Düsseldorf, Univ., Diss., 2004. / Computerdatei im Fernzugriff.

Düsseldorf, Universiẗat, Diss., 2004.

No description available.

Total syntheses of the neuroregenerative natural products vinaxanthone and xanthofulvin have been accomplished. The synthetic routes to both molecules utilize a highly regioselective furan Diels-Alder cycloaddition - aromatization sequence to furnish the catechol fragment present in both natural products. The pentasubstituted catechol was elaborated to a vinylogous amide which was used twice in both syntheses, exploiting the pseudosymmetry found in vinaxanthone and xanthofulvin. This approach enabled the dimerization of 5,6-dehydropolivione forming vinaxanthone, lending significant evidence to a non-enzymatically driven formation of vinaxanthone in Nature. The total synthesis of vinaxanthone was accomplished in nine steps, the shortest synthesis to date, and an additional route was devised to access a set of analogs for biological study. The first total synthesis of xanthofulvin was accomplished in 18 steps and the convergent nature of the synthetic plan allows for analog synthesis. The sets of vinaxanthone and xanthofulvin analogs will be used to examine their inhibition of Semaphorin3A, a protein which inhibits neuronal regeneration, and is the biological target for both molecules.

The acetylcholine (ACh) receptor system belongs to rhodopsin GPCR family and is an integral membrane protein divided into two types: muscarinic and nicotinic. The naturally occurring neurotransmitter acetylcholine binds to these two receptor systems non- selectively. The regulatory effects of the neurotransmitter acetylcholine are diverse ranging from autonomic nervous system and the central nervous system through different types of neurons innervated by cholinergic inputs. Muscarinic acetylcholine receptors (mAChRs) are divided into five receptor subtypes (M1-M5). In general, M1, M3 and M5 receptor subtypes are coupled via Gq like proteins; while M2 and M4 subtypes are coupled to Gi-proteins. Muscarinic receptors are widely distributed in the body where they mediate a variety of important physiological effects. mAChRs have been the target of drug development efforts for the treatment of various disorders including overactive bladder, Alzheimer's disease, pain, cognitive impairment, drug addiction, schizophrenia and Parkinson's disease. The development subtype selective ligands possess a challenge due to a high degree of homology among mAChR subtypes, however the recent availability of the X-ray crystal structure for the M2 and M3 receptor can be utilized for the design of new ligands. The pharmacophoric requirements for cholinergic ligands have been reported by numerous investigators based on structure-activity relationship (SAR) and/or molecular modeling data of known muscarinic ligands. These fundamental requirements are useful when designing muscarinic ligands but have provided little guidance in the design of subtype selective compounds. Our interest in developing novel muscarinic receptor ligands led to the design of lactone-based ligands using an approach similar to that reported by Kaiser et al. Preliminary binding studies of our previously synthesized lactone based compounds indicated that several were nonselective, low affinity (IC50 = µM range) muscarinic agonists (based on preliminary in vivo data). Hence based on the background information, we decided to utilize the previously synthesized lactone parent compound as lead molecule set out to investigate a new series of lactone based compounds in order improve the affinity and later the selectivity of ligands. Bioisosteric approach has been investigated for the metabolic lability of the lactone ring. Four probable bioisosteres have been evaluated: tetrahydrofuran, 1,3-benzodioxole, oxazolidinone and chromone. Thermal/microwave assisted synthesis has been utilized in the generation of intermediates as well as final compounds. Preliminary screening and further evaluation (IC50/ subtype selectivity) has resulted in the identification of promising fragments as bioisosteres for the lactone ring. / Pharmaceutical Sciences / Accompanied by one .pdf file.

