Dissertations / Theses on the topic 'Privileged structure'

This thesis investigates a new proposal for a privileged ground state of a free scalar quantum field in arbitrary regions of spacetime. This Sorkin-Johnston (SJ) state, implicit in work by S. Johnston on quantum field theory on causal sets, is defined solely in terms of the spacetime causal structure and is unique in any globally hyperbolic spacetime region. The first part of the thesis contains an analysis of the simplest possible setting: a flat two-dimensional causal interval. The simplicity of the setup makes analytic calculations tractable and allows for some general features of the state to be better understood. The second part deals with an investigation of the SJ state in de Sitter space. It turns out to be possible to construct the state explicitly using limiting procedures, which provides further interesting insights. In particular, the state is found to depend on the spacetime dimension, field mass, and on the choice of subregion, differing in many cases from the usual 'Bunch-Davies' vacuum. The formalism does not select a unique state in spacetimes that are not globally hyperbolic, which include, among others, spacetimes exhibiting spatial topology change. These are relevant in the context of quantum gravity and in relation to the old question as to whether violent spacetime curvature fluctuations at Planckian scales can lead to changes in spatial topology, or whether such transitions are unphysical. Some efforts to understand the SJ state in the topology-changing two-dimensional 'trousers' spacetime are discussed in the final part of the thesis.

Pharmaceutical Sciences
Ph.D.
In drug discovery there are several approaches to lead generation and one traditional approach involves the synthesis and screening of a structurally diverse compound library against a number of biological targets to identify high affinity lead compounds. The use of a `privileged' structure-based compound library represents a viable approach that could lead to drug like lead compounds. Privileged structures are defined as those ligand substructures that may be used to generate high affinity leads for more than one type of receptor. Examples of privileged structures include phenyl substituted monocycles such as biphenyls, diphenyl methane derivatives, 1,4-dihydropyridines, fused ring systems such as chromones, quinoxalines, quinazolines, 2-benzoxazolones, indoles, benzimidazoles and benzofurans. There are several instances in the literature describing the development of compound libraries based on privileged structures with reportedly high hit rates. Privileged structure based approaches has been used with notable success in the identification of high affinity ligands especially for G-protein coupled receptors (GPCRs). The scaffold 2-aminothiazole (fused and non-fused) may be considered a privileged structure because of its occurrence in a wide variety of pharmaceuticals. The scaffold is found in antibacterials, anti-inflammatory agents, glutamate transporter (GLT-1) modulators, serotonin and muscarinic ligands. The present study involves the synthesis of a 2-aminothiazole (fused and non-fused) based compound library (60 compounds) by incorporating bioactive fragments shown to produce hits in the biological targets of interest. Microwave assisted organic synthesis (MAOS) has been employed at key steps of scaffold synthesis as well as in Suzuki coupling to generate the target aminothiazoles. Preliminary biological screening has resulted in the identification of some promising lead compounds. Trifluoromethoxy substituted aminothiazoles were found to be potent antimicrobials with MIC values in the range of 4-16 microgram/ml. Furanone based aminothiazoles showed affinity for muscarinic receptors. Piperidine based aminothiazoles showed greater than 90% of control (8-OH-DPAT) specific agonist response at the 5-HT1A receptor subtype. The Clog P values of the most potent antimicrobials were found to be in the range of 4.5-6.2 indicating the high lipophilicity of the compounds. High lipophilicity is known to cause solubility issues that may hamper future development. Therefore in an effort to make compounds with intermediate lipophilicity, the phenyl core of the potent aminothiazoles will be replaced with pyridine core using literature procedures (Pyridine core containing aminothiazoles showed Clog P < 4). Future plans include expanding the library, improving the yields of compounds and to evaluate the compounds as modulators of glutamate transporter (GLT-1). The work could be extended to include other privileged structures such as 2-aminooxazole, 2-aminobenzoxazole, 2-aminoimidazole and 2-aminobenzimidazole. These mono and bicyclic heterocyles may be considered bioisosteres of 2-aminothiazole.
Temple University--Theses

Thesis (Ph. D.)--Ohio State University, 2003.
Title from first page of PDF file. Document formatted into pages; contains xxiii, 249 p. : ill. Advisor: Robert W. Brueggemeier, College of Pharmacy. Includes bibliographical references (p. 234-249).

