Tesis sobre el tema "C]pyrazole"

Les structures bicycliques azotées sont parmi les entités les plus utilisées dans le domaine thérapeutique.Les bicycles 5:5 polyazotés sont des structures moins décrites que leurs analogues 6:6 ou6:5. Malgré le potentiel pharmacologique des pyrazolo [3,4-d] thiazoles et des pyrazolo [3,4-c] pyrazoles,deux exemples de ces familles rares, seuls quelques procédés de préparation et de fonctionnalisationdirecte de ces charpentes hétérocycliques sont décrits.De ce fait, l’objectif principal de nos recherches vise à développer de nouvelles voies de synthèse vers cesdeux charpentes bicycliques et ce, à partir de substrats facilement accessibles. Des stratégies efficaces ontété mises au point et s’appuient sur réactions de condensations avec des hydrazines, des N-cyclisationsintramoléculaires, des halogénations chimiosélectives et diverses réactions de couplage-croisé. De surcroît,le motif pyrazolo[3,4-d]thiazole a été fusionné à une structure triazapentalène, afin d’évaluer les propriétésspectroscopiques
Nitrogen-rich fused bicyclic structures are undisputedly one of the most used scaffolds for therapeutic use.The 5:5 polynitrogenated bicycles are moieties considerably less documented then their 6:6 or 6:5analogues. Despite the pharmacological potential of the pyrazolo[3,4-d]thiazoles and of thepyrazolo[3,4-c]pyrazoles, two examples of such rare families, only few methods of preparation and directfunctionalization of these heterocyclic moieties have been described.In this context, the main goal of our research aims at exploring new routes towards these bicyclic systemsfrom readily available and affordable starting materials. Efficient strategies were developed relying onhydrazine condensations, on intramolecular N-cyclizations, on chemo-selective halogenation and variouscross-coupling reactions. Moreover, the pyrazolo[3,4-d]thiazole entity was fused to a triazapentalenestructure in order to assess the spectroscopic properties

L’accès à de nouveaux composés hétérocycliques originaux biologiquement actifs, constitue l’un des principaux objectifs de notre groupe de recherche. Dans ce contexte, les travaux de cette thèse ont pour but principal, la conception de trois nouvelles familles de composés hétérocycliques contenant un motif pyrazolique susceptibles de présenter des activités biologiques, à savoir les pyrido[1',2':1,5]pyrazolo[4,3-d]pyrimidine, les pyrrolo[3,4-c]pyrazoles et les pyrazolo[5,1-b]thiazoles. Ce manuscrit est essentiellement dédié à un travail de méthodologie décrivant les différentes voies d’accès à ces hétérocycles originaux, tricycliques et bicycliques potentiellement modulables. La réactivité de ces synthons clés est ensuite étudiée avec divers procédés de fonctionnalisation palladocatalysés (Activation au PyBrOP-(hétéro)arylation, Liebeskind-Srogl, Suzuki-Miyaura, Buchwald-Hartwig, C-H arylation, substitution nucléophile aromatique) pour élaborer d’intéressantes chimiothèques construites autour de ces structures inédites, ouvrant ainsi de nombreuses perspectives pharmacologiques
The access to new original biologically active heterocyclic compounds, is one of the main objectives of our research group. In this context, the main purpose of this thesis is the design of three new families of heterocyclic compounds containing a pyrazolic motif that may exhibit biological activities, namely pyrido[1',2': 1.5]pyrazolo[4,3-d]pyrimidine, pyrrolo[3,4-c]pyrazole and pyrazolo[5,1-b]thiazole.This manuscript is essentially dedicated to a methodology work describing the different routes of access to these originals and potentially modular tricyclic and bicyclic precursors. The reactivity of these key synthons is then studied towards aromatic nucleophilic substitutions reactions and various pallado-catalyzed methods of functionalization (Activation with PyBrOP- (hetero) arylation, Liebeskind-Srogl, Suzuki-Miyaura, Buchwald-Hartwig, C-H arylation, aromatic nucleophilic substitution) to develop interesting libraries built around these unusual structures, thus opening numerous pharmacological perspectives

