791c0a18f8 (MD5) Previous issue date: 2009
Resumo: As b-piperonil-g-butirolactonas são intermediários importantes, tendo em vista que a partir delas é possível dar origem a uma série de lignanas, classe de substâncias de grande interesse científico, por apresentarem diversas atividades biológicas, tais como: antiretroviral, antitumoral, antimalárica, entre outras. Neste trabalho realizamos estudos visando melhorar a diastereosseletividade na preparação de g-butirolactonas com estereoquímica relativa trans, já que a cis já era preparada com boa diastereosseletividade em nosso laboratório. A metodologia desenvolvida baseia-se na redução de um b-ceto-éster obtido a partir da oxidação de um a-ciano-metil-b-hidroxi-éster, este último obtido com um bom rendimento a partir de uma reação de adição de Michael sobre um aduto de Morita-Baylis-Hillman ( MBH). Na segunda parte do trabalho preparamos b-amino-ésteres a partir dos adutos de Morita-Baylis- Hillman (MBH). Utilizamos como estratégia uma reação de adição do tipo Michael com várias aminas. Os b-amino-ésteres foram obtidos com rendimentos variando de 78-93%. Os produtos foram caracterizados e a estereoquímica relativa foi determinada, por nOe, através da formação de um intermediário oxazinanona. Esses b-amino-ésteres são importantes intermediários para a síntese de heterociclos, tais como b-lactamas e oxazinanonas funcionalizadas.
Abstract: The b-piperonil-g-butirolactones are important synthetic intermediates, since they can be used as substrates for the synthesis of different type of lignans, a class of substances of great scientific interest. Lignans exhibit relevant biological activites, as anti-tumoral, anti-retroviral, anti-malarial, etc. In this work, studies have been carried out aiming at improving the diastereoselectivity for the preaparation of butirolactones having anti relative stereochemistry. A method to synthesize g-butirolactone have already been established in our laboratory. The methodology used was based on the the stereoselective reduction of a b-ketoester prepared from the oxidation of a a-cyanomethyl-b-hydroxy-ester. The latter was promptly prepared, in good yields, from a cyanide 1,4 addition over the double bond of Morita-Baylis-Hillman (MBH) adducts. In the second part of this work, we have prepared several b-amino-esters from Morita-Baylis- Hillman (MBH) adducts. The strategy was based also on a Michael addition of different amines over the double bond of MBH adducts. The b-amino-esters were obtained in good yield. Their stereochemistries were determined by nOe experiments of the corresponding oxazinanones. These b-amino-esters are important intermediates for the synthesis of heterocycles, as b-lactams and functionalized oxazinanones.
Mestrado
Quimica Organica
Mestre em Química

Tropical American Piper spp. have insecticidal activities comparable to those of previously studied African and Asian species. Effects of dietary administration of the crude ethanolic extracts of Piper spp. to the European corn borer, Ostrinia nubilalis Hubner, include a reduction of larval growth, a high death rate of larvae, pupae and adults, and a limited effect on the consumption and digestion of food. Among 16 Piper extracts the most active American species were, in decreasing order of growth reducing activity: P. tuberculatum, P. aduncum, P. pseudo-lindenii, P. lanceiaifolium, P. guanacastensis, P. decurrens, P. carilloanum, and P. auritum. Bioassay-guided isolation, using mosquito larvae, led to the isolation of a monolignan, dillapiol, as an active principle of P. aduncum, two neolignans as active principles of P. decurrens, and an amide, piperlonguminine as an active principle of P. tuberculatum. The new isolation of the neolignans and the amide gives further evidence of the biological significance of these two classes of compounds as chemical defenses of the piperaceae. The activities of a series of 15 pure monolignans, lignans, and neolignans were investigated with the polyphagous lepidopteran herbivore, the European corn borer, which has a high adaptive capacity to tolerate plant allelochemicals. The lignans (at a dose of 100 $\mu$g/g in the diet) were generally not highly toxic to the larvae, except for the monolignan dillapiol. However, delayed toxicity was revealed as mortality increased later in the life cycle, reaching at the adult stage a cumulative mortality of 95%, 68%, 60%, 43% and 40% with dillapiol, epiashantin, podophyllotoxin, epiyangambin and cubebin, respectively. The growth profile of larvae further showed that lignans are slow acting toxins, except for dillapiol and cyclolignans of the podophyllotoxin series. Antifeedant activity of the lignans was generally poor. Cubebin was the most active antifeedant with respect to the ECB with a protective concentration, PC$\sb{50}$, of 74 $\mu$g/g. There was a trend of increasing toxicity of lignans which generally parallelled the evolutionary advancement in biosynthesis. Because of their role in reversing insecticide resistance, lignans were tested for their activity on multidrug resistant (MDR) cells with overexpression of the membrane P-glycoprotein. MDR cells responded to the group of cyclolignans in a way similar to the response of other drugs which belong to the multiresistant group, while they showed important collateral sensitivity to the furans and even more to the monolignan dillapiol. An increased uptake of the anticancer drug vinblastine was observed upon co-administration of dillapiol. This activity constitutes a novel mode of action of this lignan, and possibly other insecticide synergists such as piperonyl butoxide, with regards to resistance to drugs and insecticides.