Les macrolides du résorcinol présentant une fonction cis-enone se sont révélés être de puissants et irréversibles inhibiteurs de protéines kinases, des enzymes impliquées dans toutes les transductions de signaux dont le dysfonctionnement est à l’origine de pathologies telles que le cancer, les inflammations ou les maladies neurodégénératives. Attiré par leur activité biologique, notre laboratoire a développé une voie synthétique pour ces composés, basée sur la technologie des tags fluorés. La première partie de ma thèse a consisté à appliquer cette synthèse à l’élaboration d’une chimiothèque de 51 macrocycles. Cette dernière a permis d’identifier deux modifications permettant d’accroître l’activité biologique : l’ajout d’un carbone supplémentaire dans le macrocycle et d’un groupement hydroxyl en position β du diol. La seconde partie de ma thèse a consisté à développer une voie de synthèse générale permettant d’accéder à divers membres d’une autre classe de puissants inhibiteurs irréversibles : les lactones sesquiterpéniques. Ces composés présentent un large spectre de propriétés biologiques comme des propriétés cytotoxiques, anti-tumorales et anti-inflammatoires. Malheureusement la plupart des cibles biologiques et mécanismes associés à ces propriétés n’ont pas encore été identifiés. La voie de synthèse élaborée, basée sur un intermédiaire central bicyclique simple accessible en 13 étapes (avec pour étape clé une métathèse domino d’enyne) et inspirée de la biosynthèse, devrait permettre de développer des « composés outils » pour lever ces interrogations. Cette synthèse a notamment pu être appliquée à la préparation des molécules naturelles geigérine et 6-deoxy-geigérine
The resorcylic acid lactones bearing a cis-enone functionality proved to be potent and irreversible inhibitors of protein kinases, a class of enzymes implicated in every transduction pathways whose dysfunction is at the origin of pathologies ranging from oncology to inflammation and neurodegenerative diseases. Attracted by their important biological activity, our laboratory developed a synthetic pathway to these pharmacophores, based on the fluorous tags technology. The first part of my thesis consisted in applying this synthesis to the elaboration of a library of 51 macrocycles. This library allowed to identify two modifications as increasing the biological activity : the introduction of an extra carbon in the macrocycle and of a hydroxyl group in β position of the diol. The second part of my thesis consisted in developing a general synthetic pathway to access various members of another class of potent irreversible inhibitors : the sesquiterpene lactones. These compounds exibit a wide spectrum of biological activity including cytotoxic, anti-tumor and anti-inflammatory properties. Unfortunately most of the targets and mode of action associated with these properties have not been identified yet. The synthetic pathway developed, based on a simple central bicyclic intermediate achievable in 13 steps (with the key step being a domino enyne metathesis) and inspired by the biogenesis, should allow the development of "tool compounds" to address these questions. This synthesis has been applied in particular to the preparation of the natural products geigerin and 6-deoxy-geigerin

This thesis explores the lives and works of Carlo Gozzi and Carlo Goldoni. Specific emphasis is placed on their feud, positions in society, the motivations behind their theatrical styles, and the ways they used theatre to either attempt to maintain the status quo (Gozzi) or strive for social change (Goldoni). Contrary to previous studies, this study suggests that Goldoni tried to influence the world around him, rather than merely reflect it. This study examines the above through the lens of several twentieth century theories including semiotics, structuralism, and the avante-garde. The contents of this work are essential to anyone seeking biographical information, doing dramaturgical research or producing one of their plays, and those investigating the ways theatre has been used to incite change and create an atmosphere of social equity. This work demonstrates that theatre can, has been, and should be actively used to influence that change.

