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Leung, Pui-hong, and 梁沛康. "Structural activity relationship of flavonoids on the expression and activity of cyclooxygenase." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42712129.
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Leung, Pui-hong. "Structural activity relationship of flavonoids on the expression and activity of cyclooxygenase." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B42712129.
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張凱德 and Hoi-tak Cheung. "Structural activity relationship of flavonoids on endothelial nitric oxide expression." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40733671.
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Cheung, Hoi-tak. "Structural activity relationship of flavonoids on endothelial nitric oxide expression." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40733671.
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Tan, Mengmeng. "Structural optimization of polypod-like structured DNA based on structural analysis and interaction with cells." Kyoto University, 2020. http://hdl.handle.net/2433/253233.
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Basu, Rathin. "An analysis of the relationship between sectoral activity, diversification, and structural change in the economy." Diss., This resource online, 1990. http://scholar.lib.vt.edu/theses/available/etd-09162005-115007/.
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Xing, Li. "Non-enveloped virus infection probed with host cellular molecules : a structural study /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-289-2.
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Al-Dbass, Abeer M. "Structural basis of acute intermittent porphyria and the relationship between mutations in human porphobilinogen deaminase and enzyme activity." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390590.
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Haslem, Elizabeth Bailey. "The Relationship Between Health-Related Fitness Knowledge, Perceived Competence, Self-Determination, and Physical Activity Behaviors of High School Students." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/4386.
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The purpose of this study was (a) to test a hypothesized model of motivation grounded in the Self-Determination Theory within the context of conceptual physical education (CPE), and (b) to explore the strength and directionality of perceived competence for physical activity as a possible mediator for health-related fitness knowledge and actual physical activity behaviors. Participants were 280 high school students who were at the end of a CPE course. Participants completed the Behavioural Regulation in Exercise Questionnaire–2, the Godin Leisure–Time Exercise Questionnaire, the Perceived Competence Scale, and a Health-Related Fitness Knowledge Questionnaire. Structural equation modeling analysis was used to explore the relationships between the variables of health-related fitness knowledge, perceived competence, motivation, and physical activity. The analysis resulted in a modified model that showed a relationship between perceived competence and physical activity, mediated by introjected and identified regulation. Implications and recommendations for physical education professionals are made.
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Bonano, Julie S. "Structural Determinants of Abuse-Related Neurochemical and Behavioral Effects of Para-Substituted Methcathinone Analogs in Rats." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3911.
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Methcathinone (MCAT) is the β-ketone analog of methamphetamine, and like its amphetamine analog, MCAT functions as a monoamine releaser that selectively promotes the release of dopamine (DA) and norepinephrine (NE) over serotonin (5-HT). MCAT produces amphetamine-like psychostimulant effects and is classified as a Schedule I drug of abuse by the United States Drug Enforcement Administration (DEA). Recently, synthetic MCAT analogs have emerged as designer drugs of abuse in Europe and the United States and have been marketed under deceptively benign names like “bath salts” in an attempt to evade legal restriction. These dangerous, recently emergent and novel drugs of abuse display varying selectivity to promote release of DA/NE vs. 5-HT, and selectivity for DA neurotransmission is believed to correlate with abuse liability. The goal of this dissertation was to conduct preclinical research to examine structural determinants of abuse-related behavioral and neurochemical effects produced by a series of synthetic MCAT analogs. Specifically, this project focused on one feature of the methcathinone scaffold: the para substituent of the benzene ring. A series of six novel MCAT analogs will be examined to evaluate how physicochemical parameters (steric, Es; electronic, σp; lipophilic, πp) of the para substituent influence in vitro monoamine transporter selectivity as well as in vivo neurochemical and behavioral effects. Results from this body of work implicate steric factors as being particularly important in determining a compound’s abuse-related neurochemical and behavioral effects. Thus, these data not only offer an improved understanding of the mechanism of abuse-related drug effects produced by synthetic MCAT analogs, but also help in the generation of homology models of the human DA and 5-HT transporters (DAT and SERT, respectively).
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Ayass, Wassim W. [Verfasser], Ulrich [Akademischer Betreuer] Kortz, Ulrich [Gutachter] Kortz, Thomas [Gutachter] Nugent, Imre [Gutachter] Tóth, and Helge [Gutachter] Jaensch. "Structure-Activity Relationship of Polyoxopalladates as Hydrogenation Catalysts & Synthesis and Structural Characterization of Thallium-Containing Polyoxometalates / Wassim W. Ayass ; Gutachter: Ulrich Kortz, Thomas Nugent, Imre Tóth, Helge Jaensch ; Betreuer: Ulrich Kortz." Bremen : IRC-Library, Information Resource Center der Jacobs University Bremen, 2018. http://d-nb.info/1153607301/34.
