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1
Berg, Michael Arthur George. "Studies in the stereoselective synthesis of 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines." Diss., This resource online, 1992. http://scholar.lib.vt.edu/theses/available/etd-10032007-171522/.
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Jones, Michael William Chemistry Faculty of Science UNSW. "Enhancing the cooperative binding properties of 1,1'-bis(1,2,3,4-tetrahydroisoquinolines)." Awarded by:University of New South Wales. School of Chemistry, 2005. http://handle.unsw.edu.au/1959.4/27400.
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The design of partially reduced 1,1'-bisisoquinoline derivatives was investigated with the aim of controlling the conformation about the C1-C1' axis. This would produce ligands with unusual but predictable ligand binding properties, particularly cooperativity. The introduction of ??-aminoalkyl, ??-azidoalkyl, ??-alkynyl and ??-alkenyl groups onto the nitrogens of the reduced bisisoquinoline core was conducted with the intention of broadening the scope of the ligand. Subsequent epoxidation, hydroboration and Huisgen 1,3-dipolar cycloaddition of terminal unsaturated groups and nucleophilic displacement of the chlorine of the corresponding known bischloroacetyl derivative afforded representative examples of new ligand types for future study. 1,1'-Bis(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline) was found to readily condense with a wide range of aldehydes to give imidazolines and aspects of the rates of condensation were determined. Mono-alkyl bisisoquinolines were obtained efficiently by cleavage of the imidazolines through a newly defined treatment with sodium cyanoborohydride under acidic conditions. A procedure was developed whereby these two steps could be accomplished in a sequential one-pot process. The mono-alkyl compounds were further derivatized through acetylation, alkylation, sulfonylation and reductive alkylation. Synthetic strategies towards ??-excessive N-arenealkyl derivatives were established with the goal to create scaffolds for the coordination of ??-deficient systems, of which the X-ray crystal structures of three N-arenemethyl derivatives were elucidated. These are each closely related in conformation about the C1-C1' axis. Reaction of two examples of the N-arenealkyl compounds with copper(II) and palladium(II) chlorides, furnished the first known examples of this type of highly reduced 1,1'-bisisoquinoline-metal complex. Single crystal X-ray crystallography was used to analyse the structures of these complexes in the solid state. Preliminary physicochemical investigations were conducted with a view to determining the conformation of the molecules about the bisisoquinoline C1-C1' bond. The interaction of intermolecular N-aryl ??-excessive compounds with ??-deficient systems was found to result in minimal spectroscopic changes. Complementary intramolecular ??-excessive/??-deficient systems were found through fluorometric analysis to readily form charge transfer complexes. Finally, it was determined that the conformation of 1,1'-bis[2-(methoxy-18- crown-6)ethanoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline] could be controlled by the simultaneous coordination of the termini of the diperchlorate salt of 1,3-diaminopropane to the crown ether moieties of the ligand. A range of new N-substituted bisisoquinolines have been synthesised and methods developed for determining interactions between parts of these molecules that through these physicochemical characteristics could allow monitoring of conformational behaviour in future studies. Keywords: 1,1'-bisisoquinoline, conformational analysis, supramolecular chemistry, functional ligands, metal complexes.
3
Donaghy, Michael. "Studies in benzimidazo [2,1-a] isoquinoline chemistry." Thesis, Northumbria University, 2001. http://nrl.northumbria.ac.uk/1217/.
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Studies in Benzimidazo[2,1-a]isoquinoline Chemistry by Michael John Donaghy B. Sc. (Hons.) Ellipticine, a member of the pyrido[4,3-b]carbazole alkaloid family first isolated in 1959 from the leaves of the plant Ochrosia Elliptica has been shown to possess anti-cancer activity against various tumours. Ellipticine is thought to undergo biological oxidation to give the more active 9-hydroxyellipticine that is subsequently converted to a highly reactive quinone-imine intermediate. The quinone-imine is then thought to interact with bionucleophiles in the body promoting cell death. The aim of the project was to synthesise a series of benzimidazo[2,1-a]isoquinolines. The benzimidazo[2,1-c]isoquinolines were similar in general structure to ellipticines and should therefore undergo similar biological reactions. The target benzimidazo[2,1-a]isoquinolines have been screened to evaluate their ability to inhibit the enzyme topoisomerase II that is involved in DNA replication and ultimately cell reproduction. The target compounds have also been evaluated by the American National Cancer Institute.
4
Clifton, Mary Jennifer. "Studies in stereoselective synthesis via reissert compound chemistry." Thesis, This resource online, 1991. http://scholar.lib.vt.edu/theses/available/etd-08222009-040256/.
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Guimond, Nicolas. "Part A: Rhodium-catalyzed Synthesis of Heterocycles / Part B: Mechanistic Studies on Tethering Organocatalysis Applied to Cope-type Alkene Hydroamination." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23222.
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The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.
6
Ford, Alan John. "Synthesis of substituted isoquinoline ligands for homogeneous catalysis." Thesis, University of Hull, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361496.
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Muzanila, Charles Nobert. "Heterocyclic transformations involving #DELTA#'2-oxazolines and 1,2-benzisoxazoles." Thesis, University of Salford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327958.
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Hamilton, Lynne. "Synthesis, stereochemistry and reactions of quinoline, isoquinoline and acridine metabolites." Thesis, Queen's University Belfast, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.334710.
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Streetley, Guy Bradwell. "New approaches for the asymmetric synthesis of pyrroloisoquinoline and isoquinoline alkaloids." Thesis, Loughborough University, 2006. https://dspace.lboro.ac.uk/2134/34917.
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Pyrroloisoquinoline (n = 1) and the pyridoisoquinoline (n = 2) ring systems (2) are found to be the major structural motif of the Erythrina and the protoberberine group of alkaloids, respectively. We have recognised that suitable bicyclic lactams (1) could act as precursors, in an intramolecular N-acyliminium ion-mediated cyclisation, resulting in a stereoselective approach to the core of the Erythrina and protoberberine ring systems. [Illustration omitted.] Access to the tetracyclic core of the Erythrina alkaloids (3) through the application of N-acyliminium ion chemistry is well established within our group. This has been demonstrated in a formal asymmetric synthesis of both enantiomers of the Erythrina alkaloid, 3- demethoxyerythratidinone (4), and described in this thesis. [Illustration omitted.] Our investigations have also involved the manipulation of this methodology toward the synthesis of the Erythrina alkaloid (-)-erysotrine (5) and the protoberberine alkaloid (-)-xylopinine (6).
10
Chow, Yit Lai. "Caenorhabditis elegans as a whole organism screening system for isoquinoline alkaloid bioactivities." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/188834.
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Sampaio, Tuane Bazanella. "AVALIAÇÃO DOS EFEITOS FARMACOLÓGICO E TOXICOLÓGICO DE 4- ORGANOCALCOGENO-ISOQUINOLINAS." Universidade Federal de Santa Maria, 2014. http://repositorio.ufsm.br/handle/1/11226.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior<br>Monoamine oxidase (MAO) is a target enzyme in the treatment of several
pathologies, being that new molecules which inhibit of a selective, potent and
reversible manner their isoforms and without adverse effects are searched. In this
way, the first manuscript of this dissertation evaluated the in vitro inhibitory potential
of the 4-organochalcogen-isoquinolines on cerebral MAO-A and B activities,
elucidating their kinetics profile and the interaction compound x enzyme. The results
demonstrated that all compounds were selective inhibitors of MAO-B, being
compound 3-phenyl-4-(selenophenyl) isoquinoline the most potent. The kinetics
profile revealed a mixed and reversible inhibition of enzyme, consistent to the results
of molecular docking. It is known that both organic selenium compounds and
isoquinolines are linked to pro-oxidants situations, thus, it was investigated the in
vitro effect of 4-organoseleno-isoquinolines on cerebral activities of the enzymes δ-
aminolevulinate dehydratase (δ-ALA-D) e Na+, K+-ATPase, which have easily
oxidized cysteine residues. Data demonstrated that compounds substituted with
chloro, fluoro and trifluoromethyl in the aromatic ring bonded to the selenium atom of
compound 3-phenyl-4-(selenophenyl) isoquinoline inhibited both sulfhydryl enzymes,
which was not observed in the compound substituted with methyl and in a nonsubstituted
compound. Furthermore, since the inhibition of enzymes δ-ALA-D and
Na+, K+-ATPase was restored by dithiothreitol it is possible to propose the oxidation
of cysteine residues by compounds. The selective and reversible inhibition of MAO-B
and the low toxicological potential demonstrated by compound 3-phenyl-4-
(selenophenyl) isoquinoline become this compound a candidate for more studies,
which aim this enzyme as a therapeutic target.<br>A monoamina oxidase (MAO) é uma enzima alvo no tratamento de diversas
patologias, sendo que novas moléculas que a inibam de maneira seletiva, potente,
reversível, e ausente de efeitos adversos suas isoformas são procuradas. Neste
sentido, o primeiro manuscrito desta dissertação avaliou o potencial inibitório dos 4-
organocalcogeno-isoquinolinas na atividade cerebral da MAO-A e B in vitro,
elucidando seus perfis cinéticos e a interação composto e enzima. Os resultados
demonstram que todos os compostos apresentam inibição seletiva da MAO-B,
sendo o composto 3-fenil-4-(selenofenil) isoquinolina o mais potente. O perfil cinético
revelou inibição do tipo mista e reversível da enzima, coerente aos resultados do
docking molecular. Sabe-se que tanto compostos orgânicos de selênio quanto
isoquinolinas relacionam-se a situações pró-oxidantes, deste modo, investigou-se o
efeito in vitro dos 4-organoseleno-isoquinolinas na atividade cerebral das enzimas δ-
aminolevulinato dehidratase (δ-ALA-D) e Na+, K+-ATPase, as quais possuem
resíduos de cisteína facilmente oxidáveis. Os dados demonstram que os compostos
substituídos com cloro, flúor e trifluormetil no anel aromático ligado ao átomo de Se
do composto 3-fenil-4-(selenofenil) isoquinolina inibem ambas as enzimas
sulfidrílicas, o que não foi observado com o composto substituído com metil e com o
composto não substituído. Além disso, visto que a inibição das enzimas δ-ALA-D e
Na+, K+-ATPase foi revertida por ditiotreitol é possível propor o envolvimento da
oxidação dos resíduos de cisteína pelos compostos. Devido à inibição seletiva e
reversível da MAO-B e ao baixo potencial toxicológico demonstrado, o composto 3-
fenil-4-(selenofenil) isoquinolina torna-se um candidato a mais estudos que possuam
esta enzima como alvo terapêutico.
12
Morishige, Takashi. "Molecular characterization of O-methyltransferases involved in isoquinoline alkaloid biosynthesis in Coptis japonica." Kyoto University, 2002. http://hdl.handle.net/2433/149491.