This work was conducted to evaluate the activity anti-inflammatory and antinocieptive two series of derivatives of N-acilidrazonas (NAH) rationally designed and synthesized by LASSBio® UFRJ. The first series consists of four compounds, being two metal complexes generated from the coordination of prototypes LASSBio-1064 and LASSBio-466 and second prototype LASSBio-1064 and LASSBio-466. The second series comprised eight derivatives, designed as structural analogues of piroxicam. Were performed nociception models of functional chemical (writhing induced by acetic acid 0.1 N, formalin test), thermal nociception (hot plate test), cell migration assay (peritonitis induced by zymosan A and / or induced by carrageenin) assay evaluation of inhibition of COX-1/COX-2. All compounds and standards were administered 40 min before starting the test (p.o) at a dose of 100 mmol / kg. In the first series, Animal constriction induced by acetic acid was inhibited by all the compounds studied, highlighting the [Zn(LASSBio-466)H2O]2 and H2LASSBio-1064 that inhibited (p˂0.01) at 82.7 % (p˂0.01) and 81.3% (p˂0.01) the number of writhes, as the standard drug (dipyrone) inhibited 77.7% (p˂0.01). In the first phase of the formalin test H2LASSBio-466 and H2LASSBio-1064 reduced the latency time to lick 53.1% (p ˂ 0.05) and 46.5% (p˂0.01), respectively. In the second phase of the test compounds H2LASSBio-1064 and [Zn(LASSBio-466)H2O]2 reduced the latency time to lick at 48.5% (p˂0.05) and 37.3% (p˂0.05), respectively. All compounds showed levels of inhibition of peritonitis induced by zymosan comparable or superior to indomethacin (drug standard). In the second series, the compounds were active in the assay of writhing induced by acetic acid highlighting the LASSBio-1638, LASSBio-1604 and LASSBio-1639 inhibited the contortions that abdmoniais in 84.0% (p˂0.01), 82.7% (p˂ 0.01) and 90.4% (p˂ 0.01), respectively, whereas piroxicam (drug standard), inhibited by 95.4% (p˂0.01) . In the formalin test, only LASSBio-1617 significantly inhibited the nociceptive activity in the first stage by 58.2% (p<0.01). In the second phase the LASSBio-1637, LASSBio-1638 inhibited the nociceptive activity in 60.0% (p<0.05) and 54.2% (p<0.05), respectively, and piroxicam inhibited 53.9 % (p<0.01). In models of acute inflammation, the compounds showed inhibitory activity against cell migration similar to or greater than the piroxicam. In the trial of carrageenan-induced acute peritonitis compounds LASSBio-1604LASSBio-1637, LASSBio-1638 and LASSBio-1639 inhibited cell migration by 74.2% (p˂ 0.01), 73.2% (p˂0.01), 77.6% (p˂ 0.01) and 81.8% (p ˂ 0.01), respectively, where as piroxicam inhibited by 25.5% (p˂0.01). The compounds LASSBio-1637, LASSBio-1638-1639 and LASSBio highlighted in the testing of acute peritonitis induced by zymosan A, inhibiting cell migration in 78.6% (p˂0.01), 81.2% (p ˂ 0.01) and 82.7% (p ˂ 0.01), showing that, in this essay, more active than piroxicam (57.3%). LASSBio-1604 and LASSBio-1617 inhibited the enzyme COX in vitro, presenting, respectively, IC50 values of 0.22 M and 0.28 M for inhibition of COX-1 and 0.24 M and 0.26 M for inhibition of COX-2. Pharmacological Evaluation results suggest that in the first series, the coordination of zinc (II) is a good strategy to improve the antinociceptive activity of the compound H2LASSBio-466 associated with inflammatory pain, and in the second series, all compounds exhibit antinociceptive and anti-inflammatory similar or superior to piroxicam.