Two different synthetic approaches to the synthesis of pyrano[2,3-c]pyrazoles have been investigated. In one approach, dehydroacetic acid derivatives were treated with phenylhydrazine and methylhydrazine led to the formation of the phenylhydrazones and methylhydrazones, which undergo rearrangement in refluxing acetic acid to diketo-phenylpyrazoles and diketo-methylpyrazoles. Upon treatment with a mixture of acetic and sulfuric acid these compounds isomerize to the phenylpyrano[2,3-c]pyrazol-4-one and methylpyrano[2,3-c]pyrazol-4-one derivatives. In a second approach, phenylhydrazine and methylhydrazine reacted with dimethyl(methoxymethylene)malonate (34) to give phenylpyrazole and methylpyrazole ester derivatives which were converted to phenylpyrazolone and methylpyrazolone by hydrolysis and decarboxylation. C-acylation of these compounds with trans-cinnamoyl chloride gave á,â-unsaturated-4-acetyl-5-hydroxypyrazoles. Bromination of these á,â-unsaturated-4-acetyl-5-hydroxypyrazoles with spontaneous cyclization, followed by dehydrobromination led to pyrano[2,3-c]pyrazol-4-one derivatives, respectively. Phototochemical excitation of 1-phenyl and 1-methylpyrano[2,3-c]pyrazol-4-ones in acetonitrile led to the formation of cis-head-to-tail [2+2] cycloaddition products. Irradiation in ethanol solvent led to photodimerization and to photofragmentation to yield pyrazole ethylesters.

Ce travail est centré sur la synthèse de complexes du rhodium contenant un ligand azoté et leur mise en œuvre dans la réaction catalytique de carbonylation du méthanol en acide acétique. Dans une première partie, nous nous intéressons à la préparation de complexes neutres de formule générale [RhI2(CO)(L)] (L = amines, imidazoles et pyrazoles) et à quelques homologues chlorés. Ces complexes plans carrés manifestent une réactivité directement liée à l’encombrement stérique du ligand azoté L dans la réaction d’addition oxydante de l’iodomethane suivie de la cis-migration du groupement méthyle pour former l’espèce acétyle. Dans une deuxième partie, les complexes précédents ont été engagés dans des essais catalytiques de carbonylation du méthanol dans les conditions du procédé industriel. Comme il s’est avéré que les complexes neutres se transforment en espèce [RhI2(CO)2]- pour laquelle les contre-cations associés sont constitués du ligand azoté protoné ou methylé, nous avons effectué la préparation et la caractérisation des complexes [HNR3][RhI2(CO)2] ou [MeNR3][RhI2(CO)2]. Par IR, RMN et électrochimie, nous nous sommes intéressés aux phénomènes d’appariement d’ions et nous montrons qu’il s’agit dans le meilleur des cas d’interactions hydrogènes. Celles-ci influent la vitesse de la réaction oxydante de CH3I. Dans la dernière partie, nous avons complété une étude, précédemment initiée au laboratoire, sur le mécanisme, qui dans la dernière étape du cycle catalytique permet de passer de l’espèce acétyle [RhI3(COCH3)(CO)2]- à l’espèce active [RhI2(CO)2]- avec production de l’iodure d’acyle. A l’inverse du concept admis d’élimination réductrice de CH3COI suivie de son hydrolyse immédiate en CH3COOH et HI, nous montrons, avec l’appui de calculs théoriques (DFT) qu’en fait un ligand I- est substitué par un ligand acetate pour conduire à l’espèce [RhI2(OAc)(COCH3)(CO)2]-. L’élimination réductrice produit alors l’anhydride acétique qui est hydrolysé en CH3COOH régénérant [RhI2(CO)2]-. Un tel mécanisme opère en présence d’ions acetate dans les milieux faiblement hydratés visés par l’industriel
This study focuses on the synthesis and reactivity of rhodium complexes bearing N- containing ligands or counter-cations for the [Rh]-catalyzed methanol carbonylation reaction to produce acetic acid under the industrial Celanese Acid Optimization (AO) process conditions. In a first part, full synthesis and characterization of neutral Rh(I) square planar cis- [RhX(CO)2(L)] (X = Cl or I) complexes have been described, for which L is an N-ligand belonging to the amine, imidazole or pyrazole family. For the [RhI(CO)2(L)] complexes, variable-temperature 13C{1H} NMR spectroscopy has put in evidence a fluxional behavior for the different sized L ligands involved. The rate of this fluxional process reveals to be related to both electronic and steric contributions brought by L to the Rh center. These parameters (mainly steric), supported by single-crystal X-ray analyses in the solid state, also influence significantly the kinetics of the methyl iodide oxidative addition reaction followed by rapid CO migratory insertion, the overall being the rate determining step of the [Rh]-catalyzed methanol carbonylation cycle. In absence of CO, this reaction gives rise to the corresponding neutral Rh(III) acetyl complex, which immediately dimerizes to afford [Rh(μ- I)I(COMe)(CO)(L)]2 complex, for which several X-ray crystal structures have been obtained and studied. In addition, the surprising C-H activation in the case of a tBu-pyrazole ligand giving rise to a cyclometalated Rh dimer is reported. In a second part, the reactivity of the latter neutral Rh(I) [RhI(CO)2(L)] complexes as potential precursors has been investigated by batch experiments for the methanol carbonylation reaction. Mechanistic understanding via VT-HP-NMR experiments enabled to detect mainly anionic Rh(I) [RL][RhI2(CO)2] (R = H or CH3 according to the working conditions) complexes formed by decoordination followed by quaternization of the L ligand. Despite this result, the pyrazole family ligands showed better stability under the harsh process conditions. Thus, it cannot be ruled out that equilibrium between neutral and anionic species co-exist in the reaction medium at high temperatures and that [RL]I salt dissociation occurs, restoring the L ligand into the Rh coordination sphere. At this stage we focused on the anionic Rh(I) complex and prepared a series of [XNR3][RhI2(CO)2] (X = H or CH3) species, which have been fully characterized. Infrared, NMR, conductivity experiments and DFT model calculations together put in evidence ion interactions according to the nature of the ammonium counter-cation. Protonated cations significantly impact on the kinetics of the methyl iodide oxidative addition presumably due to H-interactions with the Rh square plane. The final part deals with the mechanism of the reductive elimination reaction, the last step of the [Rh]-catalyzed methanol carbonylation cycle, which from complex [RhI3(COCH3)(CO)2]-, regenerates [RhI2(CO)2]-. In contrast to the classically admitted mechanism of reductive elimination of CH3COI followed by subsequent hydrolysis to form AcOH and HI, we demonstrate from experimental DFT calculation that substitution of an iodo ligand by an acetate ion occurs to give rise to the [RhI2(OAc)(COCH3)(CO)2]- species. Thus, reductive elimination regenerates [RhI2(CO)2]- and produces acetic anhydride, which after hydrolysis affords two molecules of acetic acid. Such a mechanism operates under process conditions at low water content with a significant amount of acetate ions