Lignans are natural products composed of two β-β linked phenylpropanoid units. Lignans have acquired considerable importance owing to their broad range of biological activities. Indeed, many lignans have antitumor, antiviral, and insecticidal activities. Norway spruce lignans are of particular interest to researchers because they have been shown to play an important role in the prevention of breast, prostate, and colon cancers. The work within the thesis describes the synthetic approach to the development of enantiopure lignans or lignan like structures. The first chapter provides a through introduction about lignans biological activities and synthesis with the emphases on the lignans found in Norway spruce. The second chapter describes methods for extraction and analysis of these lignans using GCIMS analysis. Biological activities on bone cell differentiation were reported in chapter 3. Chapters 4, 5, 6 and 7 focus on the development of methodology towards the asymmetric synthesis of the lignans that found in the Norway spruce utilizing organocatalytic asymmetric aldol reaction. Enantiopure tetrahydrofuran and lactone rings synthesis utilising oxy-Michael and Michael addition was also described since these are the core structure of these lignans.

Background: The emergence of viral diseases has been the major threat to public health and social stability. A hundred years ago, 1918 Spanish flu (H1N1) pandemic spread worldwide, and about 3% ~ 5% of the world's population died from the flu-related illnesses. It is known as the deadliest catastrophic pandemics in human history. There have been five Public Health Emergency of International Concern (PHEIC) declarations over the past decade, including the 2014 Ebola outbreak in west Africa, the 2016 Zika outbreak and the ongoing COVID-19 pandemic. There is always a new strain of virus emerging on the horizon. We have urgent need to develop more broad-spectrum antivirals, which work effective against multiple viruses, for thwarting outbreaks in the future. Objective: Based on our previous experience in search of anti-HIV compounds from topical plants, we aimed to discover novel antiviral lead compounds from Justicia plants collected in Hong Kong. Further, structure modification of the natural compounds can lead to optimization of their drug properties for further development as drug candidates. To determine the antiviral targets of the lead compounds will further provide insights to elucidate the mechanism of actions. The present studies are to discover the antiviral lead compounds from Justicia plants, to analyze the structure-activity relationship of the modified structures, to identify the molecular targets of the lead compounds as antiviral agents against the multiple viruses. Methodology: Four common Justicia plants were collected in Hong Kong. The plant extracts and compounds isolated from the plants were explored for their antiviral activities via our established "One-Stone-Two-Birds" antiviral assay. Time-of-addition experiments were performed to determine the target stages of the antiviral compounds on the viral replication. Computational techniques (3D-QSAR and in silico pharmacokinetics evaluation) were employed to elucidate the structure-activity relationship of the compounds and thereby optimize their structures to enhance the antiviral activity. Comprehensive activity-based protein profiling (ABPP) of biotin-linked compounds using SWATH-MS technique was performed to identify the protein target(s) of the lead compounds in an unbiased manner. The role of the molecular target in viral replication was further verified by mRNA knockdown using siRNA. Result: The extracts of Justicia procumbens and Justicia championii showed potent antiviral effects with low cytotoxicity among the collected Justicia plants. By correlating the antiviral activity with their HPLC-UV profiles, arylnaphthalene lignans (ANLs) were determined as the principle active components. Among the isolated compounds from J. procumbens, diphyllin exhibited strong antiviral activities against VSV/HIV, H5N1/HIV and EBOV/HIV pseudoviruses with EC50 values ranging from 30-100nM. In time-of-addition experiments, diphyllin mainly acts on the entry stage of the viral infection. Considering the broad-spectrum antiviral properties and antiviral mechanism together, diphyllin is probably a host-targeting antiviral agent. In a subsequent lead optimization, a reliable and predictive 3D-QSAR was established from 25 synthesized ANLs. Compound 31 was found as the most potent antiviral agent based on the 3D-QSAR model. It showed 70 times more potent antiviral activity than the parent diphyllin, with retained broad-spectrum antiviral properties and improved predicted ADMET properties. In addition, comprehensive ABPP analysis of the biotin-linked diphyllin was employed for the target identification of the ANL compounds. Total 2343 proteins were captured by the ABPP probes. By quantitative analysis, the protein TFAM showed significant affinity to the diphyllin-based ABPP probes. The viral susceptibility of TFAM-deficient cells was shown to be reduced in the subsequent validation. We thus determined TFAM as the potential antiviral drug target of the ANL compounds against a broad spectrum of viruses.