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Kyoto University (京都大学)<br>0048<br>新制・課程博士<br>博士(農学)<br>甲第9734号<br>農博第1283号<br>新制||農||850(附属図書館)<br>学位論文||H14||N3697(農学部図書室)<br>UT51-2002-J516<br>京都大学大学院農学研究科応用生命科学専攻<br>(主査)教授 佐藤 文彦, 教授 關谷 次郎, 教授 島田 幹夫<br>学位規則第4条第1項該当
13
Shitan, Nobukazu. "Structural and functional analyses of an ABC protein in isoquinoline alkloid-producing plant cells." Kyoto University, 2003. http://hdl.handle.net/2433/78151.
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Kyoto University (京都大学)<br>0048<br>新制・課程博士<br>博士(農学)<br>甲第10251号<br>農博第1323号<br>新制||農||865(附属図書館)<br>学位論文||H15||N3772(農学部図書室)<br>UT51-2003-H672<br>京都大学大学院農学研究科応用生命科学専攻<br>(主査)教授 佐藤 文彦, 教授 關谷 次郎, 教授 矢崎 一史<br>学位規則第4条第1項該当
14
Si, Chong. "Synthesis of Cortistatin Alkaloids and a Versatile Synthesis of Isoquinolines." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10444.
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The cortistatins are a recently identified class of marine natural products that were found to exhibit potent and selective inhibition of human umbilical vein endothelial cells (HUVECs), making them promising leads for the development of anti-angiogenic drugs. In our synthesis, we envisioned that natural cortistatins and unnatural analogs could be prepared by late-stage introduction of isoquinolines to 17-keto precursors, and that these differentially substituted precursors could all be derived from a common key intermediate 112. We developed a robust synthetic route to prepare gram quantities of key intermediate 112 starting from readily available benzylzinc reagent 116 and enol triflate 117. Key intermediate 112 was next converted to cortistatin precursors 108, 109, 110, and 111 in three to eight steps, representing each of the four natural cortistatin ABC-ring substitution patterns. Subsequently, a generally applicable method was developed to introduce the isoquinoline moiety. After complexation to N,N,N',N'-tetramethylethylenediamine (TMEDA), 7-lithio-isoquinoline added to 17-keto precursors to provide the corresponding 1,2-addition products; the resulting tertiary alcohols underwent radical deoxygenation via their trifluoroacetates to afford the desired (17S)-products. This organolithium-addition-deoxygenation sequence provided cortistatins A (1, on a 20-mg scale), J (9), K (10), and L (11) in good overall yields. We also synthesized cortistatin primary amines (176 and 186) and used them to prepare several cortistatin based affinity reagents. By employing these reagents in pull-down experiments, we identified a 55-kD membrane kinase as a putative protein target of cortistatins. We wanted to prepare cortistatin analogs with isoquinoline modifications due to the importance of this ring for the biological activity of cortistatins. This led us to develop a novel and versatile synthesis of substituted isoquinolines. In our method, lithiated o-tolualdehyde tert-butylimines were condensed with different nitriles to generate eneamido anion intermediates, which were trapped in situ with various electrophiles at the C4-position, affording a wide range of substituted isoquinolines. Further diversification was achieved by modification of the work-up conditions and by subsequent transformations.<br>Chemistry and Chemical Biology
15
Xu, Yiting. "Identification of [beta]-carboline/isoquinoline biosynthetic enzymes from brain tissue and characterisation of mupirocin biosynthetic proteins." Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.506563.
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Tittle, James Alfred. "Ab Initio Studies of High Temperature Pyrolysis Mechanisms in Heterocyclic Nitrogen-Containing Compounds." Digital Commons @ East Tennessee State University, 2000. https://dc.etsu.edu/etd/21.
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The decomposition mechanisms of various coal constituents undergoing pyrolysis are of great concern in environmental circles (especially those coal constituents containing nitrogen). Most methods of burning coal that are efficient involve doing so at high temperatures. This invariably results in a large portion of non-combusting coal being heated to high temperatures also causing pyrolysis of the original coal constituents. The end result of such pyrolysis is the production of a number of noxious gaseous products. If we are to design methods of reducing the amount of toxins that are produced from the industrial use of coal, it is necessary to understand the pyrolysis process mechanistically. Due to the great number of coal constituents, a reasonable approach to such a mechanistic study is to use a simpler model. Pyridine makes an excellent starting model upon which to build. Our study focuses on interpretation of proposed reaction channels from experimental work on pyridine, quinoline and isoquinoline shock-tube decomposition in light of new ab initio energy calculations using Gaussian 98. The pathways thus determined support the proposed pyrolysis mechanisms and agree with experimental evidence obtained from independent groups of researchers performing shock tube pyrolysis.
17
Smith, Catherine Claire. "The mouse tail model in dermatology : a histological study on the effects of crude coal tar and isoquinoline." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236062.
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This study involves a morphological and histological investigation of normal mouse tail skin and its response to crude coal tar and isoquinoline (a major constituent of coal tar). Mouse tail skin is unusual in that it undergoes both parakeratotic and orthokeratotic keratinization in adjacent sites. The former develops without a granular layer and resembles psoriasis, while the latter, with a granular layer, resembles normal human skin. Based on this property, mouse tail skin has frequently been used as a model for psoriasis but in spite of this, an integrated, detailed picture of its structure has not previously been described. This was achieved in this study by using a range of complementary techniques: light microscopy of embedded and frozen material, scanning and transmission electron microscopy, quantitative image analysis and autoradiography. Such a study may help to elucidate the mechanism of both orthokeratotic and parakeratotic keratinization. Coal tar has been used extensively in the treatment of psoriasis and is safe and effective. However, it is cosmetically unappealing, its mechanism of action is unknown and its efficacy varies with its composition which is extremely heterogeneous. Isoquinoline may significantly contribute to its anti-psoriatic properties. The mode of action of these substances as modifiers of the keratinization process may be clarified by studying their effects on the model. Both substances induced granular layer formation in previously parakeratotic areas, with concommitant development of an orthokeratotic stratum corneum, a desirable property in a potential anti-psoriatic. However, they also induced epidermal thickening and hyperkeratosis. The effects on the pilosebaceous unit were strikingly different: coal tar caused metaplasia of sebaceous glands with follicular hyperkeratosis and hair loss while isoquinoline caused sebaceous gland hypertrophy. Isoquinoline also caused far more epidermal irritation than coal tar, and caused damage to the basal lamina and dermal collagen. The irritant effects were modified to some extent by hydrocortisone cream but this also reduced granular layer induction. These studies suggest that isoquinoline may act on parakeratotic epidermis in a similar way to coal tar. It has the advantages of being a cleaner substance, with a more consistent action. However, its usefulness may be limited by its irritancy.
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Tims, Michael C. "The chemical ecology of Hydrastis canadensis L. (Ranunculaceae) effects of root isoquinoline alkaloids on the Hydrastis endophyte, Fusarium oxysporum /." College Park, Md. : University of Maryland, 2006. http://hdl.handle.net/1903/4052.
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Thesis (Ph. D.) -- University of Maryland, College Park, 2006.<br>Thesis research directed by: Cell Biology & Molecular Genetics. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
19
McNaught, Kevin St Patrick. "The neurotoxic potential of isoquinoline derivatives structurally related to the Parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321681.
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Pulman, Jane. "A transcriptomics approach to understanding polymorphic and transcript level differences linked to isoquinoline alkaloid production in triploid varieties of Narcissus pseudonarcissus." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2006379/.
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The Amaryllidaceae have characteristic isoquinoline alkaloids including galanthamine that is approved for treatment of Alzheimer’s disease. The daffodil (Narcissus pseudonarcissus) is an industrial source of this alkaloid. This project undertook analysis of the daffodil transcriptome as an approach to understanding this alkaloid biosynthetic pathway. Material from the basal plate of var. Carlton was analysed using the Roche 454 GS FLX Titanium and Illumina HiSeq platforms to assemble reference transcripts (45324 transcripts from 454, 165065 from Illumina). Annotation was via a bespoke BLAST pipeline utilizing UniProt, TAIR, Rfam and RefSeq. Further functional annotation and enrichment studies were carried out using the DAVID platform encompassing KEGG, GO and EC annotations. Illumina HiSeq sequencing of a second variety, Andrew’s Choice, was used alongside the reference transcripts to identify SNPs and transcript level differences. A bioinformatics method to determine ploidy indicated both varieties were triploid, in agreement with microscopy results. The level of selected transcripts was also assessed using qPCR. Several transcripts putatively involved in alkaloid biosynthesis were identified. Comp75950_c0_s1 showed homology to a C4H gene from peppers and could be involve in protocatechuic acid biosynthesis in daffodils. Two transcripts, Daff106212 and Contig1404, were predicted to catalyse the synthesis of norbelladine from protocatechuic acid and tyramine, and its subsequence conversion to 4’-O-methylnorbelladine. Finally, transcripts HDA57HA0AK3FX and Daff88927 were suggested for the final step in galanthamine biosynthesis, an intermolecular phenol coupling. This is the first transcriptomic comparison of two daffodil varieties and is an important resource for further investigation into genes involved in Amaryllidaceae alkaloid biosynthesis.