Une multitude de composés organiques présente une structure bicyclique azotée insaturée.Parmi ceux-ci, le motif pyridine-[b]-bicyclique est extrêmement fréquent, et se compose d’unepyridine accolée à un autre cycle aromatique. Cependant, les méthodes de synthèse de cescomposés sont aujourd’hui encore trop spécifiques. Les conditions réactionnelles ne sont pastoujours utilisables, ou ne permettent pas de préparer certains produits spécifiques. Afin des’affranchir de ces limitations, une nouvelle méthode de construction du cycle pyridine à partirdu motif ß–aminoacrylonitrile est proposée dans ce manuscrit, utilisant un alcène activé par unmotif trichlorométhyle.Outre la préparation de ces pyridines-[b]-bicycliques, la réactivité des pyrazolo[3,4-b]pyridines a été étudiée. Des réactions de fonctionnalisation de fin de synthèse ont étédéveloppées, qui exploitent des procédures basées sur la chimie du palladium. Trois positionsdes pyrazolopyridines ont pu être arylées, permettant d’accéder à de nouveaux composés
Bicyclic unsaturated structures containing one or more nitrogen atom appear in a widerange of organic compounds. In particular, the [b]-fused pyridine is a frequent structural motif,with striking biological activities. However, there is still a lack for general methods, withrespect to the reaction conditions or the scope. In order to override these limitations, a newsynthetic procedure for preparation of the pyridine ring starting from ß–aminoacrylonitrile isproposed. This procedure relies on a trichloromethyl-activated alkene.The reactivity of pyrazolo[3,4-b]pyridine, a subclass of [b]-fused pyridine, have beeninvestigated. Some late-stage functionnalization have been developped, relying on palladiumcatalyzed chemistry. Three positions of the pyrazolopyridine core have been arylated, thusgiving access to new structures