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Abdallah, Bassim Violla. "Structural and functional analysis on GacS homodimeric histidine kinase reveals a non-canonical autokinase activity and new insights into the heterodimer partnership with RetS." Thesis, Aix-Marseille, 2020. http://www.theses.fr/2020AIXM0256.
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Pseudomonas aeruginosa (PA) est un pathogène qui infecte particulièrement les patients atteints de la mucoviscidose. PA provoque des infections aiguës et chroniques et alterne entre des modes de vie planctonique et sédentaire. Cette transition est principalement régulée par les systèmes à deux composants (TCS). Durant ma thèse, je me suis focalisée sur le TCS GacS/GacA, impliqué dans un réseau de signalisation multikinase. GacS est une histidine kinase (HK) et GacA est son régulateur de réponse (RR). La région cytoplasmique de GacS est composée des domaines HAMP, S-Hélice, H1, D1 et H2. Des tests fonctionnels ont montré que la région HAMP/S-Hélice est nécessaire pour la transduction du signal et contribue à son activité. L’analyse structurale a montré une boucle de fixation de l’ATP structurée contrairement à ce qui est observé dans d'autres HKs. De plus, un nouveau domaine (ND) a été identifié et s’est révélé essentiel pour assurer une activité autokinase. Nous avons proposé que le ND contribue à des changements conformationnels pour placer GacS dans une configuration active. Par ailleurs, RetS HK inhibe GacS par des interactions directes. Des tests de spectrométrie de masse native et des tests d’interaction ont montré que le domaine HAMP est nécessaire pour assurer l'interaction entre ces HKs. De plus, des anticorps à domaine unique contre GacS nous ont permis d’identifier des sites potentiels d'inhibition de la voie GacS/GacA et de la formation de biofilm. Dans cette étude, nous avons dévoilé une activité autokinase non canonique de GacS et de nouvelles perspectives sur son interaction avec RetS qui contribuent au processus décisionnel pendant l'infection par PA<br>Pseudomonas aeruginosa (PA) is a pathogen that particularly infects patients with cystic fibrosis. PA causes acute and chronic infections and can switch from a planktonic to a sedentary lifestyle. This transition is mainly coordinated by Two-Component Systems (TCS). During my thesis, I focused on GacS/GacA TCS, a master regulator of the acute-to-chronic transition. In fact, GacS is a membrane-bound histidine kinase (HK) and GacA is the response regulator (RR). GacS cytoplasmic region is composed by the HAMP, S-Helix coiled-coil region. This helical part is followed by the H1, the D1 and H2 domains. GacS/GacA TCS is involved in a multikinase regulatory network and its activity is modulated by three HKs. Mutagenesis and functional assays showed that the HAMP and S-Helix orchestrate the signal transduction prior to its autokinase activity. In addition, GacS presented a folded ATP lid in contrast to what is observed in other HKs. Furthermore, we unveiled a new domain (ND) in GacS sequence. Functional assays showed that the ND domain is essential to insure a full autokinase activity of GacS. We proposed that this domain contributes in conformational rearrangements in order to shift GacS to its active state. RetS HK is known to inhibit GacS/GacA via direct interactions. Native mass spectrometry and microscale thermophoresis assays showed that the HAMP domain is essential for this interaction. Furthermore, nanobodies generated against the cytoplasmic region of GacS revealed potential sites of inhibition of GacS activity. In this study, we unveiled a non-canonical autokinase activity in GacS and new insights into its interaction with RetS that underlie the decision-making of PA
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Ranchio, Alessandro. "Structural studies of protein kinase CK2: Inhibition mechanisms and structure-activity relationships." Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3422666.
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The subject of this thesis is the protein kinase CK2 which is a family of enzymes that in humans consists of two catalytic subunits, termed CK2α and CK2α’, and one regulatory subunit, CK2β. CK2 is a highly conserved acidophilic Ser/Thr protein kinase, ubiquitously distributed in different cell compartments. CK2 is a member of the superfamily of eukaryotic protein kinases (EPKs), meaning the catalytic subunit is related by sequence homology and structural features to the other 478 kinases of the superfamily.