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Pesarico, Ana Paula. "ENVOLVIMENTO DOS SISTEMAS SEROTONINÉRGICO E DOPAMINÉRGICO NA AÇÃO DO TIPO ANTIDEPRESSIVA DO 7-FLÚOR-1,3 DIFENILISOQUINOLINA-1-AMINO EM CAMUNDONGOS." Universidade Federal de Santa Maria, 2014. http://repositorio.ufsm.br/handle/1/11237.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior<br>Depression is a psychiatric disorder associated with a negative impact on quality of life. Monoaminergic system has been involved in this disease and in the action of antidepressants. This study aimed to investigate the potential antidepressant-like of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) and the possible involvement of monoaminergic system. Results showed that FDPI (1, 10 and 20 mg/kg, intragastric (i.g.)) reduced the immobility time, increased swimming time, but did not alter climbing time of mice in the modified forced swimming test (FST). These effects were similar to those of paroxetine (8 mg/kg, intraperitoneally (i.p.)), a selective serotonin reuptake inhibitor, which was used as positive control. Pretreatments with p-chlorophenylalanine (pCPA, an inhibitor of serotonin (5-HT) synthesis, 100 mg/kg, i.p., once a day for 4 consecutive days), N-[1]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY 100635, a 5-HT1A receptor antagonist, 0.1 mg/kg, subcutaneous injection (s.c.)) and ondansetron (a 5-HT3 receptor antagonist, 1 mg/kg, i.p.) reversed the antidepressant-like effect of FDPI at the dose 1 mg/kg in FST, this did not occurs with ritanserin (a 5-HT2A/2C receptor antagonist, 1 mg/kg, i.p.). Antagonist related with dopaminergic system, as haloperidol (a D2 receptor antagonist, 0.2 mg/kg, i.p.) and SCH23390 (a D1 receptor antagonist, 0.05 mg/kg, s.c.) were able to reverse the antidepressant-like effect of FDPI at the dose 1 mg/kg in FST, this did not occurs with sulpiride (a D2 and D3 receptors antagonist, 50 mg/kg, i.p.). FDPI, at doses of 10 and 20 mg/kg, inhibited monoamine oxidase-B activity in prefrontal cortex of mice. These results suggest that FDPI produced an antidepressant-like action in the FST in mice, possibly by an involvement of the monoaminergic system. Additional studies are necessary in order to propose FDPI as a drug for depression treatment.<br>A depressão é uma doença psiquiátrica associada com um impacto negativo na qualidade de vida. O sistema monoaminérgico parece estar envolvido nessa doença e na ação dos antidepressivos. Esse estudo teve como objetivo investigar o potencial do tipo antidepressivo do 7-flúor- 1,3 difenilisoquinolina-1-amino (FDPI) e o possível envolvimento do sistema monoaminérgico. Os resultados mostraram que o FDPI (1, 10 e 20 mg/kg, intragástrico (i.g.)) reduziu o tempo de imobilidade, aumentou o tempo de nado, mas não alterou o tempo de escalada dos camundongos durante o teste do nado forçado (TNF) modificado. Esses efeitos foram similares aos da paroxetina (8 mg/kg, intraperitoneal (i.p.)), um inibidor seletivo da recaptação de serotonina, o qual foi usado como controle positivo. Os pré-tratamentos com p-clorofenilalanina (pCPA, um inibidor da síntese de serotonina (5-HT), 100 mg/kg, i.p., uma vez por dia, por 4 dias consecutivos), N-{2-[4-(2-metoxifenil)-1-piperazinil]etil}-N-(2-piridinil) ciclohexanocarboxamida (WAY 100635, um antagonista dos receptores 5-HT1A, 0,1 mg/kg, subcutâneo (s.c.)) e ondansetrona (um antagonista dos receptores 5-HT3, 1 mg/kg, i.p.) conseguiram reverter o efeito do tipo antidepressivo do FDPI na dose de 1 mg/kg no TNF, o que não aconteceu com a ritanserina (um antagonista do receptores 5-HT2A/2C, 1 mg/kg, i.p.). Antagonistas relacionados com o sistema dopaminérgico, como haloperidol (um antagonista do receptor D2, 0,2 mg/kg, i.p.), e SCH23390 (um antagonista do receptor D1, 0,05 mg/kg, s.c.) foram capazes de reverter o efeito do tipo antidepressivo do FDPI na dose de 1 mg/kg no TNF, o que não aconteceu com o sulpiride (um antagonista dos receptores D2 e D3, 50mg/kg, i.p.). O composto FDPI nas doses de 10 e 20 mg/kg inibiu a atividade da monoamino oxidase B em córtex pré-frontal de camundongos. Estes resultados sugerem que o FDPI apresentou
uma ação do tipo antidepressiva no TNF em camundongos, possivelmente por um envolvimento do sistema monoaminérgico. Mais estudos se fazem necessários antes que se possa propor o FDPI como uma droga para o tratamento da depressão.
22
Ozcan, Sevil. "Development Of New Synthetic Methodologies For The Synthesis Of Unusual Isocoumarin And Indole Derivatives:the Chemistry Of Homophthalic Acid." Phd thesis, METU, 2007. http://etd.lib.metu.edu.tr/upload/3/12608197/index.pdf.
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Many heterocyclic compounds containing nitrogen, oxygen and sulfur show wide
range of physiological activities and their synthesis has always been attracted the interest
of chemists.
The aim of this research is to develop new synthetic methodologies leading to the
synthesis of new derivatives of isocoumarines, indoles, isoquinolines, benzodiazepinones
and quinazolines, which have been found to show important biological activities.
Starting from homophthalic acid and bishomophthalic acid the corresponding acyl
azides were proposed to be synthesized, which then would be used for the synthesis of
various heterocycles. The proposed diazide from homophthalic was not formed due to the
tendency of the ortho-positioned acid to undergo cyclization.
Instead, new unusual benzochromen and isocoumarin derivatives have been
synthesized in a single step, for which reasonable mechanisms have been proposed.
The half ester produced from homophthalic acid was an important key compound
for the synthesis of new highly substituted indole derivatives, which are expected to be
biologically active.
The diisocyanate derived from was synthesized directly from ortho-bromo xylene
was treated with alcohols and hydrazine to produce seven membered rings. Instead of the
intramolecular cyclization reaction, they underwent polymerization to form new
polymers.
Furthermore, new synthetic method for the synthesis of pyrazoles has been
developed.
23
Charpentier, Langlois Patricia. "Activation d'une réaction entre un acide et une amine par reconnaissance moléculaire. Synthèse d'un récepteur d'amine." Rouen, 1995. http://www.theses.fr/1995ROUES027.
Full textAbstract:
Notre objectif a été de définir un récepteur hétérocyclique susceptible de faciliter, de manière générale, la réaction entre un acide carboxylique et une amine afin de conduire à un amide. La première partie de ce travail a consisté en l'examen de diverses stratégies d'approche de la partie tricyclique du récepteur. Nous nous sommes notamment intéressés à des dérivés de la tétrahydroisoquinoléine. A cette occasion, nous avons été amenés à apporter une contribution intéressante à la chimie de ce type de dérivés. Dans une seconde partie, nous nous sommes attachés à synthétiser la partie simplifiée du récepteur, correspondant selon nos hypothèses, aux sites de fixation de la fonction amine. En effet, ce récepteur semble capable d'interagir avec diverses amines comme l'ont montré d'une part, les valeurs des constantes d'association déterminées par RMN et d'autre part, l'étude des interactions dipolaires intermoléculaires par NOESY
24
Tinkleman, Joseph M. Smith Forrest T. "Synthesis of 10, 11, 12, 12a, 12b, 13-hexahydro-5hbenzo[f]cyclopropa[d]pyrido[1,2-b] isoquinoline-5,7(9H)dione and related compounds." Auburn, Ala, 2009. http://hdl.handle.net/10415/1655.
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25
Laughlin, Sarah R. "Arylboronic Acids With Strong Fluorescence Intensity Changes Upon Sugar Binding." Digital Archive @ GSU, 2011. http://digitalarchive.gsu.edu/chemistry_theses/46.
Full textAbstract:
Boronic acids play an important role in the design and synthesis of chemosensors for carbohydrates due to their ability to reversibly bind with diol-containing compounds. Along this line, the availability of boronic acids that change fluorescence upon sugar binding is critical to a successful sensor design effort. Here, two boronic acids that show strong fluorescent intensity changes upon sugar binding are reported: isoquinoline-7-boronic acid (7-IQBA) and phenoxathiin-4-boronic acid (4-POBA).
26
Müller, Thomas. "C-H Activation by Nickel and Iron Catalysis." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2019. http://hdl.handle.net/21.11130/00-1735-0000-0003-C189-8.
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Brine, Natalie Dawn. "Investigation of the phytochemistry and biological activity of isoquinoline alkaloids isolated from the South African medicinal plants, cyrtanthus sanguineus (Lindl.) walp. and cyrtanthus obliquus (L.f.)ait." Doctoral thesis, University of Cape Town, 2001. http://hdl.handle.net/11427/3274.
Full textAbstract:
Bibliography: p. 128-140.<br>The term "traditional medicine" refers to the ways of protecting and restoring health that existed before the arrival of modern medicine. These approaches to health belong to the traditions of each country and have been handed down from generatio to generation.
28
Hedouin, Jonathan. "Etude de cascades réactionnelles pallado-catalysées de fermeture d’allènamides et d’allylation directe de liaisons C-H et C-CO2H d’azoles, d’énamides et d’acides propioliques pour la diversité structurelle." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMIR21/document.
Full textAbstract:
Le développement de plans synthétiques de molécules de complexité variable qui utilise des réactifs aisés d’accès et qui sont économes en atomes et en étapes est constamment au cœur des préoccupations du chimiste organicien pour accroître la diversité moléculaire de façon efficace et éco-responsable. La catalyse par les métaux de transition a permis de faire des progrès considérables dans la construction et la fonctionnalisation combinées d’hétérocycles d’intérêt à valeur ajoutée dans les sciences des produits naturels et les industries pharmaceutiques et phytosanitaires. Le principe synthétique consiste en l’enchaînement de processus standards élémentaires de transformations chimiques en un seul pot au sein de la sphère catalytique métallique. Un axe de progrès contemporain repose en particulier sur l’incorporation de processus de métallation catalytique de liaisons C-CO2H et C-H. Les travaux de thèse s’inscrivent dans ce jeune domaine de recherche initié au cours de la dernière décennie par plusieurs équipes de recherche dont celle de Jieping Zhu de l’école polytechnique fédérale de Lausanne compte parmi les pionnières et les plus actives. Ils ont visé notamment à implémenter consécutivement aux processus standards de carbopalladation intramoléculaire d’ortho-halogéno allénamides de Grigg de construction d’hétérocycles azotés très variés, d’une part des réactions d’allylation directe de la liaison C-H d’hétérocycles et d’énamides et d’autre part d’allylation décarboxylante d’acides propioliques. Après avoir évalué la réactivité des complexes pi-allypalladium conjugués à un atome d’azote dans la réaction, l’allylation directe de la laison C-H d’oxadiazoles et de 1,3-diazoles à fort caractère acide ainsi que des énamides, des séquences originales de construction et d’hétéroarylation combinées pallado-catalysées d’isoquinolinones et d’indoles ont été établies. Un protocole séquencé conduit en un seul pot et basé sur la génération in situ des allénamides, qui ne sont plus isolées, suivie de la réaction de construction et d’hétéroarylation combinées pallado-catalysée a ensuite été mis au point. Il a été exploité pour la préparation d’indoles, 1(2H)-isoquinoléïnones, isoquinoléïnes mais également des hétérocycles de taille supérieure, benzo-(2H)-azépine et benzo-(2H)-azocine intégrant des oxadiazoles et oxa(thia)zoles. Une première étude d’extension du concept synthétique a finalement été ciblée sur la construction et la propargylation combinée de la large gamme d’hétérocycles azotés obtenus précédemment en utilisant les acides propioliques comme partenaire de couplage<br>The design of efficient and eco-friendly atom and step-economical synthetic plans of molecules using highly available starting materials is one of major objectives of organic chemist. Transition metal catalysis has allowed a bold step to build and functionalize consecutively, through a one-pot reaction, major nitrogen-containing heterocycles which are broadly present into numerous natural products, pharmaceutics and agrochemicals. The catalysis is based upon tandem inner-sphere elemental chemical transformations and one of major current challenge is to implement catalytic metallation of C-CO2H and C-H bonds. Involved in this young field of research initiated since the past decade from sevaral groups including pioneering and high active Jieping Zhu team of the Polytechnic School of Lausanne, the present study has been directed towards the design of innovative palladium-catalyzed domino Grigg nitrogen-containing heterocycles building through ortho-halogeno allenamides intramolecular carbopalladation process followed by direct C-H allylation of heterocycles and enamides or direct decarboxylative allylation of propiolic acids. After demonstrating the reactivity of nitrogen-conjugated pi-allypalladium complex in direct C-H allylation of acidic heterocycles, first palladium-catalyzed tandem build and heteroarylation of 1(2H)-isoquinoleinone and indole from ortho-halogeno allenamides was first envisaged. Efforts were next directed to the setting up of a one-pot protocol including in situ generation of allenamide followed by palladium-catalyzed domino building and functionalization of heterocycles. It was then hugely evaluated to the preparation of indole, 1(2H)-isoquinoleinones, isoquinolins as well as high-membred ring heterocycles such as benzo-(2H)-azepine and benzo-(2H)-azocine embedding with oxadiazoles and oxa(thia)zoles. An first extended synthetic concept towards the palladium-catalyzed tandem build and propargylation of nitrogen-containing heterocycles using sevral propiolic acids as coupling partners
29
Carvalho, Kaline Rodrigues. "Bioactive alkaloids and phenolic Hippeastrum solandriflorum (Lindl.) - Amaryllidaceae." Universidade Federal do CearÃ, 2014. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=13544.