Les recherches effectuées au cours de ce travail de thèse sont centrées sur les dérivés cycliques de type 2-azahetaryl-3-énaminonitrile qui représentent une structure d'intérêt du fait de son nombre élevé de sites réactifs potentiels. La fonctionnalisation régiosélective de chaque site donne en effet accès à des une grande diversité structurelle de composés azoté et substitué par un azahétérocycle. Un atout majeur des 2-azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acétonitriles est leur grande accessibilité à partir de matières premières simples et bon marché. Nous avons pu étudier leur emploi dans la synthèse des pyrazoles (isoxazoles). Ils jouent alors le rôle de diélectrophiles 1,3. L'action d'hydrazine (hydroxylamine) conduit à des 5-amino-4- azahetaryl-3-(ω-aminopropyl)-1H-pyrazole (isoxazole) formés avec une régiosélectivité complète et de bons rendements 50-85%. Ceci établit une approche en deux étapes efficace et facilement reproductible à des amino-pyrazoles substitués par des hétérocycles à partir d'acétonitriles hétérocycliques. Des transformations subséquentes ont été réalisées donnant accès à des polyamino-azoles dérivatisés régiosélectivement, à des composés tétracycliques jusqu'à un rendement global de 45% et à des pyrazoles arylés jusqu'à 71% de rendement par diazotation suivie d'une arylation par couplage croisé Suzuki-Miyaura ou C-H activation. Nous avons illustré une protection de l'azote efficace sous forme de nitrosamine pendant le couplage croisé catalysé par Pd. Nous avons également effectué la quaternarisation de l'azote de l'hétérocycle pour étudier l'effet d'une moitié cationique sur la régiosélectivité de la réaction de tels dérivés 2-azahetaryl-3-énaminonitrile avec des 1,2-binucléophiles. L'augmentation de la demande en électrons sur l'hétérocycle a induit un changement de chemin réactionnel qui a conduit à un produit issu de l'ouverture du cycle azole. Une différence de réactivité entre les dérivés du benzoxazole et du benzimidazole d'une part et du benzothiazole d'autre part a été observée. Alors que les premiers suivent la voie d'ouverture de cycle, le second suit une transformation "classique" puis une substitution nucléophile au centre C-2 du benzothiazole conduisant à la formation du cycle de l'azépine. Dans le cas des énaminonitriles substitués par un benzoxazolyle dans les mêmes conditions, les deux régioisomères sont formés. La réaction de formylation du 2-(benzo[d]thiazol-2-yl)-2-(pyrrolidin-2-ylidène) acétonitrile avec le N,N-diméthylformamide diméthylacétal (DMF DMA), suivie d'une amination et d'une cyclisation dans des conditions basiques a engendré à la pyrrolo[3,2-c]pyridine-6-imine, un composé qui présente un rendement quantique fluorescent élevé (Φ = 61%) et s'est révélé très sensible à la protonation. Les deux caractéristiques devraient être utiles pour développer un test de détection d'eau originaux pour les solvants aprotiques. Nous avons démontré qu'une telle méthode fluorométrique pour déterminer la teneur en eau dans le DMSO présente une limite de détection de 0,068%
The research carried out in the course of this PhD work is centered on cyclic 2-azahetaryl-3-enaminonitrile derivatives which represent an attractive scaffold due to its high number of potential reactive sites. Regioselective functionalization of each site may give access to various structurally different Nitrogen-containing moieties featuring an azaheterocycle substituent. One first application in heterocyclic synthesis of 2-azahetaryl-2-(1-R-pyrrolidin-2-ylidene)acetonitriles, readily accessed from available and cheap starting materials, is their involvement in Knorr-type synthesis of pyrazoles (isoxazoles) where they play the role of the 1,3-dielectrophiles. Thus 4-azahetaryl-3-(ω-aminopropyl)-1H-pyrazole (isoxazole)-5-amines are formed with complete regioselectivity in good yields 50-85%. This establishes an efficient and easily reproducible two-step approach to heterocycle- substituted amino-pyrazoles from heterocyclic acetonitriles. Unprecedented subsequent transformations were carried out providing an access to regioselectively derivatized polyamino azoles, tetracyclic compounds in up to 45% overall yield and arylated pyrazoles in up to 71% yield through diazotization, followed by arylation through Suzuki-Miyaura cross-coupling or C-H activation. We illustrated the unprecedented but efficient nitrogen protection as a nitrosamine during the Pd-catalyzed cross-coupling. Also the possibility of pyrazoles C-H activation in order to get densely substituted pyrazoles was shown for the first time. We also performed the quaternarization of the nitrogen of the heterocycle to investigate the effect of a cationic moiety on the regioselectivity of the reaction of such azahetaryl-3-enaminonitrile derivatives with 1,2-binucleophiles. The increased electron demand on the heterocycle induced a reaction path shift that produced the azole ring- opened product. Derivatives of benzoxazole and benzimidazole form second way products straight away, while the one of benzothiazole undergoes the "classical" transformation pathway and subsequent nucleophilic substitution at C-2 center of benzothiazole leading to azepine cycle formation. In the case of benzoxazolyl substituted enaminonitriles under the same conditions both regioisomers are formed. Formylation reaction of 2-(benzo[d]thiazol-2-yl)-2-(pyrrolidin-2-ylidene) acetonitrile with N,N-dimethylformamide dimethyl acetal (DMF DMA), followed by further reamination and cyclization under basic conditions gave rise to pyrrolo[3,2-c]pyridine-6-imine, a compound that exhibits a high fluorescent quantum yield (Φ = 61%) and proved to be very sensitive to protonation. Both characteristics are expected to be useful to develop an unprecedented water detection test for aprotic solvents. We have demonstrated that such a fluorometric method for determining water content in DMSO presents a limit of detection of 0.068%. From other enaminonitriles reactions with DMF DMA provided either a mixture of methylated and formylated products, or only methylated products (few adducts also shown non reactivity). These observations prompted us to assume that the presence of easily accessible NH group is essential in formylation of the C-3 center of pyrrolidine allowing to propose a mechanism for this uncommon reaction. 2-Azahetaryl-2-(pyrrolidin-2-ylidene)acetonitriles and their 3-oxo-benzo- analogues were also used to create: a) visible spectrophotometric probes for Zn(II) b) water stable BF2-rigidified complexes that overcome the limitations of BODIPY-dyes and have Stokes shifts up to 9000 cm-1, emission at violet-blue range, fluorescence both in solution (Φ up to 90%) and crystalline state; c) films of polymeric composites exhibiting photovoltaic effect