Ces travaux de thèse ont permis dans un premier temps, d'aborder différentes voies de synthèse d'un nouvel antipsychotique potentiel (F17464) proposé par les laboratoires Pierre Fabre. Trois stratégies basées sur des synthèses convergentes ont été initiées. La première stratégie repose sur une étape clé de métathèse croisée, la seconde sur une réaction de Sonogashira et la troisième aborde une nouvelle méthodologie d'alkylation des chromones en position 3. Ces méthodes nous ont permis d'accéder à des intermédiaires de synthèse originaux, utiles pour préparer la molécule F17464 en respectant les contraintes industrielles.Dans un deuxième temps, différents types de molécules polycycliques complexes ont été synthétisés par cascades réactionnelles palladocatalysées. Une série de naphtalènes condensés a été préparée par réaction domino palladocatalysée issue de cyclocarbopalladations successives suivies d'une activation C(sp2)-H. Plusieurs types de cycles à sept atomes de carbone condensés ont été synthétisés en une seule étape, à partir de substrats faciles d'accès, via des cascades réactionnelles cyclocarbopalladations/activation C(sp2) ou C(sp3)-H.Finalement, des cyclooctatriènes et des fenestradiènes ont été obtenus à partir du même substrat,en une seule étape, via des réactions en cascade débutant par une cyclocarbopalladation 4-exodigsuivie d'un couplage de Stille puis d'une addition d'alcynes sur une triple liaison s'achevant par des réactions d'électrocyclisations. La température est le seul paramètre réactionnel qui diffère dans la synthèse de ces deux polycycles complexes, à partir du même substrat. / This PhD thesis allowed us in the first part to develop different synthesic pathways to a new potential antipsychotic (F17464) invented by Pierre Fabre laboratories. Three strategies based on convergent syntheses are initiated. The key step of the first strategy is olefin cross metathesis. The second strategy rests on Sonogashira coupling and the third one involves a new methodology ofchromones alkylation in position 3. These methods allowed us access to novel synthetic intermediates, useful in the preparation of the F17464 molecule by following industrial confines.ln the second part, different types of polycyclic molecules were synthesized by palladium-catalyzed cascade reactions. A set of fused naphthalenes was prepared by palladium-catalyzed dominoreaction including cyclocarbopalladations followed by C(sp2)-H bond activation. Several types of fused seven-membered carbocycles were synthesized in a one-pot reaction from convenient substrates, via cascade reactions including cyclocarbopalladations followed by C(sp2 or sp3)-Hbond activation. Finally, cyclooctatrienes and fenestradienes were obtained also in a one-pot reaction from the same substrate via cascade reactions involving 4-exo-dig cyclocarbopalladation, followed by Stille coupling, alkyne addition onto a triple bond, finishing by electrocyclization reactions. Temperature is the only parameter that differs in the synthesis ôf the two complex polycycles starting from the same substrate.