O estudo químico das folhas e dos frutos de P. richardiaefolium resultou no isolamento de oito lignanas, sendo duas lignanas furofurânicas (sesamina e kobusina), quatro lignanas dibenzilbutirolactônicas (hinokinina, kusunokinina, arctigenina e haplomirfolina), duas lignanas dibenzilbutirolactólicas (cubebina e 3,4- dimetoxi-3,4-desmetilenodioxicubebina), dois cinamatos de bornila (ferulato de bornila e cumarato de bornila) e na identificação de duas amidas (piplartina e diidropiplartina). Das folhas de P. richardiaefolium foi extraído e analisado o óleo volátil. As estruturas das substâncias isoladas foram identificadas através de métodos espectroscópicos (RMN de 1H e de 13C e espectrometria de massas). O estudo de análise de componentes principais (PCA) das espécies Piper (P. truncatum - k 616, P. richardiaefolium - k 290, P. richardiaefolium - k 350, P. richardiaefolium - k 593, P. truncatum - k 597, P. pseudopotifolium - k 598, P. richardiaefolium - k 854, P. richardiaefolium - k 610, P. truncatum - k 112, P. pseudopotifolium - k 211 e P. cernuum - k 137) permitiu agrupar as espécies em dois grandes grupos e quatro subgrupos em relação à similaridade entre elas. Ligninas do caule de seis espécies de Piper foram extraídas utilizando o método de degradação de Klason e método de Bjorkman, e analisadas por métodos espectroscópicos (IV, RMN de 1H e de 13C). O método de degradação por oxidação por nitrobenzeno foi o escolhido para determinar a relação entre os monolignóis siringila e guaiacila. Os principais metabólitos das espécies estudadas foram comparados com os tipos de ligninas das mesmas espécies e os resultados sugeriram uma independência entre as vias biossintéticas de ligninas e lignanas.
The chemical study of leaves and the fruits of P. richardiaefolium resulted in the isolation of eight lignans, being two furofurânics lignans (sesamin and kobusin), four dibenzylbutirolactonics lignans (hinokinin, kusunokinin, arctigenin and haplomirfolin), two dibenzylbutirolactolics lignans (cubebin and 3\',4\'-dimethoxy-3,4- desmethylenedioxicubebin), two cinnamates (bornyl ferulate and bornyl cumarate) and in the identification of two amides (piplartine and dihydropiplartine). Of leaves of P. richardiaefolium was extracted and analyzed the volatile oil. The structures of isolated substances had been identified using the spectroscopic methods (1H and 13C NMR) and mass spectrometry. The study of principal components analysis (PCA) of the species Piper (P. truncatum - k 616, P. richardiaefolium - k 290, P. richardiaefolium - k 350, P. richardiaefolium - k 593, P. truncatum - k 597, P. pseudopotifolium - k 598, P. richardiaefolium - k 854, P. richardiaefolium - k 610, P. truncatum - k 112, P. pseudopotifolium - k 211 and P. cernuum - k 137) allowed the separation in two groups and four sub-groups. Lignins of stem of six species of Piper had been extracted using the method of degradation of Klason and method of Bjorkman, and analyzed for spectroscopic methods (IR, 1H and 13C NMR). The degradation method by nitrobenzene oxidation was chosen to determine the relationship between monolignols syringil and guaiacyl moieties. The major metabolities of the Piper species were compared to the lignins types of the same species and the results suggested independence between the biosynthetic pathways of lignins and lignans.