碩士
中國醫藥大學
藥物化學研究所碩士班
97
1-Benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) was has been identified as a potential antitumor agent. In order to extend the structure-activity relationships of YC-1 analogs, in this study a series of selenolo[3,2-c]pyrazoles were synthesized as target compounds. The key intermediates 7-8 were synthesized by reacting acyl chlorides 5-6 with methyl furan-2-carboxylate. The reacted intermediates 7-8 were then treated with phenylhydrazine or substituted phenylhydrazine to give the corresponding hydrazones 9-17. The above hydrazones were then treated with mixed reagents of lead tetraacetate and boron trifluoride etherate cyclization to yield the designed compounds 27-35. These selenolo[3,2-c]pyrazoles 27-35 were reduced with calcium borohydride to afford their corresponding carbinol derivatives 36-40 and hydrolyzed to give their corresponding carboxylic acids 41-42.The newly synthesized compounds 27-42 were evaluated for their cytotoxicity against human renal A-498 and non-small cell lung cancer NCI-H226 cell lines. The results demonstrate that the carbinol derivatives 3-(5-hydroxymethyl-2-furyl)-1-phenyl-5-methylselenolo[3,2-c]pyrazole- (36) and 3-(5-hydroxymethyl-2-furyl)-1-phenylselenolo[3,2-c]pyrazole- (37) show significant cytotoxity against human renal cancer cell line A498.

博士
中國醫藥大學
藥物化學研究所博士班
97
The purpose of this study is to develop compounds with potential anticancer activity as new drug candidate. This thesis consists of two parts. In the first part, four different skeletons of YC-1 derivatives [furopyrazole derivatives (11-22, 28-36), thienopyrazole derivatives (42-45, 50-53), selenopyrazole derivatives (67-72, 75-77), and indazole derivatives (99−118, 123−128)] were synthesized in order to expand the substance patent’s inclusion of YC-1 and find new candidate with better anticancer activity than YC-1, and constructed their SAR in NCI-H226 and A498 cells. Compound 13 (CLC107), 44 (CLC015), 69 (CLC005), and 127 (CLC802a) were chosen for evaluation against 60 human cancer cell lines (the NCI-60) and COMPARE program analysis, and indicated that four compounds were with great development value since they possessed novel mechanism of action different from existing anticancer drugs. Finally compound 127 was proved to demonstrate anticancer activity similar to YC-1 in animal model, it is thus a new candidate of YC-1 in drug development. In the second part, the problem of 2-phenyl-4-quinolone derivatives in pharmacokinetics is resolved. In order to improve solubility problem, a phosphoric acid was attempted to be attached to 4-ketone of 2-phenyl-4-quinolone, and thus phosphate monosodium salts of 2-phenyl-4-quinolone derivatives were successfully created, which were expected to be applied by po and iv routes in clinics. Among 2-phenyl-4-quinolone derivatives, we focus on compound 8 which demonstrated the most significant antitumor activity. According to the data of Pharmacokinetics, compound 35 was proved to be transformed in vivo to compound 8 (CHM-1). After the assessment of safety pharmacology of compound 35 in enzyme activity assay and receptor binding assay, we predict it is very effective and safe drug while there should not be too many side effects in clinical trials. Besides, it showed excellent antitumor activity in SKOV-3 Xenograft SCID mice model and CT-26 colon adenocarcinoma Balb/c mice orthotopic model. It is confirmed that compound 35 (CHM-1-P-Na) is a drug candidate for further development as a potential anticancer agent in the clinic. We hope this series of compounds can successfully become clinical therapeutic agents which are beneficial to human beings.

碩士
中國醫藥學院
藥物化學研究所
81
A series of 1-substituted 5-methyl-3-phenylfuro[3,2-c] pyrazoles(III1-11) and its intermediates (II1-13) have been synthesized,and evaluated for antipletelet activities.Most of them showed significant effect on the inhibition of platelet aggregation that induced by collagen and arachidonic acid. Among them 5-methyl-2-furyl phenyl ketone 3',4'-dichlorophenyl hydrazone (II6) was the most promising and therefore the action mechanism of this compound was further studied.When 5-methyl-2 -furyl phenyl ketone 4-chlorophenylhydrazone treat with lead tetraacetate,boron trifluoride etherate to carry out oxidative cyclization,side product p-chlorobiphenyl also obtained. Therefore we react substituted pphenylhydrazine with benzene or toluene in the present of lead tetraacetate,we can obtain high yield of biphenyl deratives.The application and the really mechanism were worthy of further studied.