Ziel dieser Arbeit war die Entwicklung von Methoden zur Synthese von auf Phenol basierenden Naturstoffen. Insbesondere wurde bei der Methodenentwicklung die Nachhaltigkeit in den Vordergrund gerückt. Dies bedeutet, dass durch die Zusammenfassung mehrerer Syntheseschritte zu einem (Tandem-Reaktion) beispielsweise unnötige Reaktionsschritte vermieden werden sollten. Ferner sollten im Sinne der Nachhaltigkeit möglichst ungiftige Reagenzien und Lösungmittel verwendet werden, ebenso wie mehrfach wiederverwertbare Katalysatoren zum Einsatz kommen. Im Rahmen dieser Arbeit wurden Methoden zum Aufbau von Biphenolen mittels Pd/C-katalysierten Suzuki-Miyaura-Kupplungen entwickelt. Diese Methoden sind insofern äuÿerst ezient, da der ansonsten gebräuchliche Syntheseweg über drei Reaktionsschritte somit auf lediglich eine Reaktionsstufe reduziert wurde. Weiterhin wurden die Reaktionsbedingungen so gestaltet, dass einfaches Wasser als vollkommen ungiftiges Lösungsmittel verwendet werden konnte. Des Weiteren wurde für diese Reaktionen ein Katalysator gewählt, der einfach durch Filtration vom Reaktionsgemisch abgetrennt und für weitere Reaktionen mehrfach wiederverwendet werden konnte. Darüber hinaus konnte durch die Synthese von mehr als 100 Verbindungen die breite Anwendbarkeit der Methoden aufgezeigt werden. Mit den entwickelten Methoden konnten 14 Naturstoffe - z. T. erstmals - synthetisiert werden. Derartige Stoffe werden u. a. von den ökonomisch bedeutenden Kernobstgewächsen (Äpfeln, Birnen) als Abwehrmittel gegenüber Schädlingen erzeugt. Folglich konnte mit Hilfe dieser Methoden ein Syntheseweg für potentielle Pflanzenschutzmittel entwickelt werden. Im zweiten Teil dieser Arbeit wurde ein Zugang zu den sich ebenfalls vom Phenol ableitenden Chromanonen, Chromonen und Cumarinen untersucht. Bei diesen Untersuchungen konnte durch die Entwicklung zweier neuer Tandem-Reaktionen ein nachhaltiger und stufenökonomischer Syntheseweg zur Darstellung substituierter Benzo(dihydro)pyrone aufgezeigt werden. Durch die erstmalige Kombination der Claisen-Umlagerung mit einer Oxa-Michael-Addition bzw. konjugierten-Addition wurden zwei vollkommen atomökonomische Reaktionen miteinander verknüpft und somit eine überaus effiente Synthese von allyl- bzw. prenylsubstituierten Chromanonen und Chromonen ermöglicht. Ferner konnten durch die Anwendung einer Claisen-Umlagerung-Wittig-Laktonisierungs-Reaktion allyl- bzw. prenylsubstituierte Cumarine erhalten werden. Herausragendes Merkmal dieser Methoden war, dass in nur einem Schritt der jeweilige Naturstoffgrundkörper aufgebaut und eine lipophile Seitenkette generiert werden konnte. Die Entwicklung dieser Methoden ist von hohem pharmazeutischem Stellenwert, da auf diesen Wegen Verbindungen synthetisiert werden können, die zum einem über das notwendige pharmakologische Grundgerüst verfügen und zum anderen über eine Seitenkette, welche die Aufnahmefähigkeit und damit die Wirksamkeit im Organismus beträchtlich erhöht. Insgesamt konnten mittels der entwickelten Methoden 15 Chromanon-, Chromon- und Cumarin-Naturstoffe z. T. erstmals synthetisiert werden. / The aim of this work was the development of methods for the synthesis of natural products based on phenol. In particular, in developing methods, sustainability has been brought to the fore. This means that, for example, unnecessary reaction steps should be avoided by the combination of several synthetic steps to a (tandem reaction). Furthermore, non-toxic as possible in terms of sustainability reagents and solvents should be used, as well as multiple reusable catalysts are used. In this work, methods have been developed for the synthesis of bisphenols using Pd / C-catalyzed Suzuki-Miyaura coupling reactions. These methods are so far äuÿerst e? Cient, since the otherwise common synthetic route was thus reduced to merely a reaction stage, three reaction steps. Furthermore, the reaction conditions were designed to plain water could be used as a completely non-toxic solvent. It was also elected a catalyst for these reactions, which could be easily separated by filtration from the reaction mixture and reused several times for further reactions. In addition, it could be demonstrated through the synthesis of more than 100 compounds, the broad applicability of the methods. ., For the first time T. - - Using the methods developed 14 natural compounds could be synthesized. Such substances are among others generated by the economically important pome fruit crops (apples, pears) as a defense against pests. Consequently, it could be developed using these methods, a synthetic route for potential plant protection products. In the second part of this work, access to the likewise derived from phenol chromanones, chromones and coumarins was investigated. In these studies, a sustainable and economical route in stages to represent substituted benzo (dihydro) pyrones could be demonstrated by the development of two new tandem reactions. The initial combination of the Claisen rearrangement with an oxa-Michael addition or conjugated addition of two perfectly atom-economical reactions were interlinked and thus allows a very effiente synthesis of allyl or prenylsubstituierten chromanones and chromones. Furthermore or prenylsubstituierte coumarins could be obtained by the application of a Claisen rearrangement Wittig lactonization reaction allyl. The outstanding feature of these methods was that built up in only one step of the respective natural product base and a lipophilic side chain could be generated. The development of these methods is of great pharmaceutical importance, since these paths compounds can be synthesized on a the necessary pharmacological Backbone and on the other hand have a side chain, which increases the absorption and thus the effectiveness in the body considerably. Overall, z. T. were synthesized using the methods developed Chromanon- 15, chromone and coumarin-natural products for the first time.

