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Submitted by Maike Costa (maiksebas@gmail.com) on 2017-07-10T13:59:53Z No. of bitstreams: 1 arquivototal.pdf: 4398305 bytes, checksum: c95cf82f72f9c0e04311709786123245 (MD5) / Made available in DSpace on 2017-07-10T13:59:53Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 4398305 bytes, checksum: c95cf82f72f9c0e04311709786123245 (MD5) Previous issue date: 2016-05-27 / Alkaloids are secondary metabolites of great medical importance, covering a diverse group of nitrogen containing molecules in its structure, the number of alkaloid containing the tetrahidroisoquinolínico skeleton 1-substituted is extensive and impressive pharmacological versatility of this class arouses interest in experimental pharmacologists, the importance. This work has as objective, the synthesis of tetrahydroisoquinolines and provide material for future pharmacological studies both in-vivo and in-vitro. For the synthesis of phenyltetrahydroisoquinolinics alkaloids, benzyltetrahydroisoquinilinic and phenyltetrahydro-β-carboline the Pictet-Spengler reaction was aplicated. With the aim of expanding the pharmacological studies of the alkaloid (1-(3-dimethoxy-4-hydroxyphenyl)-7-methoxy-1,2,3,4,-tetrahydroisoquinoline (MTHP) your synthesis was repeated. 4 alkaloids were obtained, 2 phenyltetrahydroisoquinolinic (1-(3,5-dimethoxy-4-hydroxyphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (73%) and 1-(2-hydroxyphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (54%)), 1 phenyltetrahydro-β-carboline (1-(3,5-dimethoxy-4-hydroxyphenyl)-1,2,3,4,-tetrahydro-β-carboline (38%)) and 1 benzyltetrhydroisoquinilínic (1-(1-ethyl-3,4-metilenodioxidofenil)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (87%)). From the material available for the pharmacological MTHP tests showed low toxicity without genotoxicity, its immunomodulatory mechanism in asthma is related to regulation of TH2 profile. / Alcaloides são metabólitos secundários de grande importância medicinal, abrangendo um grupo diverso de moléculas contendo nitrogênio na sua estrutura. O número de alcaloides que contém o esqueleto tetrahidroisoquinolínico 1-substituído é extenso e a impressionante versatilidade farmacológica desta classe desperta o interesse nos farmacologistas experimentais. Visto a importância dos alcaloides isoquinolínicos, o nosso trabalho tem como objetivo a síntese de derivados tetrahidroisoquinolínicos e fornecer material para futuros estudos farmacológicos tanto in-vivo como in-vitro. Para a síntese dos alcaloides feniltetrahidroisoquinolínicos, benziltratrahidroisoquinilínicos e feniltetrahidro-β-carbolínicos foi utilizado a reação de Pictet-Spengler. Com o objetivo de ampliar os estudos farmacológicos a respeito do alcaloide (1-(3-dimetoxi-4-hidroxifenil)-7-metoxi-1,2,3,4,-tetrahidro isoquinolina (MTHP) refizemos a sua síntese como descrito na literatura. Obtivemos 4 alcaloides, sendo 2 deles feniltetrahidroisoquinolínicos (1-(3,5-dimetoxi-4-hidroxifenil)-7-metoxi-1,2,3,4,-tetrahidro isoquinolina (73%) e 1-(2-hidroxifenil)-7-metoxi-1,2,3,4,-tetrahidro isoquinolina (54%)), 1 feniltetrahidro-β-carbolínicos (1-(3,5-dimetoxi-4-hidroxifenil)-1,2,3,4,-tetrahidro-β-carbolina (38%)) e 1 benziltratrahidroisoquinilínicos (1-(1-etil-3,4-metilenodioxidofenil)-6,7-dimetoxi-1,2,3,4,-tetrahidro isoquinolina(87%)). A partir da disponibilização de material para os testes farmacológicos do MTHP, apresentou baixa toxicidade sem genotoxicidade, seu mecanismo imunomodulador na asma está relacionado a regulação do perfil TH2.