Made available in DSpace on 2015-05-14T12:59:35Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 4764817 bytes, checksum: 8105827c2685ad07e0a52db2b5d814c5 (MD5) Previous issue date: 2012-02-16
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
The Lamiaceae family composes aproximately 260 genera and 7.193 species, occurring as herbs, shrubs and trees, distributed in both hemispheres. It includes a large number of medicinal plants of significative importance. In Brazil, occurs about 26 genera and 350 species. The Hypenia (Mart. ex Benth) R. Harley genus presents a restrict distribution in South America with approximately 27 species distributed in some regions of Venezuela, Paraguai, Bolívia and southern Brazil. Among these species, Hypenia salzmannii is popularly known as canela-de-urubu . The population uses this plant for the treatment of respiratory illnesses such as colds, flu and other respiratory diseases in general. This work describes the results of the phytochemical study of Hypenia salzmannii. The plant was subjected to extraction, partition and chromatographic processes for chemical constituents isolation. Their chemical structure were determined by spectroscopic methods of InfraRed (IR) and 1H e 13C NMR, uni and bidimensional, mass spectrometry and comparisons with literature data. From the dichloromethane extract were isolated three terpenoids: ursolic acid, oleanoic acid and betulinic acid; a steroid: β-sitosterol glycoside; two flavanones: isosakuranetin and sakuranetin; two lignans: hinoquinin and β-peltatin-A-methylether. From the ethyl acetate extract were obtained a flavonoid glycoside: hyperin; two phenolic derivatives: rosmarinic acid and methyl rosmarinate; and a novel lignan, (-)-secoisolaricirenisol-9-O-β-D-glucopiranoside-(6 -p-cumaroyl). The results from this work contributed to the phytochemical and chemotaxonomic knowledge of Hypenia salzmannii (Benth.) Harley, the Hypenia genus and Lamiaceae family as well.
A família Lamiaceae possui 7.193 espécies distribuidas em aproximadamente 260 gêneros que ocorrem na forma de ervas, arbustos e árvores distribuídos em ambos os hemisférios e inclui um grande número de plantas medicinais de importância significativa. No Brasil ocorrem aproximadamente de 26 gêneros e 350 espécies. O gênero Hypenia (Mart. ex Benth) R. Harley possui distribuição restrita na América do Sul com aproximadamente 27 espécies distribuídas em algumas regiões da Venezuela, Paraguai, Bolívia e Sul do Brasil. Entre essas espécies, a Hypenia salzmannii é popularmente conhecida como canela-de-urubu. A população utiliza esta planta para o tratamento de afecções do trato respiratório como gripes, resfriados e outras doenças respiratórias em geral. O presente trabalho descreve os resultados do estudo fitoquímico de Hypenia salzmannii. O material botânico foi submetido a processos de extração, partição e cromatografia para isolamento dos constituintes químicos. A estrutura química dos mesmos foi determinada por métodos espectroscópicos no Infravermelho e Ressonância Magnética Nuclear de 1H e 13C uni e bidimensionais, espectrometria de massas e comparações com modelos da literatura. Da fase diclorometano foram isolados três terpenoides: ácido ursólico, ácido oleanóico e ácido betulínico; um esteróide: β-sitosterol-glicosilado; duas flavanonas: isosakuranetina e sakuranetina; duas lignanas: a hinoquinina e a β-peltatina-A-metileter. Da fase acetato de etila foram obtidos um flavonóide glicosilado: hiperina; dois derivados fenólicos: ácido rosmarínico e rosmarinato de metila; e uma nova lignana, a (-)-secoisolaricirenisol-9-O-β-D-glicopiranosídeo-(6 -p-cumaroil). Os resultados obtidos nesse trabalho contribuíram para o conhecimento fitoquímico de Hypenia salzmannii e para a o conhecimento quimiotaxonômico do gênero Hypenia e da família Lamiaceae.