Full textAbstract:
This work describes the phytochemical study of Hippeastrum solandriflorum(Amaryllidaceae)aiming the isolation and structural elucidation of new bioactive compounds, as well as its pharmacological investigation. The chemical investigation realized with the EtOH extract from bulbs, through chromatographic methods, including HPLC (reverse phase), resulting inthe isolation of ten compounds: a furan derivative: 5-(hydroxymethyl)furan-2-carbaldehyde(HS-1),
two phenolic derivatives: piscidic acid (HS-2), eucomic acid (HS-3), and seven isoquinoline alkaloids: narciclasin (
HS-4), 2α-hydroxypseudolycorin (HS-5), 10α-hydroxy homolycorin (HS-6), galantamin (HS-7), sanguinin (HS-8),N-oxid galantamin (HS-9) andnarcissidin (HS10). The alkaloids (HS-5) and (HS-6) are being reported for the first time inthe literature, while the other ones have been isolated for the first time in the investigated species. The structures of all isolated compounds were determined based on spectrometricmethods (IR, HRMS, NMR 1H and13Câ1D and 2D), besides comparison with published data. The cytotoxic potential of all alkaloids were evaluated against several tumor cell lines:colon (HCT-116), leukemia (HL-60), ovary (OVCAR-8) and brain (SF-295) showing IC50ranging from 0.01 to 35.7 μM.<br>Este trabalho descreve o estudo fitoquÃmico de Hippeastrum solandriflorum (Amaryllidaceae) visando o isolamento e elucidaÃÃo estrutural de novos constituintes quÃmicos bioativos, bem como o estudo farmacolÃgico dos compostos obtidos. A investigaÃÃo quÃmica realizada com o extrato etanÃlico dos bulbos, atravÃs de mÃtodos cromatogrÃficos, incluindo CLAE (fase reversa), resultou no isolamento e identificaÃÃo de dez substÃncias, sendo um derivado do furano: 5-(hidroximetil)furan-2-carbaldeido (HS-1), dois derivados fenÃlicos: acido piscidico(HS-2), acido eucÃmico (HS-3) e sete alcaloides isoquinolÃnicos: Narciclasina (HS-4), 2α-hidroxipseudolicorina (HS-5), 10αhidroxi-homolicorina (HS-6), Galantamina (HS-7),
Sanguinina (HS-8),N-oxido galantamina (HS-9), Narcissidina (HS-10). Os alcaloides (HS-5)e (HS-6) esta sendo relatado pela primeira vez na literatura e os demais como sendo inÃditos na espÃcie estudada. As substÃncias isoladas tiveram suas estruturas elucidadas por mÃtodos espectromÃtricos (IV, IES-EM e RMN de1H e13C 1D e 2D), alÃm de comparaÃÃo com dados da literatura. O potencial citotÃxicodos alcaloides isolados foi
avaliado frente Ãs linhagens decÃlulas tumorais humanas: cÃlon (HCT-116), leucemia (HL-60), ovÃrio (OVCAR-8) e cÃrebro
(SF-295) mostrando valores IC50
variando 0,01â35,7 μM.
30
Rinaldi, Maria Valeria Nani. "Avaliação da atividade antibacteriana e citotóxica dos alcalóides isoquinolínicos de Annona hypoglauca Mart." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-28032008-134727/.
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Annona hypoglauca Mart. foi coletada em área inundada da Floresta Amazônica, próximo à Manaus (Brasil). Os alcalóides foram obtidos do extrato bruto do caule por partição ácido-base, e a partir do resíduo dessa extração foi realizada a partição com solventes de diferentes polaridades, originando as frações livres de alcalóides. A partir da análise de CG-EM dos alcalóides totais foi possível caracterizar sete alcalóides aporfínicos (actinodafinina, anonaina, glaucina, isoboldina, isodomesticina, nornuciferina e roemerina) e possivelmente duas protoberberinas (esculerina e caseadina). Os alcalóides totais foram fracionados em coluna cromatográfica e posteriormente purificados em placa cromatográfica preparativa permitindo o isolamento de dois alcalóides aporfínicos: actinodafinina e isoboldina. As estruturas desses produtos naturais foram definidos com base em espectros de dados, incluindo 1H RMN, 13C RMN, 13C DEPT e CG-EM. Pela primeira vez a ocorrência da actinodafinina esta sendo reportada em uma espécies de Annona. O extrato bruto, as frações livres de alcalóides, os alcalóides totais e suas frações foram submetidos a avaliação da atividade antibacteriana por microdiluição e atividade citotóxica in vitro frente a células de tumores humanos. Para todos os extratos testados, somente os alcalóides totais e suas frações apresentaram atividade frente a bactérias Gram +. No ensaio de citotoxicidade com linhagens de células de tumores, o extrato bruto foi capaz de inibir o crescimento de todas as linhagens celulares testadas, apresentando efeito letal para a linhagem de Câncer de Cólon (KM-12), enquanto as frações livres de alcalóides demonstraram baixa atividade. Por outro lado, as frações livres de alcalóides apresentaram atividade mais pronunciada para a linhagem de Câncer de Pulmão (NCIH-460) do que os alcalóides. Assim, a atividade citotóxica encontrada no extrato bruto é decorrente do sinergismo ou complementação entre os componentes das frações alcaloídicas e não alcaloídicas, isto é, nenhuma das frações isoladamente é responsável pela atividade observada no extrato bruto.<br>Annona hypoglauca Mart. was collected in the flooded areas of the Amazonian Forest near Manaus (Brazil). The alkaloids were obtained from the stems crude extract by acid-base partitioning and the remaining alkaloid-free extract was partitioned with organic solvents of different polarity. The GC/MS analysis of the total alkaloids allowed the identification of seven aporphine alkaloids (actinophanine, anonaine, glaucine, isoboldine, isodomesticine, nornuciferine and roemerine) and possibly two proberberine alkaloids (scoulerine and caseadine). The total alkaloids were fractionated by column chromatography and further purified by preparative thin-layer chromatography allowing the isolation of two aporphine alkaloids: actinodaphnine and isoboldine. The structures of these natural products were defined based on their spectral data, including 1H NMR, 13C NMR, 13C DEPT and CG/MS. This is the first report for the occurrence of actinodaphnine in Annona species. The crude extract, alkaloid-free organic extracts, total alkaloids and its fractions were tested for their antibacterial activity by the microdilution broth assay and cytotoxic activity against in vitro tissue culture cells of human. From all the extracts assayed, only the total alkaloids and their fractions showed a relevant antibacterial activity against Gram positive organisms. In the cytotoxicity assay with human tumor cell lines, the crude extract was able to inhibit the growth of all cell lines tested, with a lethal effect for the colon cancer (KM-12) cell line. The evaluation of this activity with the total alkaloid and alkaloid-free fractions indicated selectivity for the different cellular lines. The alkaloid fraction presented high growth inhibition for the colon cancer cell line (KM-12), while the alkaloid-free fractions displayed lower activity. On the other hand, the alkaloid free fractions showed a higher activity for the lung cancer cell line (NCIH-460) than the total alkaloids. Thus, the cytotoxic activity found in the crude extract is the result of the synergism or complementary activity among the components of the alkaloid and alkaloid-free fractions, e.g, none of the fractions separately is responsible for the activity observed in the crude extract.
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Siqueira, Carlos Alberto Theodoro. "Aspectos químicos e atividade antiprotozoária in vitro de Annona coriacea Mart. (Annonaceae)." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-31012011-140840/.
Full textAbstract:
Estudos anteriores dos alcalóides totais (AT) de Annona coriacea Mart. (Annonaceae) revelaram atividade antiprotozoária promissora. No presente trabalho, realizou-se o fracionamento biomonitorado dos AT de folha e selecionaram-se duas frações ativas (100% morte), frente às formas promastigotas de Leishmania (L.) chagasi in vitro, para a caracterização dos alcalóides, por CG-EM. Os AT bioativos de caule (100% morte) foram analisados sem fracionamento prévio. Em paralelo, efetuou-se amostragem de três exemplares de A. coriacea, analisados em conjunto, para o acompanhamento da variação do rendimento em AT e da atividade leishmanicida, por 12 meses. Nas frações bioativas de folha, foram caracterizados: estefarina (proaporfínico) e nornuciferina (noraporfínico) e nos AT de caule: pronuciferina (proaporfínico), asimilobina (noraporfínico) e boldina (aporfínico). A presença de boldina foi confirmada pela análise CG-EM do padrão, nas mesmas condições dos AT. Os resultados mostraram-se inéditos para a espécie e a ocorrência de pronuciferina e boldina constituiu o primeiro relato, no gênero Annona. Os dados referentes ao rendimento em AT (folha e caule) e à atividade antipromastigota in vitro indicaram comportamento, praticamente, constante dos parâmetros ao longo do ano. O óleo volátil de folha foi analisado, por CG-EM, tendo-se identificado 60 compostos, em mistura complexa de sesquiterpenos (76,7%) e monoterpenos (23,3%). O constituinte majoritário foi o sesquiterpeno biciclogermacreno (39,8%). O óleo volátil foi avaliado in vitro e apresentou atividade frente às formas promastigotas de quatro espécies de Leishmania e nas formas tripomastigotas de T. cruzi. A determinação e obtenção dos compostos bioativos motiva a continuidade da pesquisa.<br>Previous studies of total alkaloids (TA) from Annona coriacea Mart. (Annonaceae) have revealed potential antiprotozoal activity. In this study a bioguided fractionation of leaves TA was conducted and two fractions were active in vitro against Leishmania (L.) chagasi promastigotes (100% death) and selected in order to identify the alkaloid constituents, by GC-MS analysis. Stem bioactive TA (100% death) were also analyzed, without previous fractionation. Parallel to that, a sample of three combined specimens of A. coriacea (leaves and stem) was evaluated for the annual variation of TA production and the leishmanicide activity. Stefarine (proaporphine) and nornuciferine (noraporphine) were identified in the bioactive fractions of leaves while pronuciferine (proaporphine), asimilobine (noraporphine) and boldine (aporphine) were identified in stem TA. Boldine was confirmed by the GC-MS evaluation of the standard, under the same conditions of the TA. It was the first report of those alkaloids in this species and for pronuciferine and boldine occurrence in Annona genus. The TA yields (leaves and stem) and the in vitro antipromastigote activity remained almost unaltered throughout the year. The volatile oil of leaves was also analyzed by GC-MS. Sixty compounds were indentified in a complex mixture of sesquiterpenes (76.7%) and monoterpenes (23.3%). Byciclogermacrene was its major component (39.8%). The volatile oil was evaluated in vitro and was active against four species of Leishmania promastigotes and also against T. cruzi tripomastigotes. The identification of the bioactive constituents and their isolation are promising for further studies.