Neste trabalho foi realizado a avaliação da atividade antinocieptiva e anti-inflamatória de duas séries de derivados N-acilidrazonas (NAH) racionalmente planejadas e sintetizados pelo LASSBio® da UFRJ. A primeira serie é formada de 4 compostos, sendo 2 complexos metálicos gerados a partir da coordenação dos protótipos LASSBio-466 e LASSBio-1064 e 2 protótipos LASSBio-466 e LASSBio-1064. A segunda série formada por 8 derivados, desenhados como análogos estruturais do piroxicam. Foram realizados modelos funcionais de nocicepção química (contorção abdominal induzida por ácido acético 0,1N, ensaio de formalina), nocicepção térmica (ensaio da placa quente), ensaio de migração celular (peritonite induzido por zymosan A e/ou induzido por carragenina) ensaio de avaliação de inibição da COX-1/COX-2. Todos os compostos e padrões foram administrados 40 min antes do início ensaio (vo) na dose de 100 μmol/kg. Na primeira série, a constrição animal induzida por ácido acético foi inibida por todos os compostos estudados, destacando-se o [Zn(LASSBio-466)H2O]2 e H2LASSBio-1064 que inibiram (p˂0,01) em 82,7% (p˂0,01) e 81,3% (p˂0,01) o numero de contorções, enquanto o fármaco-padrão (dipirona) inibiu em 77,7% (p˂0,01). Na primeira fase do ensaio de formalina o H2LASSBio-1064 e H2LASSBio-466 reduziram o tempo de latência de lambida em 53,1% (p˂0,05) e 46,5% p˂0,01), respectivamente. Já na segunda fase do ensaio os compostos H2LASSBio-1064 e [Zn(LASSBio-466) H2O]2 reduziram o tempo de latência de lambida em em 48,5% (p˂0,05) e 37,3% (p˂0,05), respectivamente. Todos os compostos mostraram níveis de inibição da peritonite induzida por zymosan comparáveis ou superiores à indometacina (fármaco padrão). Na segunda série, os compostos mostraram-se ativas no ensaio de contorções abdominais induzida por acido acético destacando-se o LASSBio-1638, LASSBio-1639 e LASSBio-1604 que inibiram as contorções abdmoniais em 84,0% (p˂0,01), 82,7% (p˂0,01) e 90,4% (p˂0,01), respectivamente, ao passo que o piroxicam (fármaco padrão) inibiu em 95,4% (p˂0,01). No teste de formalina, apenas LASSBio-1617 inibiu significativamente a atividade nociceptiva na primeira fase em 58,2% (p <0,01). Na segunda fase o LASSBio-1637, LASSBio-1638 inibiram a atividade nociceptiva em 60,0% (p <0,05), e 54,2% (p <0,05), respectivamente, e o piroxicam inibiu em 53,9% (p <0,01). Em modelos de inflamação aguda, os compostos apresentaram atividade inibitória sobre a migração celular semelhante ou maior que o piroxicam. No ensaio de peritonite aguda induzida por carragenina os compostos LASSBio-1604, LASSBio-1637, LASSBio-1638 e LASSBio-1639 inibiram a migração celular em 74,2% (p˂0,01), 73,2% (p˂0,01), 77,6% (p˂0,01) e 81,8% (p˂0,01), respectivamente, ao passo que o piroxicam inibiu 25,5% (p˂0,01). Os compostos LASSBio-1637, LASSBio-1638 e LASSBio-1639 destacaram-se no ensaio de peritonite aguda induzida por zymosan A, inibindo a migração celular em 78,6% (p˂0,01), 81,2% (p˂0,01) e 82,7% (p˂0,01), mostrando-se, nesse ensaio, mais ativos que o piroxicam (57,3%). LASSBio-1604 e LASSBio-1617 inibiram a enzima COX in vitro, apresentando, respectivamente, valores de CI50 de 0,22 M e 0,28 M para inibição de COX-1 e 0,24 M e 0,26 M para inibição de COX-2. Os resultados da avaliação farmacológica sugerem que, na primeira série, a coordenação do zinco (II) é uma boa estratégia para melhorar a atividade antinociceptiva do composto H2LASSBio-466 associada a dor inflamatória, e na segunda série, que todos compostos apresentam atividades antinociceptiva e anti-inflamatória semelhantes ou superiores ao piroxicam.

Polypharmacology-based strategies are gaining ever-increasing attention as useful approaches to develop disease-modifying drug candidates for effective Alzheimer’s disease (AD) treatment. In this scenario, multitarget-directed ligands could increase efficiency by simultaneous modulation of several targets involved in AD pathogenesis. In drug discovery, natural products (NPs) represent an excellent source of evolutionary-chosen “privileged structures”. In this thesis, the polyphenol curcumin, found in Curcuma longa L, encompassing the essential structural elements for the concurrent inhibition of two validated AD targets, BACE-1 and GSK-3β, was rationally identified as lead compound. Aimed at developing well-balanced dual BACE-1/GSK-3β modulators with good BBB permeability, different series of curcumin-based derivatives were designed and synthetized by introducing suitable chemical modifications on the side aryl ring(s) and in the 4-position of the main scaffold. Furthermore, considering the pivotal role of the intramolecular H-bond network of curcumin’s central fragment in establishing appropriate interactions with target binding sites, several complexation and bioisosteric cyclization strategies were performed. Thanks to its strong Michael acceptor reactivity toward critical cysteine residues, curcumin exerts neuroprotection by additional activation of the Keap1-Nrf2-ARE signaling pathway. Thus, aimed at affecting the electrophilicity of its α,β-unsaturated carbonyl fragment, allowing a fine-tuning of its reactivity, diverse electrophilic functions were inserted in different positions of the curcumin scaffold. Furthermore, considering the neuroprotective and antioxidant potentials of simple coumarins, several curcumin-coumarin hybrids were also prepared. Recently, the inhibition of additional AD-correlated protein kinases (PKs), such as CK1 and LRRK2, could offer promises to achieve a successful treatment and indole was envisaged as useful scaffold for both PKs’ inhibition. Thus, a small library of indole-based derivatives was designed and synthetized as valuable BBB permeable pharmacological tools. Finally, chitosan (CS), a natural, nontoxic, biocompatible and biodegradable polysaccharide, was selected to develop CS-based bioconjugates for nanoparticles’ preparation as innovative drug delivery and targeting systems.