Made available in DSpace on 2015-05-14T12:59:44Z (GMT). No. of bitstreams: 1 ArquivoTotal.pdf: 3688068 bytes, checksum: 2a796c235bc859cfcc93483db6d3f202 (MD5) Previous issue date: 2012-04-25 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The Caatinga biome is a promising source of biomolecules of plant origin. In Paraíba, Northern Brazil, the Pico do Jabre state park is the largest area of total protection and conservation included in this biome, where is possible to find the species Evolvulus linarioides Meisn, a small blue-flowered herb, distributed at lower altitudes and rocky outcrops. This work describes the results obtained in the phytochemical study of E. linarioides. The dried and pulverized plant material was subjected to extraction and chromatographic techniques in order to isolate some chemical constituents. The structural identification of these constituents was performed by spectroscopic methods, such as Infrared (IR), 1H and 13C NMR (uni and bidimensional), mass spectrometry and comparisons with literature data. A novel sesquiterpene, 5α-hydroximethyl-cariophyl-3(4)-en-8β-5α-diol, to which the name linariofileno was assigned, was obtained from the dichloromethane extract; from the ethyl acetate extract, two chromones were isolated: cnidimol C and 5,7-dihydroxy-2-hydroxymethyl-4H-1-benzopiran-4-one-9-O-β-glucoside, being reported for the first time in literature and assigned the name cnidimol C glucoside. These results emphasize the importance of this work to a better knowledge of the secondary metabolites s profile of plant origin in the Caatinga biome. Furthemore, it advances in the future perspective of interdisciplinary studies through the evaluation of biological properties of these novel molecules isolated and identified from the Convolvulaceae family. / Botanicamente, Na Paraíba, o Parque Estadual do Pico do Jabre é a maior unidade de conservação de proteção integral inserida nesse bioma, onde é possível encontrar a espécie Evolvulus linarioides Meisn., uma pequena erva com flores azuladas, distribuída nos menores níveis de altitude e afloramentos rochosos. O presente trabalho descreve os resultados obtidos no estudo fitoquímico de E. linarioides. Para tanto, o material vegetal, após secagem e pulverização, foi submetido a processos de extração e técnicas cromatográficas para isolamento dos constituintes químicos. A estrutura química dos mesmos foi determinada pela análise dos dados espectrais de Infravermelho, Ressonância Magnética Nuclear de 1H e 13C uni e bidimensionais, Espectrometria de Massas e comparações com dados da literatura. Da fase diclorometano foi obtido um novo sesquiterpeno, enquanto que da fase acetato de etila foram isolados duas cromonas, sendo uma inédita. Tais resultados ressaltam a importância do estudo de espécies do semi-árido paraibano, particularmente das atividades de isolamento e elucidação estrutural de seus constituintes, além de contribuírem para o conhecimento fitoquímico de E. linarioides e para o conhecimento quimiotaxonômico do gênero Evolvulus e da família Convolvulaceae. a Caatinga constitui-se um complexo bastante Botanicamente, Na Paraíba, o Parque Estadual do Pico do Jabre é a maior unidade deconservação de proteção integral inserida nesse bioma, onde é possívelencontrar a espécie Evolvulus linarioides Meisn., uma pequena erva com floresazuladas, distribuída nos menores níveis de altitude e afloramentos rochosos.O presente trabalho descreve os resultados obtidos no estudo fitoquímico deE. linarioides. Para tanto, o material vegetal, após secagem e pulverização,foi submetido a processos de extração e técnicas cromatográficas paraisolamento dos constituintes químicos. A estrutura química dos mesmos foideterminada pela análise dos dados espectrais de Infravermelho, RessonânciaMagnética Nuclear de 1H e 13C uni e bidimensionais, Espectrometria de Massase comparações com dados da literatura. Da fase diclorometano foi obtido umnovo sesquiterpeno, enquanto que da fase acetato de etila foram isoladosduas cromonas, sendo uma inédita. Tais resultados ressaltam a importância doestudo de espécies do semi-árido paraibano, particularmente das atividades deisolamento e elucidação estrutural de seus constituintes, além de contribuírempara o conhecimento fitoquímico de E. linarioides e para o conhecimentoquimiotaxonômico do gênero Evolvulus e da família Convolvulaceae.a Caatinga constitui-se um complexo bastante