32
Bender, Christoph. "Stereoselektive Synthese neuartiger 1,2-Dihydroisochinoline als Vorstufen für die Alkaloidsynthese." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2008. http://dx.doi.org/10.18452/15728.
Full textAbstract:
Ausgangspunkte der vorliegenden Arbeit waren stereoselektive Synthesen von Reissert-Verbindungen über chirale N-Acylisochinoliniumsalze. Es galt die Konfiguration der erhaltenen Produkte zu beweisen und deren Synthesepotential zu erforschen. Ein Ziel dieser Arbeit war es, weiterführende Reaktionen für die Synthese von alkaloidanalogen Substanzen zu entwickeln. Es gelang, die Reissert-Reaktion mit Chlorameisensäurementhylester erfolgreich auf andere Heterocyclen als Isochinolin auszudehnen. Die Annahme eine stereoselektiven Verlaufes mußte korrigiert werden. Das Reissert-Produkt konnte mit einer großen Anzahl von Alkylhalogeniden in 1-Position alkyliert werden. Die Cyanogruppe konnte in zwei Verfahren abgewandelt werden. Die Behandlung des Reissert-Produktes und der alkylierten Verbindungen mit Säuren, Halogen und Grignard-Reagenzien führte zu verschiedenen interessanten Cyclisierungen. Es gelang, die Reissert-Reaktion auf elektronenreiche Aromaten und metallorganische Reagenzien als Nucleophile zu erweitern. Es gelang eine asymmetrische C-C-Knüpfung mit Zink-Nucleophilen sowie Grignard-Verbindungen. 4-Bromsubstituierte Mannich-Produkte konnten erfolgreich in einer Suzuki-Kupplung zu 4-arylsubstituierten Isochinolinaddukten umgesetzt werden. Es gelang die Hydrierung der Enamindoppelbindung und die Abspaltung des chiralen Auxiliars auf zwei verschiedenen Wegen. Während Additionsreaktionen an die 1-Position von 2-Menthyloxcarbonylisochinoliniumsalzen im wesentlichen nicht stereoselektiv verliefen, konnte beim Einsatz von geschützten Aminosäurefluoriden als chirale Auxiliare Diastereoselektivitäten bis zu 6:1 erzielt werden. Der Einsatz der elektronenreichen Aromaten als Nucleophile führte zu Mannich-Produkten in guten Ausbeuten. Auch der Einsatz von Grignard-Reagenzien als Nucleophile konnte erfolgreich getestet werden. Hiermit ist die erste stereoselektive Addition von elektronenreichen Aromaten an cyclische Iminiumsalze gelungen.<br>Starting points of the present work were stereoselective syntheses of Reissert compounds about chiral N-acylisoquinoliniumsalts. It was a matter of proving the configuration of the preserved products and of investigating synthesis potential. A purpose of this work was to develop continuing reactions for the synthesis of alkaloide-analogous substances. One succeeded in expanding the Reissert reaction with menthylchloroformat successfully to other heterocycles than isoquinoline. The acceptance a stereoselective course had to be corrected. The Reissert product could be alkylated with a big number of alkylhalides in 1 position. The Cyanogroup could be modified in two procedures. The treatment of the Reissert product and the alkylated compounds with acids, halogens and Grignard reagents led to different interesting cyclisations. One succeeded in extending the Reissert reaction to electronrich aromatic and heteroaromatic compounds and metal-organic reagents as nucleophiles. An asymmetrical C-C-bondformation with Zink-nucleophiles as well as Grignard compounds succeeded. 4-Bromine-substituted Mannich products could be transformed successfully in a Suzuki coupling to 4-arylsubstituted isoquinolineadducts. The hydrogenation of the enamindoublebond and the splitting off chirale auxiliary on two different ways succeeded. While addition reactions ran to the 1 position of 2-Menthyloxcarbonylisoquinoliniumsalts basically not stereoselectively, could be achieved by the application by protected Aminosäurefluoriden as chirale auxiliaries slide stereo selectivities up to 6:1. The application of the electronrich aromatics as nucleophiles led to Mannich products in good exploiting. Also the application of Grignard reagents as nucleophiles could be tested successfully. Herewith the first stereoselective addition from electronrich aromatics to cyclic iminiumsalts has succeeded.
33
Pilgrim, Ben Samuel. "Novel palladium-catalysed routes to aromatic heterocycles." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:d143b5bf-1738-48ce-be75-4a25249acb9d.
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A brief summary of the use of palladium as a catalyst, the characteristic reactivity of palladium complexes and the commonly used palladium-catalysed cross coupling reactions is given, with a special focus on the palladium-catalysed α-arylation of enolates and its application to the synthesis of aromatic heterocycles. The synthesis of aromatic heterocycles via both traditional methods and more recent metal-catalysed approaches is discussed in the context of isoquinolines. The palladium-catalysed oxidation of dihydrofurans bearing an ortho-bromophenyl group at the 2-position to the corresponding 2-phenyl furans is disclosed along with some preliminary mechanistic investigations. A novel synthetic route to isoquinolines is detailed involving the palladium-catalysed α-arylation of ketone enolates with an appropriate ortho-substituted aryl halide to furnish a protected 1,5-dicarbonyl intermediate. The versatility of these intermediates is demonstrated with their conversion into isoquinolines, isoquinoline N-oxides and naphthols. The scope of the synthetic procedure is fully exemplified across more than 30 different scaffolds covering the full spectrum of electron-rich to electron-deficient moieties. The intermediates were shown to be amenable to functionalisation with electrophiles, leading to isoquinolines bearing additional substitution at the C4 position. Sequential one-pot procedures were developed allowing three and four component couplings to directly deliver highly-substituted isoquinolines from commercially available starting materials. This methodology was utilised in the total synthesis of the natural product berberine in 26% overall yield and a longest linear sequence of six steps.
34
Blumenthal, Haiko. "Struktur und Reaktivität ausgewählter chiraler N-Acylaminohydroperoxide und -peroxide." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15868.
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Ausgangspunkte der vorliegenden Arbeit waren stereoselektive Synthesen von Reissert-analogen N-Acylaminohydroperoxiden über chirale N-Acylisochinoliniumsalze. Edukte waren Isochinolin(derivaten), Menthylchloroformiat und Wasserstoffperoxid. Es galt die Konfiguration der erhaltenen Produkte zu beweisen und deren Sauerstoffübertragungspotential zu erforschen. Ein zweites Ziel dieser Arbeit war es, von bekannten Diketopiperazinhydroperoxiden ebenfalls das Sauerstoffübertragungspotential zu überprüfen, weil sie die gleiche N-Acylaminohydroperoxidstruktur aufweisen aber bisher wenig untersucht wurden. Es gelang durch NMR-Untersuchungen und Vergleich mit ähnlichen Reaktionen die Annahme eines stereoselektiven Verlaufes zu widerlegen. Weiterhin wurde gezeigt, dass anstelle von Hydroperoxiden Peroxide vorliegen. Es konnte eine in situ Methode entwickelt werden, um mit dem vorgegebenen Substanzen unter Zusatz eines Metallkatalysators wie Vanadium(V)triisopropylat und Titan(IV)tetraisopropylat eine Sauerstoffübertragung auf Methylphenylsulfid zu erzielen. In Abhängigkeit der eingesetzen Isochinolinderivate gelang eine kinetische Racematspaltung, so dass eine stereoselektive Sulfoxidation möglich wurde. Das günstigste Ergebnis betrug 51 % Sulfoxid bei 73 % Enantiomerenüberschuss. Mit einem bekannten Diketopiperazinhydroperoxid konnte Methylphenylsulfid direkt in 62 % Sulfoxid mit 32 % Enantiomerenüberschuss überführt werden. Dies sind die ersten erfolgreichen stereoselektiven Sulfoxidationen mit N-Acylaminohydroperoxiden.<br>Starting points of the present work were stereoselective syntheses of Reissert analogous N-acylaminohydroperoxides derived from chiral N-acylisochinoliniumsalts. Starting materials were isochinoline (and derivates), menthylchloroformiate and hydrogen peroxide. It was a matter of proving the configuration of the preserved products and of investigating the oxygen transfer potential. The second purpose of this work was to check the oxygen transfer potential of known diketopiperazinehydroperoxides likewise because they show the same N-acylaminohydroperoxide structure, however, up to now they were only examined scarcely. One succeeded by NMR investigations and comparison with similar reactions in disproving the acceptance of a stereoselective course. Furthermore it was shown that there are peroxides instead of hydroperoxides. We developed an in situ method to achieve with the given substances under addition of a metal catalyst like vanadium(V)triisopropylate and titanium(IV)tetraisopropylate an oxygen transfer to methylphenylsulfide. In dependence of the used isochinoline derivates a kinetic resolution was observed, so that a stereoselective sulfoxidation became possible. The most favorable result amounted to 51% sulfoxide with 73% enantiomeric excess. With a known diketopiperazinehydroperoxide methylphenylsulfide could be directly transfered into 62% sulfoxide with 32% enantiomeric excess. These are the first successful stereoselective sulfoxidations with chiral N-acylaminohydroperoxides.