Linum album is an herbaceous plant with medical interest due to its content of podophyllotoxin (PTOX), an aryltetralin lignan with cytotoxic activity. The study of biotechnological alternatives has generated big interest. Organ and cell in vitro cultures offer the possibility of suppling aryltetralin lignans in accordance with a sustainable and rational utilization of biodiversity, however they need to be improved. Thus, in this work we analyzed the lignan accumulation patterns in four biotechnological systems of L.album in order to find alternatives of bioproduction. The four biotechnological platforms were established with wild type and transformed cell suspension cultures, adventitious roots isolated from in vitro plants, and hairy roots. The predominant lignan produced by wild type and transformed cells was PTOX. The main lignan produced by adventitious and hairy roots was 6- MPTOX, adventitious roots showed to be more productive, and we can infer that the transformation did not change the lignan patterns. In addition, we have studied the response to the elicitor coronatine in these systems. Transformed cells were the most sensitive after elicitation and showed an arrest of biomass growth in relation to other systems. In general, the elicitation increased the lignan content, but the more elicited route in each system resulted to be the less productive. Transcript profiling changed in elicited conditions, specially for the PLR gene in transformed cells. The analysis of morphogenesis development in the production of podophyllotoxin derivatives in callus cultures of Linum album showed that, the absence of plant growth regulators are a predominant factor, to induce the organogenic and the bioproduction as well. Finally, approaches aiming at increasing podophyllotoxin content require multiple enzymatic steps that facilitate the metabolic flow to the final products, most of them forming multiprotein complexes. Based on this, the Yeast two hibrid system allowed to identify CTB5 as a potential interactor of the PLR protein of Linum album, and evidences in other species indicate that CTB5 participates in the phenylpropanoid pathway.
Linum album es una planta herbácea con interés farmacológico debido a su alto contenido de podofilotoxina (PTOX), el cual es un lignano de característica ariltetralin con actividad citotóxica. El estudio de las alternativas biotecnológicas ha generado gran interés. Los cultivos in vitro de órganos y células ofrecen la posibilidad de suministrar aryltetralin lignanos en acuerdo con una utilización sostenible y racional de la biodiversidad, sin embargo necesitan ser mejorados. Por tanto, en este trabajo se analizaron los patrones de acumulación de lignanos en cuatro sistemas biotecnológicos de L.album con el fin de encontrar alternativas en la bioproducción. Se establecieron cuatro plataformas biotecnológicas con cultivos en suspensión celular de tipo salvaje y transformados, raíces adventicias aisladas de plantas in vitro y raíces en cabellera. La PTOX fue el lignano predominante producido por células de tipo salvaje y transformadas. El principal lignano producido por las raíces adventicias y raíces transgénicas fue la metoxipodofilotoxina (MPTOX), en general las raíces adventicias fueron las más productivas, por lo cual podemos inferir que la transformación no afecto los patrones de bioproducción. Además, hemos estudiado la respuesta a la coronatina como elicitor en estos sistemas, donde las células transformadas fueron las más suceptibles a la elicitación mostrando una disminución en la biomasa en relación con los otros sistemas. En general, la elicitación aumentó el contenido de lignanos, aunque la ruta principal fue las menos favorecida en cada sistema. El perfil de expresión genética elicitadas, especialmente para el gen PLR en las células transformadas. El análisis del desarrollo de la morfogénesis en la producción de derivados de podofilotoxina en cultivos de callos del Linum álbum mostró que la ausencia de reguladores del crecimiento es un factor predominante para inducir la respuesta organogénica y la bioproducción. Finalmente, las aproximaciones que apuntan a aumentar el contenido de podofilotoxina requieren múltiples pasos enzimáticos que faciliten el flujo metabólico hacia los productos finales, la mayoría de ellos formando complejos multiproteicos. Basado en lo anterior, la técnica del doble hibrido en levadura nos permitió identificar la CTB5 como un potencial interactor de la proteína PLR del Linum álbum, hallada en otras especies como interactor en la ruta metabolica de los fenilpropanoides.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-07-11T19:21:39Z No. of bitstreams: 1 mirnameanadias.pdf: 4854720 bytes, checksum: 6e7eee98f8d74a58201a12af9346e6f8 (MD5)
Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-08-08T15:34:44Z (GMT) No. of bitstreams: 1 mirnameanadias.pdf: 4854720 bytes, checksum: 6e7eee98f8d74a58201a12af9346e6f8 (MD5)
Made available in DSpace on 2017-08-08T15:34:44Z (GMT). No. of bitstreams: 1 mirnameanadias.pdf: 4854720 bytes, checksum: 6e7eee98f8d74a58201a12af9346e6f8 (MD5) Previous issue date: 2013-07-30
FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais
A esquistossomíase, causada por parasitos do gênero Schistosoma, é uma doença que afeta cerca de 240 milhões de pessoas no mundo. O Praziquantel é o fármaco de escolha para o tratamento desta parasitose e, devido principalmente aos casos de resistência do parasito a esta medicamento, se faz necessária a busca de novas moléculas e/ou protótipos com potencial atividade esquistossomicida. Neste contexto, a pesquisa com produtos naturais desponta como uma alternativa para o descobrimento de novos fármacos para o tratamento da esquistossomíase. Entre as espécies vegetais de interesse para a produção de substâncias esquistossomicidas, destaca-se a Arctium lappa L. (Asteraceae), a qual é reconhecida por biossintetizar lignóides, classe de metabólitos que tem demonstrado grande potencial esquistossomicida. O presente trabalho descreve o estudo fitoquímico do extrato hidroalcoólico dos frutos de A. lappa, bem como a avaliação da atividade esquistossomicida in vitro, frente aos vermes adultos de S. mansoni, do extrato e de seus metabólitos majoritários. O estudo fitoquímico de A. lappa L. resultou no isolamento de duas lignanas dibenzilbutirolactônicas, a arctiina e arctigenina. A análise dos resultados de avaliação esquistossomicida obtidos demonstrou que o extrato hidroalcoólico bruto na concentração de 200 mg/mL apresentou expressiva atividade esquistossomicida in vitro, sendo capaz de provocar a morte de 100% dos parasitos em até 24 horas de incubação. A arctiina, metabólito majoritário purificado do extrato, foi capaz de matar e provocar lesões tegumentares em 100% dos vermes adultos. Os resultados obtidos sugerem que a atividade esquistossomicida in vitro demonstrada pelo extrato hidroalcoólico pode estar relacionada à presença da arctiina, corroborando com o potencial esquistossomicida in vitro das lignanas dibenzilbutirolactônicas, frente aos vermes adultos de S. mansoni.
Schistosomiasis caused by the Schistosoma parasite is a disease that affects about 240 million people around the world. Praziquantel is the chosen drug for the treatment of this parasitosis. It is imperative to search for new molecules and / or prototypes with potential schistosomicidal activity. This requirement is due to the tough performance of the parasite against this medicine. In this context, the research with natural products has been recognized as an alternative to discover new pharmacos for Schistosoma treatment. Arctium lappa L. (Asteraceae) stands out among vegetal plants of interest for the production of schistosomicidal substances. This is recognized for being able to biosynthesize lignoid, a kind of metabolite that has performed great schistosomicidal potential. This master thesis describes the phytochemical study of the hydroalcoholic extract from A. lappa L. fruit, as well the evaluation of the schistosomicidal activity evaluation in vitro, facing the adult worms of S. mansoni from the extract and from its majority metabolite. The phytochemical study of A. lappa L. resulted in the isolation of two dibenzyl butyrolactone lignan, a arctiin e arctigenin. The results obtained schistosomicidal evaluation showed that hydroalcoholic extract crude in concentration of 200 mg/mL showed significant antischistosomal activity in vitro and is capable of causing the death of the 100% of the parasites within 24 hours of incubation. The arctiin a major purified metabolite from the extract, was capable of killing by causing tegumentary lesions en 100% of the adult worms. The obtained results suggest that the schistosomicidal activity in vitro showed by the hydroalcoholic extract can be related to arctiin presence, supporting the potencial schistosomicidal in vitro of dibenzyl butyrolactone lignan, against the adult worms of S. mansoni.