CK2 shows some singular features like its high constitutive activity and the lack of an defined mode of regulation, which make CK2 unique with respect to the other kinases. With hundreds of substrates, this kinase is involved in several cellular events, resulting essential for the cell viability: CK2β gene knockout in mouse model is lethal even at single cell level, CK2α gene knockout are embryonic lethal at day 10.5 and CK2α' (expressed only in brain and testis) mouse knockout are viable with some defects in spermatogenesis. It participates in cell cycle progression, gene expression, cell growth, and differentiation and embryogenesis. Down-regulation of CK2 leads to apoptosis while abnormal over-activation has been found coupled to several diseases: the clinical relevance of CK2 is that high levels of the protein activity have been detected in a number of cancers, such as head and neck, renal, breast, prostate, lung, and kidney.
A wide spectrum of cell permeable, fairly specific ATP site directed CK2 inhibitors are currently available which are proving useful to dissect its biological functions and which share the property of inducing apoptosis of cancer cells with no comparable effect on their “normal” counterparts. One of these, CX-4945, has recently entered clinical trials for the treatment of advanced solid tumors, Castelman’s disease and multiple myeloma.
CK2 is considered constitutively active enzyme and, unlike many other protein kinases, it does not require phosphorylation for activation. The mechanism of regulation of CK2 is not firmly established yet, however it is clear that it differs from those commonly utilized by other protein kinases.
Dozens of crystal structures of CK2 have been solved and highlighted the structural features of the main CK2 entities, the catalytic subunit CK2α, the regulatory subunit CK2β and the tetrameric α2β2 CK2 holoenzyme. Even if the structural knowledge of CK2 is very extended, no high resolution 3D-structure are available for the C-terminal part of CK2α, which has been deleted for the crystallization purpose. Moreover the structure of the CK2α’ has been solved but no structural information are present for the tetrameric holoenzyme with this catalytic subunit.
To address this issue, one part of my PhD project focused on the production and the structural characterization of the full-length wild type CK2α and a phosphomimetic mutant in the tetrameric holoenzyme, in order to study the possible structural role of the C-terminus. Starting from the three holoenzyme structures solved we were able to determine some new holoenzyme structural features, in particular the new interface of interaction between the subunits within the tetramer and the so far unknown symmetry of the complex. Moreover we dealt with the development of a purification protocol of the CK2α’2β2 holoenzyme (and a chimeric CK2αα’β2) in quantities appropriate for structural approaches.
The second part of the PhD focused on the structural characterization of a new potent dual inhibitor K164 which is specific for CK2 and Pim1; the crystal structure of the inhibitor in complex with the CK2α336 has been solved at 1.25 Å, which is the highest resolution ever reached for CK2.<br>Il soggetto di questa tesi è la protein chinasi CK2, una famiglia di enzimi che negli uomini è composta da due subunità catalitiche, CK2α e CK2α’, e da una subunità regolatoria, CK2β. CK2 è una Ser/Thr protein chinasi acidofila altamente conservata nel mondo eucariote, presente in differenti compartimenti cellulari. CK2 è un membro della superfamiglia delle protein chinasi eucariotiche (EPKs), con la subunità catalitica correlata mediante omologia di sequenza e caratteristiche strutturali alle altre 478 chinasi della superfamiglia.
CK2 mostra alcune caratteristiche singolari, come la sua elevata attività costitutiva e la mancanza di un importante meccanismo di regolazione, il quale rende CK2 unica rispetto alle altre chinasi. Con centinaia di substrati, CK2 è coinvolta in numerosi processi biologici, risultando essenziale per la vitalità cellulare: il knockout del gene CK2β nel modello murino è letale anche a livello di singola cellula, il knockout del gene CK2α è letale al giorno 10.5 dello sviluppo embrionale e il knockout CK2α' (espresso solo nel cervello e testicoli) in topo è vitale con alcuni difetti di spermatogenesi. CK2 partecipa alla progressione del ciclo cellulare, all'espressione genica, alla crescita cellulare e alla differenziazione e all’embriogenesi. Down-regulation di CK2 porta all'apoptosi cellulare mentre una sovra-attivazione anomala è stata trovata accoppiata a diverse malattie: la rilevanza clinica di CK2 risiede nel fatto che alti livelli di attività della proteina sono stati trovati in diversi tipi di tumori, come alla testa e al collo, ai reni, al seno, alla prostata e al polmone.
Un ampio spettro di inibitori di CK2, permeabili alle cellule e specifici per il sito dell’ATP, sono attualmente disponibili e si stanno rivelando utili per analizzare le funzioni biologiche della proteina; queste piccole molecole sono in grado di indurre l'apoptosi delle cellule tumorali senza alcun effetto analogo sulle loro controparti "normali". Uno di questi inibitori, CX-4945, è recentemente entrato in studi clinici per il trattamento di tumori solidi avanzati, malattia di Castelman e mieloma multiplo.