This thesis addresses the question of how structural and perceived privilege impact on political participation in the United Kingdom. In doing so it adopts the causal propositions of the Civic Voluntarism Model as its starting point and adds Pierre Bourdieu’s concepts of economic, social, and cultural capital, which are argued to encompass structural privilege. Perception of privilege is posited to be constituted by self-perceived status, explanations for that status, and explanations for status differences in society. Subsequent politically relevant components are perceptions of the difference and privilege of politically active people. Thus, the thesis proposes a model running from background characteristics through capital profiles to perception of privilege and thence political engagement and participation. An original survey covering these areas was designed and fielded online to a representative sample of 1,480 British adults. The resultant data is analysed using structural equation modelling, which allows for the simultaneous estimation of underlying tendencies and the structural relationship between them. The results of that model generally support the causal hypotheses of the research, as well as providing evidence of the impact of the three forms of capital and perception of privilege. In particular, a strong positive effect of legitimate cultural capital is observed and found to be more important in influencing political participation than the previously observed effects of social and economic capital. In addition, perception of privilege is found to promote participation and to channel people towards individualised political activities, especially where they subscribe to the fundamental attribution error. These effects are as hypothesised and confirm the role of both structural and perceived privilege in influencing political participation in the United Kingdom.

In this thesis I examine the contemporary nexus between White women and the raced and classed institution of White womanhood. More specifically, I focus on White Australian women who are middle class, rich in cultural capital, and generally consider themselves to be progressive; that is race privileged women but women who are not usually associated with overt racism. My analysis unfolds White Australian women in the discursive context of the ideologies of feminism and feminist-influenced anti-racist politics, as well as the ideologies of femininity. The thesis shows how this nexus is enacted through a vision of White women as Good as expressed in the political commitments, mentalities, relationships, narratives and corporeality of such women. The research problem that I identified and worked through in the thesis is as follows: for middle class White women, (who can be seen and see themselves as generic 'women'), Whiteness has been seen and played out as Goodness. Further, in the playing out of this Goodness White women accumulate and defend the prestige and privileges of Whiteness. Specifically, I argue that Whiteness is reproduced in some of the discourses and practices of White feminism, by the progressive White women involved in anti-racist politics, and in the femininity industry and the ways it is taken up. The nub of the problem I identify is that White women's involvement in the structures and narratives that support Whiteness is often grounded in the very qualities of character and conduct that emerge from the colonial and class-constructed ideal of White womanhood and which have historically distinguished them from denigrated others. These qualities- notably virtue, innocence and self-restraint- whilst differently nuanced in other contexts are an ongoing expression of the uses made of White womanhood as the visible sign of race and class superiority. The work examines four key periods: the Australian colony of PNG during the decolonising 1960's and 1970's; the high years of 1970's and 1980's feminism; the race debates of the 1990's; and the bodily practices of present day White women gripped by fears of fat and aging. I explore the ways in which White women's Whiteness is played out in benevolent Black/White relationships, the over-reach of difference feminism, particular kinds of anti-racist identities and activism, and body-improvement practices. In all these cultural sites, White women's Whiteness is often represented as a kind of moral being and deployed as moral authority in ways that are consonant with the raced and classed construction of White women as moral texts. My research approach was determined by the research problem I identified. Given my argument that White women mis-recognise Whiteness as Goodness in a race-structured society, then the collecting of data through interviews or surveys would have yielded material subject to this blindness. Instead, I explored sites and material where moral claims were being pressed, and case studies where 'women' were enacting themselves or being represented or interpellated as moral texts. My selection of primary source material ranges from feminist newsletters, women's and other magazines, literature, film, event programs and flyers, radio and television broadcasts, newspapers and websites, as well as reflections on my own experiences. Secondary source material includes feminist theoretical texts as well as texts drawn from a range of other disciplines, and other historical background materials. I lay out and support my arguments using a technique not dissimilar to collage, aiming to construct a picture that is compelling in its detail as well as coherent in its overall effect. This thesis is a contribution to the de-naturalisation of Whiteness. Navigating a course between the opposing hazards of essentialising Whiteness and understating its effects in contemporary Australian society, I have brought into clearer view some of the strategies which maintain the authority of Whiteness.