The vinylepoxide-diliydrofuran rearrangement offers a route to substituted 2,3- dihydrofurans with a high degree of diastereoselectivity. The rearrangement proceeds via an ylide-type intermediate arising from the thermolysis of a carbon-carbon epoxide bond. This thesis discusses work aimed at developing the rearrangement, introducing asymmetric control, and application of the dihydrofuran products in target molecule synthesis. Synthesis of the vinylepoxide rearrangement precursors is described, and development of the rearrangement to achieve a moderate scale rearrangement process is discussed. Alternative rearrangement technologies are also explored. Asymmetric induction into the rearrangement was approached by the use of chiral auxiliaries and in particular C2 symmetric amines. A novel synthesis of (S,S)-2,5-diphenylpyrrolidine and (S,S)-2,6-diphenylpiperidine is reported. High degrees of enantiomeric purity were achieved through the application of an effective oxazaborolidine catalyst in the reduction of dibenzoylethane and dibenzoylpropane. Use of this chiral reduction catalyst on further diketones is described. Application of the dihydrofuran products in the synthesis of several 2,6-disubstituted- 3,7-dioxabicyclo[3.3.0]octanes. These compounds, commonly termed furofuran lignans exhibit a wide range of biological properties. The dihydrofuran products were combined with a range of dimethylacetals, in a one pot synthesis, with high degrees of stereocontrol, by a Noyori type transacetalisation. Further derivatisation of these bicyclic compounds was accomplished and is discussed.Finally, with the vinylepoxide - dihydrofuran rearrangement established a preliminary exploration of the related vinylaziridine - 2-pyrroline rearrangement is reported.

Podophyllotoxin is an aryltetralin lignan and anticancer agent produced by the Podophyllum and some other species and is extracted from Podophyllin in up to 30 percent yield. Little definitive information is available on the biosynthetic pathways to podophyllotoxin. Administering various specifically labelled precursors into intact plants and tissue cultures can give a much improved insight into the lignan biogenesis. The first part of the work has been to the synthesis of two diastereotopically labelled with ²H at C-4. Desoxypodophyllotoxin is the penultimate intermediate of the podophyllotoxin pathway and specifically labelled compounds can be used for the C-4 hydroxylation studies. Doubly ²H labelled desoxypodophyllotoxin at C-4 was also prepared which can be used for a control experiment. This work also led to the unambiguous assignment of the proton nmr of desoxypodophyllotoxin. A second part of the work has been the synthesis of p-coumarlc acid, a known lignan precursor, doubly labeled with ²H or ²H and ¹³C at the C-3â position. This labeling was selected because the availability of a C-3-labeled monomeric precursor would thus make possible the isolation and study of dimeric compounds labeled at this key positions. These compounds were synthesized, and their identity and stereochemistry were determined by spectroscopic and analytical techniques. The isotopic incorporation of these compounds was 95% d, or d₂ (or greater), as determined by mass spectral analysis.

Master of Science

Thesis (Ph.D.)--Kent State University, 2007.
Title from PDF t.p. (viewed July 8, 2009). Advisor: Angelo L. DeLucia. Keywords: human papilloma virus, mammalian lignans, p53, E6 oncogene. Includes bibliographical references (p. 133-149).