Part I of this thesis (Chapter 1) describes the development of the first synthetic method for intermolecular palladium-catalyzed direct C-H arylation of N-substituted pyrazole compounds. The scope of the reaction and the ability to sequentially and selectively arylate specific positions on the azole core to rapidly access highly substituted pyrazoles will be discussed. Part II of this thesis addresses two separate targets to modulate neuroplasticity. In Chapter 2, the TrkB receptor as a potential target for pharmacological modulation is examined. Its signaling, role in brain disease, and reported agonists and antagonists are reviewed. In addition, our attempts at establishing an assay to assess TrkB activation, as well as our results using the reported agonists and an antagonist in several model cell lines, are discussed. The third chapter of this work features the development of rationally-designed isoquinuclidines that induce GDNF production by brain cell models. In addition to examining the mechanism of action of an isoquinuclidine (XL-026) using pharmacological inhibition, the mapping of GDNF production and release by C6 rat glioma cells is described and a mechanistic model based on our results is presented.

碩士
高雄醫學大學
醫藥暨應用化學研究所碩士在職專班
97
This study analyses and modifies the model of Accerlys Discovery Studio with the pyrazolo[4,3-c]quinoline derivatives as inhibitor of p38α MAPK by computer molecular modeling. From this study we intend to find novel molecule to be potential anti-infection P38 MAPK inhibitors. The results of this study led to the discovery of 13 possible compounds which we have further predict their activities and the pharmacophore. Although preious studies suggested three amino acids involved in the interaction of typical p38α MAPK inhibitors, we have found the forth amino acid which was also involved. Through chemical binding of the forth amino acid, the inhibitory activity was further promoted.

碩士
國立中山大學
化學系研究所
104
Part I A direct ortho-aroylation of N-arylpyridin-2-amines with aldehydes to afford mono- and di-aroylated N-arylpyridin-2-amines in modest to good yields is presented. In the reaction, palladium(II) acetate, tert-butyl hydroperoxide (TBHP), and 1,4-dioxane were used as the catalyst, oxidant, and solvent, respectively. The synthetic methodology serves good functional group compatibility (Scheme a). A plausible mechanism of the catalytic C-H aroylation was suggested with the intermolecular and intramolecular experiments in Kinetic Isotope Effect and experiments in palladium intermediate with benzaldehydes. Based on our methodologies, another-catalyzed C-H bond activation method can be used to get Acridanone (Scheme b). Part II A direct arylation of pyrazolo[1,5-a]pyridines with aryl iodides selectively occurring at the C-3 and C-7 positions via palladium-catalyzed C−H activation is described. In these reactions, (a) cesium(I) fluoride and (b) silver(I) carbonate were employed as the additive to afford 3- and 7-arylated pyrazolo[1,5-a]pyridines, respectively, in modest to good yields. These reactions showed good compatibility with functional groups, and the catalytic mechanisms of these reactions were proposed. Finally, the synthetic application on the potent p38 kinase inhibitors was demonstrated.