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Made available in DSpace on 2015-05-14T12:59:52Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 3215575 bytes, checksum: 8de9cf3f200ed4dc0ee4d1b0b672ce4f (MD5) Previous issue date: 2012-08-29 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The number of alkaloids containing the 1-substituted tetrahydroisoquinoline skeleton is extensive and impressive versatility of this pharmacological class arouses interest in experimental pharmacologists. Applying the consecrated Pictet-Spengler reaction of four phenyltetrahydroisoquinoline alkaloids was obtained, three of which are unpublished. Two of them obtained with excellent yield (93.45%) in one step. Starting from allylbenzene that initially passed through an isomerization followed by oxidation by applying the Limieux-Johnson reaction were obtained from two other alkaloids with an overall yield of 50%. In experimental models of acute inflammation, the 1-(3-methoxy-4-hydroxyphenyl)-7-methoxy-1,2,3,4,tetrahydroisoquinoline (MTHP) significantly reduced (p <0.05) cell migration into the abdominal cavity of mice and the release of pro-inflammatory mediators (TNF-α, IL-1 and IL-6) in a dose one hundred thirty-eight times lower dosage than the dose of aspirin administered (200 mg/Kg).The MTHP causes hypotension in non-anesthetized normotensive rats, which can be attributed to the participation of endothelium-derived factors, including NO and metabolites COX. These data suggest that MTHP has anti-inflammatory and hypotensive effect related to different mechanisms, and further studies are needed to explore its potential. / O número de alcaloides que contém o esqueleto tetrahidroisoquinolínico 1-substituído é extenso e a impressionante versatilidade farmacológica desta classe desperta o interesse nos farmacologistas experimentais. Aplicando a consagrada reação de Pictet-Spengler obtivemos quatro alcaloides fenil tetrahidroisoquinolínicos dos quais três são inéditos. Dois deles obtidos com excelente rendimento (93,45%) em uma única etapa. Partindo-se de alilbenzenos que inicialmente passaram por uma isomerização seguida de oxidação via reação de Limieux-Johnson, foram obtidos os outros dois alcaloides com rendimento global de 50%. Em modelo experimental de inflamação aguda, a 1-(3-metoxi-4-hidroxifenil)-7-metoxi-1,2,3,4,-tetrahidroisoquinolina (MTHP) reduziu significativamente (p<0,05) a migração celular para a cavidade abdominal de camundongos bem como a liberação dos mediadores pró-inflamatórios (TNF-, IL-1 e IL-6) em uma dose cento e trinta e oito vezes menor que a dose de AAS administrada (200mg/Kg i.p.). MTHP provoca hipotensão em ratos normotensos não anestesiados, que pode ser atribuída à participação de derivados do endotélio, incluindo fatores de NO e metabolitos COX. Estes dados sugerem que MTHP tem efeitos anti-inflamatórios e hipotensores relacionados a diferentes mecanismos, e novos estudos são necessários para explorar seu potencial.

La synthèse de la 5-azagalanthamine, un analogue azoté de galanthamine, utilisée dans le traitement palliatif de la maladie d’Alzheimer, a été envisagée dans le cadre d’une étude de relations structure-activité. Durant cette thèse nous avons examiné quatre voies de synthèse afin d’accéder à la 5-azagalanthamine. La première voie est basée sur la réaction de Pictet-Spengler afin de fermer le dernier cycle de l’azagalanthamine. De nombreuses tentatives ont été effectuées sur différents types de substrats mais cette stratégie s’est révélée inefficace. La deuxième approche consiste en une oxydation d’anilide ortho-substitué par un groupement méthoxy, avec un réactif à base d'iode hypervalent pour accéder à une spirodiènone, un intermédiaire clé de la synthèse. En effectuant cette réaction nous n’avons pas obtenu le produit attendu, mais une 1,2-dispirodiénone, un motif inhabituel, et très rare. Après avoir optimisé les conditions réactionnelles, nous avons étudié la généralité de la réaction avec d'autres substrats. La modélisation moléculaire ainsi que des études de voltammétrie cyclique ont été réalisées (Chabaud, L.; Hromjakova, T.; Rambla, M.; Retailleau, P.; Guillou, C. Chem. Commun. 2013, 49, 11542-11544. Hromjakova, T.; Retailleau, P.; Grimaud, L.; Gandon, V.; Chabaud, L. et Guillou, C. accepté EurJOC, 2015, DOI 10.1002/ejoc.201501160).Ensuite nous avons examiné l’approche basée sur le couplage intramoléculaire pallado-catalysé. Après les premiers résultats encourageant avec le substrat modèle nous avons réalisé une optimisation des conditions réactionnelles. Une étude de généralité de la réaction avec d'autres substrats a été effectuée. Malheureusement, il s’est avéré que la substitution sur le cycle aromatique n’était pas bien tolérée conduisant à de faibles rendements. Par conséquent cette méthodologie n’a pas pu être appliquée à la synthèse de l’azagalanthamine. Dans la dernière voie de synthèse examinée nous avons repris les travaux antérieurs entrepris dans notre laboratoire concernant la réaction de Heck intramoléculaire. La diminution de la longueur de la chaîne liant les deux cycles a permis d’obtenir des résultats très prometteurs. / The synthesis of 5-azagalanthamine, the analogue of galanthamine that is used in Alzheimer treatment, was investigated for structure - activity relationship studies.During this thesis I explored four synthetic approaches with the aim of preparing the 5-azagalanthamine. The first one is based on a Pictet-Spengler reaction used for ring closure of the last cycle of azagalanthamine. We carried out many tests on various types of substrate but this strategy has proved to be ineffective. The second approach consists of an oxidation of ortho-methoxy substituted anilide by hypervalent iodine reagent to access a spirodienone, a key intermediate of the synthesis. Interestingly this reaction did not result in the expected compound but we observed the formation of an unusual motif, the 1,2-dispirodienone. After conditions optimisation we studied the scope and limitations with others substrates. Molecular modelling and cyclic voltammetry studies were also carried out (Chabaud, L.; Hromjakova, T.; Rambla, M.; Retailleau, P.; Guillou, C. Chem. Commun. 