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Santos, Maria de Fátima Costa. "Estudo fitoquímico e investigação da atividade citotóxica das folhas e cascas do caule de Guatteria pogonopus (Annonaceae)." Universidade Federal de Sergipe, 2015. https://ri.ufs.br/handle/riufs/6090.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior<br>This paper presents the results obtained of the phytochemical bioguide of methanol extracts of the leaves and stem bark of Guatteria pogonopus Mart., a species belonging to
the family Annonaceae. The botanical material (leaves and stem bark) were collected in the National Park Serra de Itabaiana (PARNA), Sergipe, Brazil. The extracts were obtained by maceration method at room temperature initially with hexane and then methanol, resulting in the hexane (EHF e EHC) and methanol (EMF e EMC) extracts, respectively. The methanol extracts from the leaves (EMF) and stem bark (EMC)
indicated the presence of alkaloids when the Dragendorff reagent was applied that was submitted to the acid-base treatment resulting in the chloroform fractions alkaloid (FCAF
and FCAC), and neutral fractions (FCNF and FCNC), respectively. The alkaloid fractions (FCAF and FCAC) were then subjected to the usual chromatographic techniques allowing
the isolation of alkaloids. The FCAF fraction resulted in the isolation of six alkaloids identified as: lysicamine, (S)-(+)-nuciferine, (S)-(+)-roemerine, (-)- tetrahydropseudocolumbamine, (S)-(+)-isocoridine and a mixture of govanine, liriodenine and lysicamine. The FCAC fraction led to the identification of ten different mixtures alkaloids, such as puterine, anonaine, nornuciferine, obovanine, isopiline, Omethylisopiline, launobine, oxoputerine, liriodenine and lanuginosine. The alkaloids were identified through the techniques of MS and NMR 1H and 13C 1D and 2D as well as,
comparison to literature data. Furthermore, the pure alkaloids isolated from the leaves were submitted the specific optical rotation measures. The extracts, fractions, pure
alkaloids and in the mixture were subjected to evaluation of the cytotoxic activity by the Alamar Blue method, which observed a high percentage of inhibition of cell proliferation
for the methanol extract of the stem bark EMC (80.11 ± 8.12%) and alkaloidal fraction of FCAF leaves (80.56 ± 8.15%) against the human hepatocellular carcinoma and for the
mixture of compounds govanine, liriodenine and lysicamine (IC50 3.10 μg mL-1) against human promyelocytic leukemia (HL-60) which can be attributed to the presence of liriodenine. Most of the identified alkaloids are described in different species of
Annonaceae, particularly in the Guatteria genus. Thus, it appears that G. pogonopus presents a caracteristic chemotaxonomy the Annonaceae family and, linked to this, is a
promising source of substances with potential cytotoxic activity.<br>O referido trabalho apresenta os resultados obtidos do estudo fitoquímico biomonitorado dos extratos metanólicos das folhas e cascas do caule de Guatteria pogonopus Mart., uma espécie pertencente a família Annonaceae. Os materiais botânicos (folhas e cascas do caule) foram coletados no Parque Nacional Serra de Itabaiana (PARNA), Sergipe, Brasil. Os extratos brutos foram obtidos pelo método de maceração à temperatura ambiente inicialmente com hexano e, posteriormente com metanol obtendo os extratos hexânicos (EHF e EHC) e metanólicos (EMF e EMC), respectivamente. Os extratos metanólicos das folhas (EMF) e cascas do caule (EMC) indicaram a presença de alcaloides frente ao reagente Dragendorff sendo então submetidos ao tratamento ácidobase resultando nas frações clorofórmicas alcaloídicas (FCAF e FCAC) e, as neutras (FCNF e FCNC), respectivamente. As frações alcaloídicas (FCAF e FCAC) foram então submetidas às técnicas cromatográficas usuais permitindo o isolamento de alcaloides. A fração FCAF resultou no isolamento de seis alcaloides que foram identificados como: lisicamina, (S)-(+)-nuciferina, (S)-(+)-roemerina, (-)-tetraidropseudocolumbamina, (S)-(+)- isocoridina e uma mistura de tetraidropseudocolumbamina, liriodenina e lisicamina. A fração FCAC levou a identificação de dez alcaloides em diferentes misturas, tais como: puterina, anonaina, nornuciferina, obovanina, isopilina, O-metilisopilina, launobina, oxoputerina, liriodenina e lanuginosina. Os alcaloides foram identificados através das técnicas de EM e RMN de 1H e 13C (1D e 2D), bem como, comparação com os dados da literatura. Além disso, os alcaloides puros das folhas foram sumetidos as medidas de rotação óptica específica. Os extratos, frações, alcaloides puros e em mistura foram submetidos ao ensaio de atividade citotóxica pelo método de Alamar Blue, em que se verificou um maior percentual de inibição da proliferação celular para o extrato metanólico das cascas EMC (80,11 ± 8,12%) e da fração alcaloídica das folhas FCAF (80,56 ± 8,15%) frente ao carcinoma hepatocelular humano e, para a mistura de compostos de govanina, liriodenina e lisicamina (IC50 3,10 µg mL-1) frente a leucemia promielocítica humana (HL-60) que pode ser atribuída à presença da liriodenina. A maioria dos alcaloides identificados é descrito em diferentes espécies de Annonaceae, particularmente no gênero Guatteria. Dessa forma, infere-se que G. pogonopus apresenta uma quimiotaxonomia característica da família Annonaceae e, atrelado a isso, é uma fonte promissora de substâncias com potencial atividade citotóxica.
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Gavin, James Patrick. "Control of regiospecificity in the synthesis of isoquinolines." Thesis, University of Manchester, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252895.
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Sutton, Benjamin Josiah. "Intramolecular radical additions to pyridines, quinolines and isoquinolines." Thesis, University of Southampton, 2003. https://eprints.soton.ac.uk/426728/.
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Majeed, Amera Jihad. "Electrochemical oxidation of isochromanones, isoquinolines and related structures." Thesis, University of Bath, 1986. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.332114.
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Gatland, Alice Elizabeth. "Palladium-catalysed enolate arylation in the synthesis of isoquinolines." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:f106760d-2375-4d56-81b2-faa6ee96cabc.
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<strong>Chapter 1. Introduction</strong> Scientific background on the development of homogeneous palladium-catalysed cross coupling reactions, focusing on the α-arylation reaction of enolates and its application to the synthesis of heteroaromatic compounds. The classical syntheses of isoquinolines are discussed, followed by an account of modern methods for their synthesis, including the recent α-arylation-based methodology developed by the Donohoe group. <strong>Chapter 2. Results and Discussion</strong> 2.1 Studies towards the development of a palladium-catalysed, C–H activation-based α arylation reaction of ketones, resulting in a C–H bromination/α-arylation sequence for the synthesis of isoquinolines and isoquinoline N-oxides. 2.2 The one-pot, four component coupling of a ketone, an acetal protected ortho-bromobenzaldehyde or ketone, an electrophile, and an ammonia source is described. This protocol, which ultimately provides C4 functionalised isoquinolines, is later extended to a novel α,α heterodiarylation protocol to furnish C4-aryl isoquinolines. 2.3 It is shown that the synthesis of 3 aminoisoquinolines can be achieved via the α arylation of nitriles. tert-Butyl cyanoacetate can act as a substitute for primary alkyl nitriles, with sequential α-arylation, in situ functionalisation, decarboxylation and cyclisation reactions provide C4 functionalised 3 aminoisoquinolines. 2.4 The synthetic utility of the α arylation based methodology for isoquinoline synthesis is exemplified by the total synthesis of the alkaloid berberine in 68% yield over five steps. This is followed by syntheses of pseudocoptisine, palmatine, dehydrocorydaline, and an unnatural fluorine containing analogue, in yields of 46%, 73%, 60% and 37%, respectively. 2.5 Finally, preliminary investigations demonstrate the utility of palladium-catalysed enolate arylation in the synthesis of β-carbolines.
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Berk, Mujde. "Development Of New Synthetic Methodologies For Isoquinolone And Isoindolinone Derivatives." Master's thesis, METU, 2010. http://etd.lib.metu.edu.tr/upload/3/12612145/index.pdf.
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ABSTRACT
DEVELOPMENT OF NEW SYNTHETIC METHODOLOGIES FOR
ISOQUINOLONE AND ISOINDOLINONE DERIVATIVES
Mü<br>jde, Berk
M.Sc., Department of Chemistry
Supervisor: Prof. Dr. Metin Balci
July 2010, 146 pages
Due to the wide range of physiological activities, heterocycles containing nitrogen and
oxygen have always attracted the interest of chemists.
The objective of this research is to develop new synthetic routes to the synthesis of
isoquinolone and isoindolinone derivatives starting from 2-(2-carboxyethyl)benzoic acid
and homophthalic acid, respectively.
The half ester produced from 2-(2-carboxyethyl)benzoic acid was an important key
compound for the synthesis of new isoquinolone derivatives which are expected to be
biologically active. The corresponding acyl azides and isocyanates were generatedwhich might be used as a precursors to construct a variety of isoquinolone derivatives.
Transformation of acyl azides into urea derivatives followed by ring-closure under the
basic conditions provided isoquinolones.
Bromo- and methoxyhomophthalic acid derivatives were synthesized to increase in
variety of isoindolinone derivative. Then corresponding anhydrides were generated to
further reactions for synthesis of isoindolinone derivatives. Surprisingly, tetrazolinone
derivatives are also formed by 1,3 dipolar cycloaddition. Whole products were
conscientiously purified and characterized.
In addition, the similar methodology which was used for the synthesis of isoquinolone
derivatives, was applied to 2-(carboxymethyl)furan-3-carboxylic acid to synthesize new
nitrogen and oxygen containing heterocycles.
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Brière, Jean-François. "Elaboration d'une enzyme artificielle se liant à des fonctions amines et des fonctions acides dans le but de catalyser la formation de liaisons amides." Rouen, 1998. http://www.theses.fr/1998ROUES097.
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Ce travail décrit l'élaboration d'un catalyseur supramoléculaire de structure hétérocyclique devant accélérer la formation de liaisons amides, en mimant les mécanismes enzymatiques. Une première synthèse à partir de la 4-amino-3-bromoisoquinoléine a ouvert deux nouvelles voies d'accès aux 2-méthyloxazolo[5,4-c]isoquinoléine et 1H-pyrrolo[3,2-c]isoquinoléine. Cette dernière structure a été fonctionnalisée en position 2 à l'aide d'une réaction de métallation. Au cours de la deuxième voie de synthèse nous avons établi l'influence de la substitution de la fonction amine d'aminopyrrolidine-2,5-diones sur la régiosélectivité de la réduction en -hydroxylactames par le borohydrure de sodium. La synthèse diastéréosélective d'un nouvel hétérocycle tricyclique de type 1a,3a,4,5-tétrahydro-1H,3Hpyrrolo[3,2-c]isoquinoléin-2-one a été alors réalisée. La fonctionnalisation de ce dernier a permis la synthèse de l'enzyme artificielle. Nous avons établi que ce récepteur se liait avec des amines et des acides avec des constantes d'association de l'ordre de 100 à 400 M-1, au sein de complexes de stoechiométrie 1:1. La structure de deux complexes, récepteur-benzylamine et récepteur-acide benzoïque, a été approchée à l'aide d'une étude par RMN 1H NOESY, suivie d'une modélisation par mécanique moléculaire. Enfin l'enzyme artificielle a permis d'accélérer de 34% la réaction d'aminolyse entre la n-propylamine et le benzoate de pentafluorophényle.
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Rathelot, Pascal. "Etude de la réactivité dans des réactions de transfert monoélectronique de nouveaux synthons isoquinoléiques à potentialités pharmacologiques." Aix-Marseille 3, 1995. http://www.theses.fr/1995AIX30005.
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Notre travail est consacre a l'etude de reactions par transfert monoelectronique en serie 5-nitroisoquinoleine. Nous avons dans un premier temps synthetise la 1-chloromethyl 5-nitroisoquinoleine dont l'etude de la reaction avec l'anion du 2-nitropropane a permis de conclure qu'elle se deroulait selon un mecanisme de substitution radicalaire nucleophile unimoleculaire (srn1). Cette reaction a ensuite pu etre generalisee a divers anions nitronate aliphatiques, cycliques et heterocycliques. Pour completer cette etude, la synthese de la 1-dichloromethyl 5-nitroisoquinoleine a ete realisee. L'etude de sa reaction avec l'anion du 2-nitropropane a permis de demontrer la participation consecutive du mecanisme skn1 et d'un mecanisme d'elimination radicalaire en chaine (erc1). Dans le but de preparer des composes biologiquement actifs, la synthese de la 1-formyl 5-nitroisoquinoleine et sa pharmacomodulation nous ont permis de preparer des series d'hydrazones et d'aldimines dont les activites antifongiques et antiparasitaires ont ete evaluees
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Mimoun, Liliane. "Synthèse de nitriles chiraux via une catalyse duale et nouvelle méthodologie de synthèse d'isoquinoléines." Electronic Thesis or Diss., Orléans, 2024. http://www.theses.fr/2024ORLE1009.