Alzheimer’s disease represents about 60-80% of all cases of dementia, mainly affecting people over 65 years. This pathology is caracterizated at the molecular level by the presence of senile plaques (Aβ amyloid peptides aggregates) and neurofibrillary tangles (NFTs). In addition, several experimental studies have revealed that acetylcholinesterase (AChE) enzyme plays a crucial role in the development of Alzheimer’s disease, leading to the formation of NFTs and senile plaques. Oxidative stress is a cause and consequence of this pathology, activating signalling pathways that promote Aβ peptides aggregation, which in turn are detected by microglia cells, leading to the formation of free radicals, including NO• , which, in turn, contributes to the marked neuroinflammation in this pathology. In this context, the development of AChE inhibitors and antioxidants, namely as radical scavengers, continue to deserve attention from researchers. The aim of the present work was the synthesis, structural characterization (mono-( 1H and 13C) and two-dimensional (HMBC and HSQC) nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, high resolution mass spectrometry and x-ray) of (aryl)(furo [3,2-c] quinolin-2-yl)methanones, 3-(3-aryl4,5-dihydro-1H-pyrazol-5-yl)-4-chloroquinolines and, as exploratory approach, (E)-3-(2-hydroxyphenyl)-5-(4-methoxystyryl)isoxazole for the evaluation of AChE inhibitory activity and antiradical activity. The anticholinergic and antiradical activities of the synthesized compounds were evaluated using Ellman's method and radical scavenging assays for (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+• ) and NO• , respectively. Whenever possible, the obtained values were expressed as a function of the concentration of compound which promoted 50% of inhibition of enzymatic activity or promoted 50% of radicals scavenging (IC50), respectively, to establish some biological structural-activity relationships. (Aryl)(furo[3,2-c]quinolin-2-yl)methanones were not effective as antiradical agents, however two derivatives exhibited AChE inhibitory activities (IC50 < 100 µM). 3-(3-Aryl-4,5-dihydro-1H-pyrazol-5-yl)-4-chloroquinolines and (E)-3-(2- hydroxyphenyl)-5-(4-methoxystyryl)isoxazole were good ABTS+• scavenger agents but were not very effective in NO• scavenging, presenting for most derivatives IC50 > 700 µM. 3-(3-Aryl-4,5-dihydro-1H-pyrazol-5-yl)-4- chloroquinolines showed promising AChE inhibitory activities with most derivatives having IC50 < 100 µM, while (E)-3-(2-hydroxyphenyl)-5-(4- methoxystyryl)isoxazole was not very effective against this enzyme. These results showed that some of the synthesized compounds have potential as AChE inhibitors and antioxidant agents.
A doença de Alzheimer representa cerca de 60 a 80% dos casos de demência afetando principalmente indivíduos com idades superiores a 65 anos. Esta patologia é caracterizada, a nível molecular, pela presença de placas senis (agregados de péptidos de Aβ amilóide) e agregados neurofibrilares (NFTs). Além disso, diversos estudos experimentais têm revelado que a enzima acetilcolinesterase (AChE) participa no desenvolvimento desta patologia, culminando na formação de NFTs e placas senis. O stress oxidativo é uma causa e consequência desta patologia, ativando vias de sinalização que promovem a agregação dos péptidos Aβ, que por sua vez, são detetados pelas células da microglia, levando à produção de radicais livres incluindo óxido nítrico (NO• ) que, por sua vez, contribuem para a neuroinflamação marcada nesta patologia. Neste contexto, o desenvolvimento de inibidores da AChE e de antioxidantes, nomeadamente como agentes captadores desses radicais, continuam a merecer atenção por parte dos investigadores. O presente trabalho teve por objetivo a síntese, caracterização estrutural (espectroscopia de ressonância magnética nuclear (RMN) mono- ( 1H e 13C) e bidimensionais (HMBC e HSQC), espetrometria de massa, espetrometria de massa de alta resolução e raio-x) de (aril)(furo[3,2-c]quinolin-2-il)metanonas, 3- (3-aril-4,5-di-hidro-1H-pirazol-5-il)-4-cloroquinolinas e ,a título exploratório, de (E)-3-(2-hidroxifenil)-5-(4-metoxiestiril)isoxazol para avaliação da atividade inibitória da AChE e antiradicalar. As atividades anticolinérgicas e antiradicalar dos compostos sintetizados foram avaliadas recorrendo aos métodos de Ellman e de avaliação da capacidade de captação dos radicais (ácido 2,2'-azino-bis(3-etilbenzotiazolina-6-sulfónico) (ABTS+•) e NO• , respetivamente. Sempre que possível, os valores obtidos foram expressos em função da concentração de composto que promoveu a inibição de 50% da atividade enzimática ou que promoveu 50% de captação dos radicais (IC50), respetivamente, para serem estabelecidas algumas relações estruturaatividade biológica. As (aril)(furo[3,2-c]quinolin-2-il)metanonas não se mostraram efectivas como agentes antiradicalares, no entanto dois derivados exibiram atividades inbitórias da AChE (IC50 < 100 µM). As 3-(3-aril-4,5-di-hidro-1H-pirazol-5-il)-4- cloroquinolinas e o (E)-3-(2-hidroxifenil)-5-(4-metoxiestiril)isoxazol foram bons agentes captadores do ABTS+• no entanto não foram muito efetivos na captação do NO• , apresentando para a maior parte dos derivados IC50 > 700 µM. As 3-(3- aril-4,5-di-hidro-1H-pirazol-5-il)-4-cloroquinolinas apresentaram atividades inibitórias de AChE promissoras com maior parte dos derivados apresentando IC50 < 100 µM, enquanto o (E)-3-(2-hidroxifenil)-5-(4-metóxiestiril)isoxazol não foi muito efetivo contra esta enzima. Os resultados evidenciaram que alguns compostos sintetizados apresentaram potencial como inibidores da AChE e como agentes antioxidantes.
Mestrado em Bioquímica