2013, 49, 11542-11544. Hromjakova, T.; Retailleau, P.; Grimaud, L.; Gandon, V.; Chabaud, L. and Guillou, C. accepté EurJOC, 2015, DOI 10.1002/ejoc.201501160).Then we investigated an approach based on palladium-catalysed intramolecular coupling. After the first encouraging results with the model substrate, we did optimization of the reaction conditions and the study of substrate scope. Unfortunately we discovered that the substitution was not well tolerated and decreased the yield. Therefore this methodology could not be applied to the synthesis of the azagalanthamine. In the last approach we used previous work of our laboratory on the intramolecular Heck reaction. The reduction of the length of the linker between both cycles showed to be beneficial. We obtained promising results with this approach.

This thesis focuses upon pacidamycin, a member of the uridyl peptide antibiotics, a family of antibiotics which exhibit an, as yet, clinically unexploited mode of action, against MraY. The Goss group has previously demonstrated the ease of accessing N and C-termini analogues of pacidamycin utilizing precursor directed biosynthesis. The central diamino acid is key to pacidamycin's activity, yet little work has been carried out, to date, to investigate the SAR around this moiety. Particularly this thesis describes work toward generating pacidamycin analogues using the complementary tools of organic synthesis and biosynthesis. Chapter 1 introduces natural compounds and their importance in clinical use, provides a brief overview of the history of antibiotics and focuses on the urgent need for new antibiotics displaying new chemical architectures and possessing novel modes of action. This chapter also introduces uridyl peptide antibiotics and overviews the SAR studies around these unusual peptides, focusing on pacidamycin in particular. Diaminobutyric acid is central to these structures and a discussion of a selection of published methods to synthesis α, β-diaminobutyric acid (DABA) is also presented. Chapter 2 describes the synthesis of DABA and two analogues, in which the C-methyl moiety has been substituted by an ethyl or a cyclopropyl group. The mutasynthesis approach utilised in the attempt to generate novel pacidamycins and discussion around the results observes is also described. Chapter 3 demonstrates a three step one-pot reaction to access 1,3-disubstituted urea molecules. The chapter starts with a brief overview of previously established methods in the literature to access these useful molecules, and then moves towards a discussion about the reaction optimisation. The chapter also describes a family of analogues generated utilising this novel approach; and exploring the use of these analogues in the mutasynthesis of pacidamycin. In order to access the desired pacidamycin analogues with the modified diamino acid residue, it was determined that it is currently not possible to use a mutasynthesis approach, instead an approach of total synthesis needed to be employed. Chapter 4 describes this total synthesis. The C- terminal urea motif was generated using a novel 1-pot phosphine free route developed during this study. To access the central native (2S, 3S)- DABA, a variation of the route of Merino et al's via Garner's aldehyde was initially utilised. Subsequently, a shorter and more flexible approach from Soloshonok et al via a Ni (II) Schiff base complex of glycine was adopted. Unpublished results from the Goss group have shown that the 2',3'dihydroxy uridine analogues in pacidamycin conferred broader spectra of activity. Work towards the synthesis of these analogues has been conducted. The order of assembly of the peptide and the nucleoside fragments was in alignment with Boojamra et al's approach. If the de-protection chemistry had worked according to plan, this would have resulted with a synthesis that is at least 6 steps shorter and higher yielding then Boojamra's. The introduction in this chapter reports the various methods previously reported in the literature for the total synthesis of pacidamycin. A discussion about the current progress in the total synthesis highlighting the difficulties faced is also shown. Chapter 5 demonstrates utilising semi-synthesis as a useful tool to generate novel pacidamycins by applying a Pictet-Spengler reaction on pacidamycin 4. This chapter starts with an overview of this phosphate mediated Pictet-Spengler reaction. In addition, a discussion about the large-scale fermentation of Streptomyces coeruleorubidus, the wild type producer of pacidamycin, and the generation of pacidamycin analogues utilising a semi-synthesis approach is also presented. Chapter 6 describes the future work following on from this study building upon each of the above chapters.