CK2 è considerato un enzima costitutivamente attivo e, a differenza di molte altre protein chinasi, non richiede fosforilazione per l'attivazione. Il meccanismo di regolazione di CK2 non è stato ancora stabilito, tuttavia è chiaro che si differenzia da quelli comunemente utilizzati dalle altre protein chinasi.
Decine di strutture cristallografiche di CK2 sono state risolte e hanno evidenziato le caratteristiche strutturali delle principali entità di CK2: la subunità catalitica CK2α, la subunità regolatoria CK2β e l’oloenzima tetramerico CK2α2β2. Anche se la conoscenza strutturale di CK2 è molto estesa, non è disponibile alcuna struttura 3D a elevata risoluzione per la parte C-terminale di CK2α, che è sempre stata deleta per scopi di cristallizzazione. Inoltre, malgrado la struttura di CK2α' sia stata risolta, non sono presenti alcune informazioni strutturali per l’oloenzima tetramerico con questa subunità catalitica.
Per raggiungere questo obiettivo, una parte del mio progetto di dottorato si è focalizzata sulla produzione e sulla caratterizzazione strutturale di CK2α wild type (completa della parte C-terminale) e di un mutante fosfomimetico nell’oloenzima tetramerico, al fine di studiare il possibile ruolo strutturale del C-terminale. Partendo da tre strutture dell’oloenzima risolte abbiamo potuto determinare alcune nuove caratteristiche strutturali dell’oloenzima, in particolare la nuova interfaccia di interazione tra le subunità all'interno del tetramero e la simmetria del complesso, finora sconosciuta. Inoltre ci siamo occupati dello sviluppo di un protocollo di purificazione dell’oloenzima CK2α’2β2 (e di una forma chimerica CK2αα’β2) in quantità appropriate per approcci strutturali.
La seconda parte del dottorato si è focalizzata sulla caratterizzazione strutturale del complesso con un nuovo potente inibitore duale (K164) il quale è specifico per CK2 e Pim1; la struttura cristallina di CK2α336 in complesso con l’inibitore è stata risolta a 1.25 Å, che è la più alta risoluzione mai raggiunta per CK2.
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Stewart, Charlotte. "Structure activity relationships of bisphosphonate analogues." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=128207.
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The nitrogen-containing bisphosphonates (NBPs) are the most widely used treatment for diseases involving excessive osteoclastic bone resorption, such as osteoporosis. The clinical efficacy of NBPs is due in large part to their affinity for bone mineral, but it has been suggested that lowering affinity may have benefits due to altered distribution and duration of action possibly allowing direct anti-tumour effects. In addition, the phosphonocarboxylate (PC) analogues inhibit prenylation more selectively through a different enzyme target, Rab geranylgeranyl transferase (RGGT), which may offer additional benefits by reducing side-effects associated with farnesyl diphosphate synthase (FPPS) inhibition. Using fluorescent analogues of PCs and NBPs demonstrated that mineral affinity not only affects initial bone-binding, but also influences desorption, reattachment and penetration at the bone surface, suggesting that lower affinity compounds have lower retention and increased access to other cell types, such as tumour cells. The work presented aimed to investigate the potential of low affinity analogues by characterising their intracellular potency for inhibiting their target enzymes. The results showed that modification to the phosphonate groups to produce phosphonoalkylphosphinate analogues reduced potency for inhibiting FPPS. By contrast, removal of one of the phosphonate groups to give a monophosphonate changed the target enzyme to RGGT. Modifications to the R1 side-chain (substituting with hydrogen or a halogen) of both NBPs and PCs were studied and showed contrasting results, modifications to the R1 side-chain of NBPs affect their ability to inhibit FPPS whereas the same modification to PCs is insignificant for inhibiting RGGT. This showed the distinction between the structural requirements for inhibition of RGGT and FPPS and furthers the understanding of the structure-activity relationships of both NBPs and PCs which could guide future drug design. Within this thesis the most potent inhibitor of RGGT to date, 3-IPEHPC, was characterised which in addition to having therapeutic potential may be used as tool to investigate the importance of Rab prenylation for cellular function.
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Shahbakhti, Hassan. "Structure/activity relationships of antitumour diazridinylquinones." Thesis, University of Salford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308289.
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McFadyen, Iain James. "Structure-activity relationships of opioid ligands." Thesis, Loughborough University, 1999. https://dspace.lboro.ac.uk/2134/33189.
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There are three different types of opioid receptor, namely mu, delta and kappa. Morphine and related clinically useful analgesics exert their actions through the mu opioid receptor. Such compounds represent a huge structural diversity, including both peptides and alkaloids. Nevertheless, there exists a common pharmacophore comprising two critical features, namely an amine nitrogen and an aromatic ring, usually with a hydroxyl substituent; the spatial relationship between them is also vital.