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Nous avons développé une nouvelle approche via la catalyse duale permettant une activation orthogonale de chacun des deux partenaires organométalliques de couplage Pd/Cu afin de réaliser les réactions dans des conditions douces. Nous avons ainsi étudié la réaction d'α-allylation asymétrique de nitrile tertiaire en tirant profit d'une part du potentiel synthétique des céténimines N-métallées (M = Si, Cu) en tant que nucléophiles et d'autre part, de complexes α-allyl chiraux de palladium, en tant que partenaires électrophiles. Les céténimines N-métallés sont douées d'une chiralité planaire intrinsèque et sont un atout dans la construction innovante, catalytique et asymétrique en une seule étape de stéréocentres quaternaires/tertiaires à partir de nitriles variés. Dans une première partie, nous avons exploré les conditions de réactions optimales impliquant des céténimines N-métallées dans des réactions de catalyse asymétrique. Le choix des conditions opératoires, des ligands et des catalyseurs a permis l'accès à divers nitriles benzyliques substitués porteurs de deux nouveaux centres stéréogènes tertiaire/tertiaire ou quaternaire/tertiaire avec une énantiosélectivité moyenne à excellente (ee > 91%). Par la suite, nous avons étudié les transformations possibles des composés nitriles originaux obtenus, mais également du motif allylique. Des réactions intramoléculaires ont permis l'accès à des motifs lactames, ainsi qu'à des cycles à six carbones entièrement substitués originaux. Ces réactions ont permis d'étendre notre méthodologie à la formation de trois et quatre centres tertiaires et quaternaires contigus. Enfin, une toute autre étude a été réalisée : une catalyse au cobalt(III) en présence de sels d'argent a été utilisée dans le cadre d'une réaction de C-H activation ortho-dirigée pour la formation de dérivés d'isoquinoléine diversement substitués, motifs couramment retrouvé dans des composés bioactifs<br>We developped a new approach based on dual catalysis, enabling orthogonal activation of each of the two organometallic coupling partners Pd/Cu, in order to carry out the reactions under mild conditions. We have investigated the asymmetric α-allylation reaction of tertiary nitrile, taking advantage of the synthetic potential of N-metallated ketenimines (M=Si, Cu) as nucleophiles, on the one hand, and of chiral α-allyl palladium complexes as electrophilic partners, on the other. It is worth noting that N-metallated ketenimines are endowed with intrinsic planar chirality and are an asset in the innovative, catalytic and asymmetric one-step construction of quaternary or tertiary stereocenters from various nitriles, themselves precursors of diversities.In the first part, we explored optimal reaction conditions involving N-metallated ketenimines in asymmetric catalysis reactions. The choice of reaction conditions, ligands and catalysts enabled access to a range of substituted benzylic nitriles bearing two new tertiary/tertiary or quaternary/tertiary stereogenic centers, with moderate to excellent enantioselectivity (ee >91%). Therefore, we investigated possible transformations of the original nitrile compounds obtained, but also of the allyl motif. Intramolecular reactions provided access to lactam units, as well as to original fully substituted six-carbon rings. These reactions enabled us to extend our methodology to the formation of three and four contiguous tertiary and quaternary centers. Finally, a completely different study was carried out: cobalt(III) catalysis in the presence of silver salts was used in an ortho-directed C-H activation reaction for the formation of variously substituted isoquinoline derivatives, motifs commonly found in bioactive compounds
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Berthault-Balâtre, Aurélie. "Synthèse et évaluation pharmacologique de ligands sélectifs du récepteur humain de l'Urotensine II." Orléans, 2005. http://www.theses.fr/2005ORLE2026.
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L'Urotensine II est un neuropeptide cyclique, initialement isolé chez les poissons téléostéens. Il est constitué par un enchaînement de 11 acides aminés avec une partie C-terminale hexacyclique, responsable de l'activité biologique. Ce système Urotensine II / UT est localisé dans différents tissus cardiovasculaires humains. Des effets puissants (vasoconstriction, prolifération vasculaire. . . ) ont été rapportés dans diverses espèces ainsi que chez l'Homme, suggérant la participation possible du système urotensinergique dans la physiopathologie cardiovasculaire. Dans la première partie de ce travail, des composés tétrahydroisoquinoléiniques ont été synthétisés en raison de leur analogie avec des molécules décrites comme antagonistes du récepteur de l'Urotensine II. La seconde partie est consacrée à la préparation de pyrroloquinoléines. La stratégie de synthèse adoptée pour l'obtention de dérivés aminométhylés en position 4, passant par la cyclisation d'une énamine, apparaît très intéressante. Celle-ci permettant d'effectuer de nombreuses pharmacomodulations. La dernière partie est réservée d'une part à l'élaboration de pipérazin-2-ones disubstituées et d'autre part à des pipérazin-2,5-diones 3,6 et N1,3,6-substituées via la cyclisation du peptide correspondant.
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Daras, Etienne. "Synthèse et évaluation biologique d’analogues aza de la combrétastatine A-4 comme inhibiteurs de la polymérisation de la tubuline." Aix-Marseille 1, 2008. http://www.theses.fr/2008AIX11079.
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Plusieurs séries de dérivés quinoléiques, isoquinoléiques et néoflavonoiques ont été préparées via une réaction clé de couplage de Suzuki, ou par cyclisation intramoléculaire de type Bischler-Napieralski. Des études de prolifération cellulaire ont mis en évidence des activités remarquables pour les composés de type 4-arylquinoléique et 4-indolylcoumarinique. Cette activité antiproliférative a été corrélée à une activité inhibitrice de l'assemblage de la tubuline. La nature et la position des substituants sur le cycle A n'influencent que très finement cette activité. Dans la série des dérivés néoflavonoïques, la position de l'atome d'azote sur le cycle indolique et sa substitution jouent un rôle déterminant. Ainsi, l'idée couramment admise qu'un noyau triméthoxylé est indispensable à l'activité antimitotique a été écartée, et seule la présence d'un groupement hydrophobe 4-méthoxy ou 4-méthylamino, porté par le noyau 4-phényle, a été identifiée comme indispensable à l'activité anti-tubuline. Il a été démontré que les quinoléines et coumarines actives se liaient au domaine de liaison colchicine de la tubuline, avec une affinité comparable à celle de la combrétastatine A4. Au niveau cellulaire, les composés antiprolifératifs ont été caractérisés comme agents dépolymérisants du cytosquelette, antimitotiques et inducteurs de la mort cellulaire, faisant de ces composés des analogues fonctionnels de la CA-4. Une étude structurale a permis en évidence les groupements pharmacophores indispensables à l'activité biologique. Cette relation structure-activité ouvre de nouvelles perspectives quant à la découverte de nouvelles générations d'agents anticancéreux
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Stein, André Luiz Agnes. "Síntese de Calcogenofenos e Isoquinolinas via Reações de Ciclização Intramolecular." Universidade Federal de Santa Maria, 2013. http://repositorio.ufsm.br/handle/1/4254.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior<br>In the first part of this work, a series of selenophenes and tellurophenes were prepared starting from of (Z)-chalcogenoenynes, by employing FeCl3 diorganyl dichalcogenide-mediated intramolecular cyclization. In general, the cyclic products were obtained in moderate to good yields.
In order to evaluate the versatility of the obtained 3-chalcogen selenophene derivatives, we tested the reactivity of these compounds toward halogenation and Li/Se exchange reactions. In this way, the reaction of 2,5-diphenil-3-(fenilselene)-selenofene with an excess of bromine, afforded the resultant product in 86% yield. In addition, the reaction of 2,5-diphenil-3-(butilselene)selenofene with n-butyllithium gave the lithiated species. The lithiated species was trapped by aldehydes affording the secondary alcohols in 68 to 73% yield.
In a second stage, we developed an alternative method to promote the intramolecular cyclization of o-alkynyl benzaldimines 3, by employing CuI and differently substituted diorganoyl diselenides as promoter agents of this process. Through this cyclization protocol we could satisfactory synthesize a series of 4-organochalcogen-isoquinolines 4 in good yields. Finally, the presence of an organochalcogen substituent in the isoquinoline structure allowed further structural elaboration through conversion of the chalcogen group into other substituents. In this sense, when the 4-(buthyltelluro)-3-phenylisoquinoline was applied to the tellurium lithium exchange conditions, followed by reaction with aldehydes, the corresponding secondary alcohols were obtained in high yields. Furthermore, we have also successfully applied this isoquinoline as a substrate in Suzuki and Sonogashira coupling conditions affording the corresponding products moderate to good yields.<br>Este trabalho relata a síntese de uma série de heterociclos através da ciclização intramolecular de substratos alquinílicos com dicalcogenetos de diorganoíla mediados por sais de cobre ou sais de ferro. Primeiramente, relatamos a síntese de selenofenos e telurofenos 2 através da ciclização intramolecular de (Z)-selenoeninos e (Z)-teluroeninos 1 com dicalcogenetos de diorganoíla mediados por FeCl3. Essa metodologia permitiu a obtenção de novos derivados de calcogenofenos de moderados a bons rendimentos com a adicional inserção de uma molécula orgânica de calcogênio na posição 3 do anel formado.
Com a finalidade de avaliar o potencial reatividade dos compostos obtidos 2, o composto 2,5-difenil-3-(selenofenil)-selenofeno foi submetido a uma reação de bromação do anel aromático resultando na formação do selenofeno substituído com bromo, nas posições 3 e 4 do anel heterocíclico, em 86% de rendimento. Adicionalmente, o composto 2,5-difenil-3-(selenobutil)selenofeno foi selecionado como material de partida para uma reação de troca selênio-lítio com a subsequente reação com aldeídos levando a formação dos álcoois secundários, na posição 3 do anel do selenofeno, em rendimentos de 68-73%.
Posteriormente, desenvolvemos uma metodologia para síntese de 4-organocalcogeno-isoquinolinas 4, partindo-se dos substratos o-alquinil benzaldiminas 3. A combinação de quantidades catalíticas de CuI com dicalcogenetos de diorganoíla mostrou-se eficiente para obtenção das isoquinolinas em bons rendimentos A fim de avaliar a versatilidade das 4-organocalcogeno isoquinolinas obtidas, como precursores para síntese de isoquinolinas com diferentes funcionalizações, o composto 4-(telurobutil)-3-fenilisoquinolina foi submetido a reações de acoplamento cruzado do tipo Suzuki e do tipo Sonogashira, catalizados por sais de paládio. Também, foram realizadas as reações de troca telúrio-lítio com a subsequente reação com diferentes aldeídos levando aos alcoóis derivados em bons rendimentos.