Les cyclopropanes sont rencontrés dans de nombreux produits naturels ou synthétiques bioactifs. Les travaux réalisés portent sur le développement de couplages catalysés par le palladium permettant d'accéder à des cyclopropanes diversement substitués. Des couplages de Suzuki-Miyaura impliquant les cis- et trans-2-benzyloxy-cyclopropyltrifluoroborates de potassium ont pu être mis au point après un important travail d'optimisation. L'accès à des aminocyclopropanes par des couplages de type Hartwig Buchwald impliquant des iodures cyclopropaniques s'est révélé beaucoup plus difficile à mettre en œuvre. Leur faisabilité a été démontrée avec un exemple, en version intramoléculaire, mais les résultats n'ont pas pu être généralisés. Les premiers exemples de couplages de Sonogashira entre des iodures cyclopropaniques diversement substitués et des alcynes terminaux ont été décrits. Les alcynylcyclopropanes correspondants sont obtenus avec d'excellents rendements et rétention de configuration. Les cis-2-alcynylcyclopropanecarboxamides préparés par cette méthode peuvent subir une cyclisation 5 exo-dig en milieu basique et conduire à des énamides incorporant un motif 3-azabicyclo[3.1.0]hexane. En milieu acide, ces composés engendrent des ions N-acyliminiums bicycliques pouvant être impliqués dans des réductions ioniques ou des cyclisations de Pictet-Spengler menant à une grande diversité de composés hétérocycliques azotés originaux de manière totalement diastéréosélective

Tetrahydroisoquinoline alkaloids are a class of structurally complex natural products and a huge number of its natural product widely exist in nature which, from the discovery has been more than a century, it compounds with high anti-tumor activity, antibacterial and other physical activity, but also because of its special structure, with low oncentration of biological activity, but these alkaloids are not sold in the market mainly due to a less natural extraction, chemical synthesis method and multi-step, low yield. Therefore, we constructed a combination of tetrahydroisoquinoline alkaloids and the pyrazino [2,1-b] quinazoline-3,6-diones structure of the new compounds, which have the quinazolinone compounds which is the drug synthesis and drug activity on the bond, is also a kind of unique and widely used drug structure, and causes a lot of scientists and drug research interest and discussion, as we develop the motivation.

The tetrahydroisoquinoline alkaloids have been studied thoroughly about their biological and chemical significance over the past 30 years. These natural products show great biological activity, especially ET-743 and saframycin A, makes them promising therapeutics, while their structural complexity and particularity provide challenging synthetic targets. These alkaloids or derivatives show interesting biological activity, but the most important drawback as potential market therapeutics is the minute amount of them available from nature, and the synthetic methods published are inconvenient, difficult, and hard to handle. Herein is described our researches about the tetrahydroisoquinoline alkaloids. Chapter 1 describes relevant background related to the biological significance of these alkaloids, and the currently synthetic studies toward these natural products. Chapter 2 describes our design and synthesis of the analogues based on the anticancer mechanism of the tetrahydroisoquinoline alkaloids, and the biological activities of these analogues. Chapter 3 describes a rapid synthetic route for the common structure of the bis-tetrahydroisoquinoline alkaloids via a controlled mono-Pictet-Spengler cyclization.