Ce travail de thèse décrit la synthèse, la réactivité et les propriétés biologiques des dérivés 2-pyridoniques obtenus à partir de substrats simples appartenant à la famille des chromones. Lors de ce projet, les énaminochromanones - représentant une nouvelle classe d’hétérocycles - ont été identifiées comme étant des intermédiaires cinétiques stables et facilement isolables. Certains composés de type pyridin-2-one ont été diversifiés et, parmi les produits synthétisés, certains ont montré des activités anticancéreuses via inhibition du processus de transition épithélio-mésenchymateuse (TEM). Ultimement, en utilisant le même substrat de type chromone, une approche innovante de la synthèse des analogues d’aromathécines (ARTs) a été également abordée et a abouti au squelette A-B-C-D de ces dernières avec un rendement global de 32%. / This work is focused on the synthesis, reactivity and biological properties of 2-pyridone derivatives obtained from simple substrates such as chromone scaffold. During this project, the enaminochromanones - belonging to a new class of heterocycles - was identified as stable an easily isolable kinetic intermediates. Some pyridin-2-one compounds have been diversified and, among the synthesized products, some of them showed anticancer activities via inhibition of epithelial-mesenchymal transition (EMT) process. Ultimately, an innovative approach to synthesize aromathecin analogs (ARTs) by using the same chromone substrate as starting material was also discussed and led to A-B-C-D core of the latter in 32% overall yield

Les travaux menés dans cette thèse s’inscrivent dans une démarche ethno-pharmacologique visant à valoriser des plantes utilisées traditionnellement en médecine au Mozambique. Cette étude a comme but principal d’apporter des éléments chimio taxonomiques concernant des espèces végétales peu décrites et de préciser la composition métabolique de parties de plante utilisées en médecine traditionnelle, pour aboutir potentiellement à de nouvelles molécules utilisables en thérapeutique. Le travail est ainsi découpé en trois parties distinctes, chacune portant sur une plante différente.La Partie 1présente l’étude phyto-chimique des racines sèches de Ptaeroxylon obliquum Radlk (Rutaceae). L’étude phyto-chimique de l’extrait chloroformique des racines de P.obliquum a permis l’isolement de cinq composés appartenant à la famille des coumarines ou de chromones dont un totalement original : un meroterpène de type chromone, le Ptaerobliquol. Les structures de ces composés ont été élucidées par différentes techniques analytiques de pointes (RMN, Spectrométrie de masse) et diffraction des rayons X.La Partie 2 porte sur l’étude phyto-chimique des écorces de tubercules de Pyrenacantha kaurabassana (Icacinaceae). Cette plante n’a été que très peu étudiée d’un point de vue phytochimique. Un criblage des métabolites présents a été réalisé, montrant la présence prépondérente de composés de la famille des quinones et des flavonoïdes. Le fractionnement de l’extrait acétate d’éthyle des écorces de tubercule a abouti à l’isolement et l’identification de 4 métabolites, dont 2 totalement originaux, appartenant à la famille des xanthones.Enfin la Partie 3 porte sur l’étude phytochimique des tiges de Monadenium lugardiae ou Euphorbia lugardiae (Euphorbiaceae). Le fractionnement de l’extrait chloroformique des tiges a permis l’isolement et l’identification de deux métabolites jamais décrits dans cette plante, le jolkinolide B, l’Hélioscopinolide F, conjointement avec la scopoletine. / This PhD work is part of an ethno-pharmacological approach to enhance plant used in traditional medicine in Mozambique. The aim of this work is to elucidate major metabolites through a chemo-taxonomic approach and clarify the phytochemical composition of plant used in traditional medicine, leading potentially to new molecules of therapeutical interest.The work is thus cut into three parts, each focusing on a different plant.The Part 1describes the phytochemical study of dry roots of Ptaeroxylon obliquum Radlk (Rutaceae). The phytochemical study of the chloroform extract of the roots of P. obliquum resulting in the isolation of five compounds belonging to coumarin or chromone. A totally original meroterpenoid chromone was then isolated and elucidated: the Ptaerobliquol. Structures of these metabolites were elucidated by various analytical techniques (NMR, mass spectrometry) and X-ray diffraction.Part 2 focuses on the phyto-chemical study of bark tubers of Pyrenacantha kaurabassana (Icacinaceae). Few phytochemical data were available about this plant in the litterature. Screening of metabolites was so carried out, showing the preponderant presence of compounds belonging to the family of quinones and flavonoids. The study of the ethyl acetate extract of the bark of tuber resulted in the isolation and identification of four metabolites, including two totally original, belonging to the family of xanthones.Finally, Part 3 focuses on the phytochemical study of stems of Monadenium lugardiae or Euphorbia lugardiae (Euphorbiaceae). Fractionnation of the chloroform extract of the stemshas led to the isolation and identification of two metabolites never described in this plant, jolkinolide B, the Hélioscopinolide F, together with scopoletin.