A própolis é uma substância resinosa complexa e que apresenta diversas propriedades biológicas como antiviral, antifúngica, antioxidante, anti-inflamatória, antitumoral, entre outras. Estas atividades têm sido atribuídas principalmente à presença de compostos fenólicos e/ou derivados. Entretanto, a composição química da própolis pode variar significativamente com a vegetação ao redor da colmeia. Neste estudo, foram coletadas 78 amostras de própolis orgânica produzidas em áreas de preservação permanente e reflorestamento, devidamente certificadas, localizadas no sul do Paraná e norte de Santa Catarina. Assim, o objetivo desse trabalho foi avaliar a composição química da própolis orgânica, bem como isolar os compostos responsáveis pela atividade antioxidante. Também foram avaliadas a composição de voláteis e a aplicação dos extratos etanólicos de própolis (EEP) e microcápsulas de própolis orgânica, produzidas por coacervação complexa, em óleo de soja sem adição de antioxidante. Dentre as 78 amostras analisadas, foram encontrados sete perfis cromatográficos distintos. Utilizando critérios como recorrência e atividade antioxidante, o perfil 1 foi selecionado para a etapa de isolamento dos compostos bioativos. O EEP do perfil 1 foi então fracionado pela técnica de extração líquido-líquido, originando as frações hexano, acetato de etila, butanol e água. As frações acetato de etila e butanol foram as que apresentaram as maiores atividades antioxidantes pelos métodos de sequestro dos radicais DPPH, ABTS e peroxil, bem como semelhança na composição química. Portanto, estas frações foram reunidas e na sequencia, recromatografadas em uma coluna aberta de vidro com sílica C18, a qual gerou 19 subfrações. As subfrações 2 e 5 foram as que apresentaram maior atividade antioxidante, que variou de 16,25 a 26,26 ?mol Trolox/mg e 2,28 a 5,71 ?mol Trolox/mg para os métodos ORAC e ABTSo+, respectivamente. Assim, a partir dessas subfrações foram isolados sete compostos com atividade antioxidante, sendo dois precursores de lignanas, álcool coniferil e aldeído coniferil, e cinco lignanas, as quais foram identificadas como pinoresinol, lariciresinol, secoisolariciresinol, matairesinol e balajaponina D, sendo as quatro últimas compostos inéditos em própolis. A aplicação das microcápsulas contendo a própolis orgânica do perfil 1 em óleo de soja não foi eficiente para evitar a oxidação. Na fração volátil dos sete perfis, foram encontrados terpenos, cetonas, aldeídos e alcoóis, sendo os compostos ? e ?-pinenos predominantes. Os resultados obtidos mostraram uma composição química bastante peculiar da própolis orgânica quando comparada à outras própolis brasileiras. De acordo com os resultados obtidos pode-se afirmar que a própolis orgânica é uma boa fonte de compostos bioativos a ser explorada
Propolis is a complex resinous substance and has many biological properties, such as antiviral, antifungal, antioxididant, anti-inflamatory, antitumor, among others. These activities have been attributed mainly due to the presence of phenolic compounds and/ or derivatives. However, propolis chemical composition depends on the vegetation around the hive. In this study, 78 samples of organic propolis were collected in permanent preservation and reflorestation areas, properly certified, in southern Paraná and north of Santa Catarina. The aim of this work was to evaluate the chemical composition of organic propolis as well as isolate the compounds responsible for the antioxidant activity. The volatile composition and application of ethanol extracts of propolis (EEP) and microcapsules of organic propolis, produced by complex coacervation, in soybean oil with no antioxidant addition were also evaluated. Among the 78 samples analysed, seven different chromatographic profiles were found. Using criteria such as recurrence and and antioxidant activity profile 1 was selected for isolation of bioactive compounds. The profile 1 was then fractionated by the technique of liquid-liquid extraction, resulting in hexane, ethyl acetate, butanol and water fractions. Fractions ethyl acetate and butanol were the ones that showed the highest antioxidant activity by radicals DPPH, ABTS and peroxyl scavenging methods, as well as similarity in chemical composition. Therefore, these fractions were pooled and rechromatographed in sequence in an open glass column with silica C18, yelding 19 subfractions. The subfractions 2-5 showed the highest antioxidant activity, ranging from 16,25 to 26,26 ?mol Trolox/mg e and 2,28 to 5,71 ?mol Trolox/mg for ORAC and ABTSo+ methods, respectively. Thus, from this subfractions were isolated seven compounds with antioxidant activity, two lignans precursors, such as coniferyl alcohol and coniferyl aldehyde and five lingans, wich were identified as pinoresinol, lariciresinol, secolariciresinol, matairesinol and balajaponin D. These four last lignans are novel in propolis. The application of microcapsules containing profile 1 of organic propolis in soybean oil was no effective to prevent oxidation. In the volatile fraction of the seven profiles, terpenoids, ketones, aldehydes and alcohols were found, and ? and ?-pinenes were the predominant compounds. The results obtained showed a very peculiar chemical composition of organic propolis when compared to other Brazilian ones. According to the results its possible to conclude that OP1 is a good source of bioactive compounds to be explored