Les pyrrolodiazépinones ont des activités biologiques intéressantes sur différents récepteurs biologiques, ce qui en font une cible de choix pour développer de nouvelles petites molécules biologiquement actives. Une méthodologie en solution a été développée pour synthétiser des pyrrolo[3,2-e][1,4]diazépin-2-ones, qui utilise la réaction de Pictet-Spengler pour former le cycle diazépinone, comme réaction clé. Il a été démontré que le pyrrolo[3,2-e][1,4]diazépin-2-one mime un tour-γ inverse par l’analyse de cristaux par rayon X. Cette méthodologie a été transposée sur trois types de support, soit la résine de Merrifield, de Wang et un support soluble (TAP). Le système urotensinergétique joue un rôle dans certaines pathologies du système cardiovasculaire, comme l’hypertension artérielle, l’insuffisance cardiaque et l’athérosclérose. Le système urotensinergétique est exprimé dans le système circulatoire, extractoire et le système nerveux central et comprend l’UII, l’URP et le récepteur UT. L’UII et l’URP humains sont composés respectivement des séquences d’acides aminés : H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH et H-Ala-c[Cys-Phe-Trp-LysTyr-Cys]-Val-OH. L’UII est le peptide vasoconstricteur le plus puissant connu à ce jour, dont l’URP est son isoforme. Les deux peptides ont des effets biologiques différents et on peut supposer qu’ils jouent un rôle distinct dans certaines pathologies. Il a été démontré que la partie active de l’UII est composée du tripeptide : Trp-Lys-Tyr. Dans l’URP, il a été démontré que ce tripeptide forme un tour-γ inverse, ce qui fait du récepteur UT une bonne cible biologique pour tester une librairie de pyrrolo[3,2-e][1,4]diazépin-2-ones, reprenant le tripeptide Trp-Lys-Tyr. Dernièrement, l’équipe du professeur David Chatenet a mis au point un peptide, l’urocontrin en remplaçant le segment Trp par un groupement biphénylalanine, qui a démontré un comportement spécifique comme antagoniste du récepteur UT. La Librairie de pyrrolo[3,2-e][1,4]diazépin-2-ones est basée sur la séquence TrpLys-Tyr de l’UII et de l’URP et de la séquence Trp-Lys-Bip de l’urocontrin. La synthèse de la librairie est faite sur la résine de Wang. La chaîne latérale de Tyr est mimée en utilisant la tyramine, Lys et Orn sont utilisés et la chaîne latérale de Trp a été reproduite II en utilisant le biphényle (comme dans l’urocontrin), le 1-naphthyle et le 2-naphthyle, sont introduits en employant les aldéhydes respectifs dans la réaction de Pictet-Spengler, ce qui donne les pyrrolo[3,2-e][1,4]diazépin-2-ones insaturés et les saturés S- et R-. L’évaluation de l’activité biologique des pyrrolo[3,2-e][1,4]diazépin-2-ones obtenues sur le récepteur UT se fait par des tests in vitro et ex vivo. Les tests in vitro consistent en un essai de liaisons sur des cellules CHO exprimant le récepteur UT en employant hUII-125I, comme contrôle radiomarqé. Les tests ex vivo sont effectués sur des aortes de rats pour mesurer la capacité à induire des contractions ou de moduler les contractions induites par hUII et URP. Certains R-pyrrolo[3,2-e][1,4]diazépin-2-ones causent une réduction de 50% du signal radioactivité du hUII-125I. Les pyrrolo[3,2-e][1,4]diazépin-2-ones ne montrent guère d’activité ex vivo, mais ils ont la capacité de moduler les contractions induites par l’hUII et l’URP. Par exemple, l’analogue Lys R-saturé avec le biphényle inhibe toutes les contractions de l’aorte à 14 µM avec un pKb de 5,54 à 4 µM, sans influencer les contractions de l’aorte induites par l’URP. Les pyrrolo[3,2-e][1,4]diazépin-2-ones ont une sélectivité pour le système urotensinergétique et sont inactifs sur le récepteur de l’endotheline-1. Les pyrrolo[3,2-e][1,4]diazépin-2-ones sont les premières petites molécules qui peuvent moduler l’activité biologique de l’UII et URP et offrir un potentiel intéressant comme outil pour étudier le système urotensinergétique.