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Chiurato, Matteo. "Synthèse de tétrahydropyrido-[isoindolones/isoquinolones/indolizinones] pour l'élaboration d'inhibiteurs de CDks." Orléans, 2007. http://www.theses.fr/2007ORLE2069.
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Cette thèse est divisée en cinq parties. La première partie traite de la chimie des ions iminiums. Après une brève introduction sur leur découverte, sont présentées leurs préparations et leurs applications dans divers champs de la chimie, en particulier dans la synthèse de produits naturels. En suite nous traiterons des ions N-acyl iminiums, en évoquant les mécanismes de leur formation, les diverses applications et leurs particularités. La première partie se termine par la présentation des différentes voies d'accès à des structures du type isoindoquinolinonique obtenues notamment par formation d’ions d'acyl iminiums. La seconde partie de la thèse concerne une étude méthodologique de la réaction de cyclisation présentée par le groupe du Prof. Y. Troin. Cette réaction, basée sur un intermédiaire N-acyl iminium, permet la synthèse d'un système de type isoquinolone. La réaction est une cycloaddition intermoléculaire d’une cétone protégée, et le carboxy benzaldéhyde. entre une amine primaire en Nous avons repris ces premiers travaux et avons étendu la méthode à toute une série de noyaux comme des systèmes benzéniques différemment substitués (avec des groupes -OMe en différentes positions du cycle), des systèmes polyaromatiques (naphtalène) et des hétérocycles (pyridine, quinoléine etc. . . ). La différence de réactivité des différents systèmes est discutée, et une méthode alternative de hydroxy lactames est proposée. synthèse passant par des Dans la troisième partie l’application de nos recherches à la problématique de la chimiothérapie anticancéreuse est abordée. Après avoir rappelé les principales causes, les mécanismes et quelques notions sur le cycle cellulaire et sur quelques médicaments utilisables à ce jour, nous évoquerons le rationnel permettant l’utilisation de la 10-amino-1,3,4,10b-tétrahydro-2H-pyrido[2,1-a]isoindol-6-one pour arriver à une série de diarylurées, inhibiteurs potentiels de kinases dépendantes des cyclines. La quatrième partie traite donc du chemin synthétique utilisé pour atteindre ces objectifs, et se termine par les résultats des tests biologiques et l’étude des premières relations entre structure et activité. Enfin, des perspectives de travail sont évoquées et une conclusion générale est proposée.
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Robveille, Jacques. "Synthèse de pyridine et d'isoquinoléine marquées au 14C sur l'hétérocycle azoté." Lyon 1, 1985. http://www.theses.fr/1985LYO10513.
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Trois procedes de synthese differents : la pyridine et les pyridines mono-2 et disubstituees-2,6 marquees c14 sont preparees a partir de composes marques dioxo-1,5 par cyclisation de leurs dioximes ; les pyridines substituees en 3 marquees c14 sont preparees par cyclisation thermique d'isocyanates de butadienyle prepares a partir des acides pentadiene-2,4oiques marques c14 ; les furo-, thieno- et pyrrolo (3,2-c) pyridines marquees c14 sont preparees a partir des acides furanne-, thiophene- et pyrroleacryliques-2 marques via les isocyanates. Application a la synthese d'isoquinoleines marques c14 a partir d'acides cinnamiques
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Gerfaud, Thibaud. "Nouvelles réactions d'hétéroannélation palladocatalysées à partir d'acyloximesSynthèse totale de l'alstoscholarine." Paris 11, 2010. http://www.theses.fr/2010PA112210.
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Ce manuscrit est consacré au développement de nouvelles réactions d'hétéroannélation palladocatalysées et à leur utilisation en synthèse totale. La première partie de ce manuscrit est dédiée au développement de nouvelles voies d'accès aux phénantridines, aux isoquinoléines, aux oxadiazolones et aux benzimidazoles à partir de dérivés d'oximes. Nous avons développé une nouvelle voie d'accès palladocatalysée aux phénantridines et aux isoquinoléines en utilisant une séquence domino aminopalladation/arylation directe. Cette approche est nouvelle et originale, car elle est basée sur l'insertion du palladium dans la liaison N-O d'une acyloxime. L'espèce aza-palladium (II) qui se forme est ensuite piégée de manière intermoléculaire par une aryne pour former un second intermédiaire Pd(II) qui subit finalement une arylation directe. Cette réaction s'avère générale sur les acyloximes dérivées de la benzophénone, et des arynes ou des alcynes très activés peuvent être utilisés pour former des phénantridines ou des isoquinoléines. Nous avons également noté que des substrats de type amidoximes secondaires, placés en présence de chlorure de pentafluorobenzoyle, pouvaient subir une rupture de liaison C-C inattendue pour former des oxadiazolones. Cette réaction a été étudiée et nous avons pu montrer qu'elle était générale pour la formation d'oxadiazolones et que dans ce cas, le chlorure de pentafluorobenzoyle pouvait être considéré comme un équivalent du phosgène. Enfin nous présentons également des résultats préliminaires pour la synthèse de benzimidazoles à partir d'acyloximes. La seconde partie de ce manuscrit présente à la première synthèse totale de l'alstoscholarine (Z et E), de manière concise et efficace. Cet alcaloïde, récemment isolé des feuilles d'Alstonia Scholaris, présente une structure pentacyclique inédite, avec un noyau indole et un noyau pyrrole placés de part et d'autre d'un bicycle ponté [3-1-3]. Notre synthèse est basée sur la formation tardive du noyau indole, en utilisant une méthode palladocatalysée développée au laboratoire. Elle est effectuée en l'absence de tout groupement protecteur et fait intervenir d'autres étapes clés comme une désymétrisation organocatalytique énantiosélective, une coupure oxydante avec formation régiosélective d'un hémiaminal à six chaînons qui permet de différencier les deux fonctions aldéhydiques formées ou encore une alkylidénation de Takeda, évitant l'épimérisation. Le rendement global de la synthèse est bon (13,5%) et le nombre d'étapes peu élevé. Enfin, la synthèse est modulable et devrait permettre la préparation de nombreux analogues<br>This PhD thesis is dedicated to the development of palladium-catalyzed heteroannulation reactions and their use in total synthesis. Ln the first part, a new access to phenantridines, isoquinolines, oxadiazolones and benzimidazoles from oximes derivatives is presented. We have developed a new domino palladium-catalyzed process involving an aminopalladation and a direct arylation step, based on the oxidative addition of palladium into N-O bonds. This aza-palladium (II) species is then intermolecularly trapped by an aryne or an alkyne. We have also noticed that secondary amidoxime, placed in the presence of pentafluorobenzoyl chloride could undergo an unexpected C-C bond cleavage to form oxadiazolones. This reaction has also been studied and we have found that it was general for the formation of oxadiazolones and that in this case pentafluorobenzoyl chloride couId be considered as a "CO" equivalent. Finally, we also present preliminary results for the formation of benzimidazoles from acyloximes. Ln the second part, we present the first total synthesis of alstoscholarine (Z and E). This alkaloid, recently isolated from the leaves of A lston ia Scholaris have an atypical pentacyclic structure, characterized by a bridged [3. 1. 3] bicycle fused with an indole ring on a side and a pyrrole ring on the other side. Our synthesis is based on a late-stage palladium-catalyzed indole formation developed in our laboratory. The synthesis is concise (8 steps), efficient (13. 5% overall yield), and protecting group free. It also features an enantioselective desymmetrization, a regioselective hemiaminal cyclisation and a Takeda olefination to avoid epimerization. We are currently exploiting these results for the synthesis of analogues
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Eriksson, Ludvig. "Transition Metal Mediated Transformations of Carboranes." Doctoral thesis, Uppsala University, Organic Chemistry, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3324.
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<p>This thesis describes the use of copper and palladium to mediate transformations of carboranes, especially <i>p</i>-carborane.</p><p>1-(1-<i>p</i>-carboranyl)-<i>N</i>-methyl-<i>N</i>-(2-butyl)-3-isoquinolinecarboxamide, a carborane containing analogue of the peripheral benzodiazepine receptor (PBR) ligand PK11195, has been synthesised. A key step in the reaction is the copper (I) mediated coupling of p-carborane with ethyl 1-bromo-isoquinoline-3-carboxylate. </p><p><i>p</i>-Carborane has been arylated on the 2-<i>B</i>-atom in high yields, using the Suzuki–Miyaura reaction. Thus the reaction between 2-I-<i>p</i>-carborane and various arylboronic acids [1-naphthyl-, phenyl-, 4-MeO-C<sub>6</sub>H<sub>4</sub>-, 3-CH<sub>3</sub>CONH-C<sub>6</sub>H<sub>4</sub>-, 4-NC-C<sub>6</sub>H<sub>4</sub>-, 3-NO<sub>2</sub>-C<sub>6</sub>H<sub>4</sub>-], gave the corresponding 2-aryl-<i>p</i>-carboranes in DME solution when reacted in the presence of cesium fluoride and the catalytic Pd<sub>2</sub>(dba)<sub>3</sub>–dppb system. Under the same conditions, the boron-boron bond forming reaction of two <i>p</i>-carboranylboronic esters (2-[(pinacolato)boron]-<i>p</i>-carborane and 2-[(neopentyl glycolato)boron]-p-carborane) was also shown feasible.</p><p><i>p</i>-Carborane has been vinylated on the 2-<i>B</i>-atom in high yields by use of the Heck reaction. The coupling between 2-I-<i>p</i>-carborane and various styrenes [4-H-, 4-C<sub>6</sub>H<sub>4</sub>-, 4-Cl , 4-Br-, 4-NO<sub>2</sub>-, 4-CH3O- and 4 CH<sub>3</sub> ] resulted in the formation of the corresponding<i>trans</i>-β-(2-<i>B</i>-<i>p</i>-carboranyl) styrene in DMF solution when reacted in the presence of silver phosphate and the palladacycle Herrmann´s catalyst. The reaction was shown to proceed at higher rate with electron rich than with electron deficient olefins.</p><p>The feasibility of palladium-catalysed isotopic exchange of an iodinated closo-carborane with a radioisotope of iodine has been studied. 2-I-<i>p</i>-carborane was selected as a model compound. It was shown, that such isotopic exchange is possible and provides a high yield (83 ± 4.2 %) during 40 min long reaction. The reaction conditions were optimised, and it was demonstrated that presence of the tetra n-butylammonium hydrogensulphate is important in order to stabilise catalyst and provide reproducibility of labelling. In this work we have modified the methodology and extended the application to a wider range of iodinated carboranes. By the use of Herrmann’s catalyst in toluene at 100 °C this [<sup>125</sup>I]-iodide labelling could be improved and extended. 2-I-<i>p</i>- 9-I-<i>m</i>-, 9-I-<i>o</i>-, 3-I-<i>o</i>-carborane, 1-phenyl-3-I-<i>o</i>-carborane and 1,2-diphenyl-3-I-<i>o</i>-carborane could be [<sup>125</sup>I]-iodide labelled in high to excellent yields within 5 minutes.This reported palladium catalyzed radio-iodination of the uncharged closo-carboranes might find use in pharmacokinetic studies of carborane derivatives.</p>