Cette thèse décrit le développement et la méthodologie pour la synthèse de 2-pyrazolo[1,5-a]pyridines à partir d’ylures de N-iminopyridinium et d’halogénures de styryle. Des dérivés de chaque ylure de N-iminopyridinium et d’halogénures de styryle ont été utilisés pour la synthèse de plusieurs composés avec un intérêt pharmaceutique. Le premier chapitre présente les précédents littéraires pour la synthèse de pyrazolopyridines. Spécifiquement trois types différents de synthèse seront présentés en détail. L’importance biologique de ces composés sera discutée. La vue d’ensemble des travaux développés dans notre groupe de recherche pour la synthèse des produits de départ sera présentée brièvement. Finalement, la science intéressante qui a apporté cette idée de recherche sera révélée. Le deuxième chapitre décrit les résultats des optimisations étudiées pour la synthèse des 2-phénylpyrazolo[1,5-a]pyridines à partir d’ylures de N-benzoyl-iminopyridinium et d’iodure de styryle. Chaque substrat de la réaction a été étudié individuellement afin d’être optimisé; les ratios, les solvants, la température du milieu réactionnel et le temps optimal de la réaction ont aussi été explorés. Le troisième chapitre présente l’étendue de la synthèse des pyrazolopyridines. L’étendue de la réaction inclut les dérivés des halogénures de styryle. L’étendue de la réaction a été élargie aux dérivés d’ylures de N-iminopyridinium et ils incluent des groupements donneurs d’électrons ainsi que des groupements pauvres en électrons. Des groupements exotiques d’iodure et de bromure de vinyle ont aussi été explorés. Le quatrième chapitre démontre les études mécanistiques que l’on a faites pour mieux comprendre les cycles catalytiques qui ont lieu durant la réaction. Des études de cyclisation avec les ylures de N-iminopyridinium ont été explorées pour les produits de départ suivants : iodure de styryle et phényl acetylène.
This thesis describes the development of a methodology for the one-pot synthesis of 2-pyrazolo[1,5-a]pyridines from N-iminopyridinium ylide and styryl-halide starting materials. Both N-iminopyridinium ylide derivatives and styryl-halide derivatives were employed for the synthesis of various pharmaceutically interesting pyrazolo[1,5-a]pyridines. The first chapter presents the literature precedents for the synthesis of pyrazolopyridines. More specifically, three different types of syntheses will be shown in detail. Furthermore, the biological importance of these compounds will be discussed. An overview of the developed methodologies previously carried out in our research group for the synthesis of the starting materials will be presented. Finally, the copper-catalyzed direct alkenylation of N-iminopyridinium ylides that brought about this research idea will be discussed. The second chapter describes the results of the optimization studies for the synthesis of 2-phenyl pyrazolo[1,5-a]pyridines from N-benzoyliminopyridinium ylides and styryl iodides. Each component of the reaction was individually screened and the loading ratios were optimized: e.g., solvent and temperature. The third chapter presents the scope of the pyrazolopyridine synthesis. The scope includes styryl iodide, –bromide and –chloride derivatives. The scope of the reaction was extended to N-iminopyridinium ylide derivatives and included electron donating and electron withdrawing groups. Substituted vinyl iodides and bromides were also investigated. The fourth chapter demonstrates the mechanistic studies conducted in order to obtain an accurate understanding of the catalytic cycles taking place during the reaction. Cyclization studies were explored for both styryl iodides and phenyl acetylene starting materials reacted with N-iminopyridinium ylides.

Resveratrol, an activator of histone deacetylase Sirt-1, has been proposed to have beneficial health effects due to its antioxidant and anti-inflammatory properties. However, the mechanisms underlying the anti-inflammatory effects of resveratrol and the intracellular signaling pathways involved are poorly understood. An in vitro model of human tenocytes was used to examine the mechanism of resveratrol action on IL-1beta-mediated inflammatory signaling. Resveratrol suppressed IL-1beta-induced activation of NF-kappaB and PI3K in a dose- and time-dependent manner. Treatment with resveratrol enhanced the production of matrix components collagen types I and III, tenomodulin, and tenogenic transcription factor scleraxis, whereas it inhibited gene products involved in inflammation and apoptosis. IL-1beta-induced NF-kappaB and PI3K activation was inhibited by resveratrol or the inhibitors of PI3K (wortmannin), c-Src (PP1), and Akt (SH-5) through inhibition of IkappaB kinase, IkappaBalpha phosphorylation, and inhibition of nuclear translocation of NF-kappaB, suggesting that PI3K signaling pathway may be one of the signaling pathways inhibited by resveratrol to abrogate NF-kappaB activation. Inhibition of PI3K by wortmannin attenuated IL-1beta-induced Akt and p65 acetylation, suggesting that p65 is a downstream component of PI3K/Akt in these responses. The modulatory effects of resveratrol on IL-1beta-induced activation of NF-kappaB and PI3K were found to be mediated at least in part by the association between Sirt-1 and scleraxis and deacetylation of NF-kappaB and PI3K. Overall, these results demonstrate that activated Sirt-1 plays an essential role in the anti-inflammatory effects of resveratrol and this may be mediated at least in part through inhibition/deacetylation of PI3K and NF-kappaB.