The pyrrolodiazepinones have interesting biological activities on various biological receptors, which makes them a prime target for developing new biologically active small molecules. A methodology in solution had been developed for synthesizing pyrrolo[3,2-e][1,4]diazepin-2-ones, which utilized the Pictet-Spengler condensation as the key reaction to form the diazepinone ring. Pyrrolo[3,2-e][1,4]diazepin-2-ones were found to mimic an inverse γ-turn conformation by X-ray crystallographic analysis. The methodology was subsequently implemented on three types of support: Merrifield resin, Wang resin and the soluble TAP support. The urotensinergic system plays a role in certain diseases of the cardiovascular system, such as hypertension, heart failure and atherosclerosis. The urotensinergic system is expressed in the circulatory system, excretory and central nervous systems and includes the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP), and the urotensin receptor UT. The ligands UII and human URP are composed of the respective amino acid sequences: H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH and H-Ala-c[Cys-Phe-Lys-Tyr-Trp-Cys]-Val-OH. The peptide UII is the most potent vasoconstrictor known to date. The two peptides have different biological effects and may exhibit distinct roles in certain diseases. Their common Trp-Lys-Tyr sequence is believed to play an important role in the activity of UII and URP, and has been suggested to adopt an inverse γ-turn conformation. Notably, the laboratory of Professor David Chatenet developed the UT receptor antagonist peptide urocontrin by replacing the Trp residue by biphenylalanine (Bip) in URP. A library of pyrrolo[3,2-e][1,4]diazepin-2-one analogs was thus designed to mimic the inverse γ-turn sequence and targeted against UT. The pyrrolo[3,2-e][1,4]diazepin-2-one library was designed based on the Trp-Lys-Tyr sequence of UII and URP, and Trp-Lys-Bip sequence of urocontrin. The synthesis of the pyrrolo[3,2-e][1,4]diazepin-2-one library was achieved on Wang resin. The side chain of Tyr was mimicked using tyramine, Lys and Orn were used as the basic amino acid component, and the side chain of Trp was replicated using biphenyl (as in urocontrin) 1-naphthyl and 2-naphthyl groups that were introduced by employing their respective aldehydes in a Pictet-Spengler reaction, which furnished unsaturated and saturated S- and R-pyrrolo[3,2-e][1,4]diazepin-2-ones. Evaluation of the biological activity of the pyrrolo[3,2-e][1,4]diazepin-2-ones on the UT receptor was performed in vitro and ex vivo. Tests in vitro measured binding in CHO-cells which expressed UT by employing hUII-125I as radiolabeled control. In rat aorta, ex vivo tests measured capacity to induce contraction, or modulate the contractions induced by hUII and URP. Certain R-pyrrolo[3,2-e][1,4]diazepin-2-ones caused an up to 50% reduction of the radioactive signal of hUII-125I. Pyrrolo[3,2-e][1,4]diazepin-2-ones exhibited little activity ex vivo; however, they modulated contractions induced by hUII and URP. For example, the saturated R-analog possessing lysine and a biphenyl side chain inhibited completely hUII-induced contractions of the aorta at 14 µM with a pKb of 5.54 at 4 µM, without influencing URP-induced contractions. Pyrrolo[3,2-e][1,4]diazepin-2-ones were selective for the urotensinergic system and inactive on the related receptor endothelin-1. Pyrrolo[3,2-e][1,4]diazepin-2-ones represent the first small molecules that can differently modulate the biological activities of UII and URP, and offer interesting potential as tools for studying the urotensinergic system.