Submitted by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2018-03-02T15:45:37Z No. of bitstreams: 2 Reprodução Não Autorizada.pdf: 47716 bytes, checksum: 0353d988c60b584cfc9978721c498a11 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2018-03-02T15:45:50Z (GMT) No. of bitstreams: 2 Reprodução Não Autorizada.pdf: 47716 bytes, checksum: 0353d988c60b584cfc9978721c498a11 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-03-02T15:45:50Z (GMT). No. of bitstreams: 2 Reprodução Não Autorizada.pdf: 47716 bytes, checksum: 0353d988c60b584cfc9978721c498a11 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-10-04 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The steady increase in the number of current drug resistance cases used without malaria treatment has encouraged studies on a discovery of potentially active new drugs. In previous work by LAPAAM / INPA has revealed the in vitro and in vivo antimalarial activity of indole alkaloids, such as elipticine, olivacin and derivatives. The great challenge has been found other indolic structures, which are easier to obtain and which present similar or superior antimalarial activity as found in these structures. In this search, nucleic acid tricyclic derivatives obtained from carbazolic and -carbolinic skeletons were synthesized and attributes against in vitro assays. In total, twenty-three derivatives were synthesized, of which eighteen were evaluated in vitro biological assays against K1 P. falciparum strains and cytotoxicity in non-tumor cells (MRC-5). In addition were submitted to the tests five commercial substances harmine (24), harmane (25), harmaline (27) and carbazole (29). As the main reactions for the nitration, demethylation, formation of salts through hydrogen chloride bubbling, condensation reaction of Pictet-Splenger and alkylation, a quality formed by the unpublished compound in the 9-(2,3-dihydroxy)-harmano (25.1). Among the derivatives submitted antimalarial assays, 3-nitrocarbazole (29.4), O-acetyl-harmol (26.1) and the harmine salt HCl (24.4) were the most active with IC50 8,87 M, 12,2 M and IC50 19,31 M, respectively. The 8-nitroharmano (25.2) and the 9-(2,3-dihydropropyl)-harmane (25.1) had their activity potentiated with IC50 values lower than the harmane. And more active commercial substances harmaline with IC50 14,7 M and the norharman with IC50 17.67 M. According to the factory, there is no concentration of 50 g / mL, except for 6-nitro-harmano (25.3) and O-acetyl-harmol, whose lower viability is less than 25%. / O constante aumento no número de casos de resistências aos medicamentos atuais utilizados no tratamento da malária tem incentivado estudos sobre a descoberta de novas drogas potencialmente ativas. Trabalhos anteriores realizados pelo LAPAAM/INPA revelaram a atividade antimalárica in vitro e também in vivo de alcaloides indólicos, tais como elipticina, olivacina e derivados. O grande desafio tem sido encontrar outras estruturas indólicas, de mais fácil obtenção e que apresente atividade antimalárica similar ou superior às encontradas nestas estruturas. Nessa busca, derivados tricíclicos com núcleo indólicos obtidos a partir esqueletos carbazólicos e -carbolínicos foram sintetizados e avaliados frente a ensaios in vitro. No total foram sintetizados vinte e três derivados, dos quais dezoito foram avaliados em ensaios biológicos in vitro contra cepas K1 de P. falciparum e citotoxidade em células não tumorais (MRC-5). Também foram submetidos aos ensaios, as cinco substâncias comerciais norhamano (23), harmina (24), harmano (25), harmalina (27) e carbazol (29). As principais reações utilizadas foram nitração, desmetilação, formação de sais através do borbulhamento de cloreto de hidrogênio, reação de condensação de Pictet-Splenger e alquilação, a qual formou o composto inédito na literatura 9-(2,3-diidroxi)-harmano (25.1). Entre os derivados submetidos aos ensaios antimaláricos, o 3-nitro-carbazol (29.2), O-acetil-harmol (26.1) e o sal de harmina.HCl (24.4) foram os mais ativos com CI50 8,87 M , 12,2 M e CI50 19,31 M, respectivamente. O 8-nitroharmano (25.2) e o 9-(2,3-diidropropil)-harmano (25.1) tiveram sua atividade potencializada com valores de IC50 inferiores ao harmano. E entre as substâncias comerciais, as mais ativas foram a harmalina com CI50 14,7 M e o norharmano com CI50 17,67 M. De maneira geral todos as estruturas estudas neste trabalho apresentaram baixa toxicidade em células normais com viablidade maior que 50 %, na concentração de 50 g/mL, com exceção do 6-nitro-harmano (25.3) e do O-acetil-harmol, cujas viablidades foram inferiores a 25%.