碩士
國立臺北科技大學
建築與都市設計研究所
101
The Urban Renewal Act stipulates: The defined rights and related, according to delimiting division, can exercises the approval power in stage; The rights and related can obtain letter of consent beyond a proportional threshold in order to handle and implement the urban renewal project, and to enforce the public interest in the delimiting division. Because the endeavor is mostly based on majority decision and, under the promotion of governmental officers, it has become the mainstream for land development in the Northern metropolis area. The Taipei Metropolis Renewal Bureau survey revealed that the rights and related generally have “three NOs” anxiety toward the renewal project. There are: 1. Trust for developers “does not exist”, 2. condition for each individual resident agreement “is not transparent”, 3. rights for investing sponsor “is indefinite”; Therefore, anxiety on “three Nos” does interfere the exercise of approval power behavior. This will retard the acquisition for the needed approval power threshold, and delay the urban renewal development. This research will focus on the renewal cases submitted on voluntarily basis. The main interest is to explore the behavior anxiety for the rights and related in the process of acquiring letters of consent. The heuristic structure theory will be applied to study the behavior pattern for exercising consent privilege of the rights and related. The research findings not only will help reduce the dispute and shorten the development time but also provide cases for future reference.

The author valorizes also his practical experiences of a left-oriented politician and first results from sociological research has set an objective to check two hypotheses: 1) that in the conditions of global capitalism development to save and fully revitalize the social state in his conception of a factor that is not only mitigating urgent social inequalities, but also raise the society and cultivates the human being, 2) that in the process of capitalist crises and the crises of a social state, senior citizens living from their pensions belong to the most threatened social groups. Methodologically the author claims to belong to modern Marxism and critically demarcate himself both from stalinism as well as from the recent official ideology, above all neoliberalism. The author refuses also the attempts to equate Marxism and the policy of KSČM to the ideology of the past governing class of controlling apparatus and comprehend the KSČM as a party disguised as Stalinist, anti human and non-democratic and in agreement with the program of this party that it represent in the Parliament of Czech Republic belongs to the self- managed socialism as a long-term objective of a societal transformation. As far as the method is concerned, in the view of a certain interdisciplinarity of the present publication, the...

The key challenge to socio-economic transformation in South Africa is closing the gap between the poor and the rich. What is distinctive about South Africa is the uneasy coexistence of poverty and opulence. This study seeks to explore the structural, historical roots of poverty among the blacks in South Africa by deploying Fanonian Critical Decolonial theory. This is the ideal theoretical approach to unmask the structural causes of poverty and inequality in South Africa. Colonial ambitions and the global political engineering of the world by America and Europe spans more than four hundred years, and is still very much alive today in subtle forms. This study asserts that this imperial history is the cause of poverty, lack of agency, and the hellish conditions under which many black people live. The rise of industrial capitalism and attendant urbanisation is at the core of this impoverishment of the black man. It is also shown that, once impoverished, the black man’s poverty gathers its own momentum, leading to more poverty that is then handed down to succeeding generations. Contrary to Eurocentric theorising, the study shows that blacks are not ‘problem’ people but people with problems, who, instead of being condemned, should be regarded with sympathy. This research thesis focuses on Alexandra Township and Sandton as symbols of poverty and privilege, respectively. The former represents Fanon’s zone of non-being where life is lived in conditions of want and poverty, whilst the latter represents the zone of being characterised by good living and prosperity. The thesis will demonstrate the fact that these anomalous socio-economic disparities are not natural but man-made, and therefore require the action of human beings to correct them.
Development Studies
M.A. (Development Studies)

abstract: This paper is seeking to use exploratory factor analysis to construct a numeric representation of Hill Collin's matrix of domination. According to Hill Collins, the Current American matrix of domination, or the interlocking systems of oppression, includes race, gender, class, sexual orientation, religion, immigration status, disability, and age. The study uses exploratory factor analysis to construct a matrix of domination scale. The study launched an on-line survey (n=448) that was circulated through the social network Facebook to collect data. Factor analysis revealed that the constructed matrix of domination represents an accurate description of the current social hierarchy in the United States. Also, the constructed matrix of domination was an accurate predictor of the probability of experiencing domestic abuse according to the current available statistics.
Dissertation/Thesis
M.A. Social Justice and Human Rights 2011