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Moore, Madeleine Henrietta. "Structure-activity relationships in Werner clathrates." Doctoral thesis, University of Cape Town, 1987. http://hdl.handle.net/11427/17038.
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Includes bibliographical references.<br>The synthesis and characterization of a series of inorganic coordination compounds which, upon crystallization, have the ability to include solvent or guest molecules spatially within the lattice are reported. The compounds have the following general formula: [NiX2B4] - where X is isothiocyanate or bromine and B is 4-ethylpyridine, 4-vinylpiridine or 3,5-dimethylpyridine; [NiX2B2]n - where X is isothiocyanate, B is 2-aminopyridine and n indicates it is a polymer; [NiX2AB2]2 - where X is isothiocyanate, B is 3-aminopyridine (two of these four ligands in the dimer are bridging) and A is water. The various guest molecules have been carefully chosen, according to their point symmetry, which is a key factor in yielding structures of a particular type. The structures of seventeen compounds have been elucidated by single crystal x-ray analysis. The difficulty has been found to lie in refining disordered guest molecules. Other techniques employed in the initial characterization of these compounds are Microanalysis, Mass Spectrometry and UV/Visible Spectrophotometry. An intramolecular potential energy study on the [Ni(NCS)2(3,5-diMepy)4] complex reveals that the orthohydrogens on the 3,5-dimethylpyridine ligands control the conformation of the molecule. Packing densities and volume comparisons of the [Ni(NCS)2(4-Etpy)4] and [Ni(NCS)2(4-Vipy)4] complexes and their clathrates have been carried out. The exact sizes and shapes of the cavities in which the guest molecules are located in the x-ray crystal structures have been evaluated by both intermolecular potential energy and molecular volume calculations. Thermodynamic and spectroscopic properties of the [Ni(NCS)2(4-Etpy)4] and [Ni(NCS)2(4-Vipy)4] clathrates have been studied in both solution and the solid state. The techniques used are x-ray powder diffractometry, IR spectroscopy and Thermogravimetry (including Differential Thermal Analysis).
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Wong, Fred Tuck Khai. "Structure-activity relationships of cardiac glycosides." Thesis, The University of Sydney, 1989. https://hdl.handle.net/2123/26271.
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It is over 200 years since William Hithering published his famous treatise on the use of the foxglove. Since that time, digitalis has been in continuous use as a therapeutic agent, and, although its efficacy has often been challenged it continues to occupy a central role in the treatment of chronic congestive heart failure.
Interest in digitalis has been sustained by its therapeutic use and by the scientific interest in its mode of action. The cardiac glycosides, generally referred to by the generic name of digitalis, are unique inhibitors of the enzyme Na*, K*-ATPase. This enzyme is found in the plasma membrane of all eukaryotic cells where it acts as a transmembrane pump that couples the outward transport of Na+ with the inward transport of K*. As a result of this action, Na*, K*-ATPase plays an important role in cell homeostasis and makes a major contribution to the maintenance of the transmembrane resting potential. Such important cellular properties as excitability and conduction of electrical impulses depend very much on the action of Na*, K*-ATPase.
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Matos, Gomes E. De. "Relationship between optical activity and crystal structures." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303933.
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Just, Baringo Xavier. "Thiopeptides: Synthesis and Structure-Activity Relationship Studies." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/128268.
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The present doctoral thesis has been devoted to the development of a new synthetic strategy to obtain a new member of the thiopeptide, or thiazolyl peptide, family of antibiotics. This new member, baringolin, was isolated and characterized by the Spanish pharmaceutical company Instituto Biomar S.A. Although a structure was proposed, no stereochemical information was provided. Thus, this thesis has several objectives; first, a novel modular and straightforward strategy must be developed to achieve its total synthesis, but also to facilitate the preparation of analogues. The achievement of the total synthesis of baringolin should serve as the final confirmation of its structure and stereochemistry.
The strategy developed herein is based in cross-coupling reactions and required the preparation of suitable building blocks and optimization of the required methodology. Moreover, L –series amino acids were chosen as the sole source of chirality to be introduced in the molecule, which is presumably synthesized in the ribosome of the producing bacteria.
Once the synthetic methodology was set up and building blocks were ready, condensation of all fragments and final steps gave rise to synthetic baringolin, which was identical to its natural counterpart, confrming its structure and stereochemistry. Comparison of both products was made by spectroscopic methods and biological function assessment.
Given the successful outcome of our synthetic plan, a small library of analogues was designed. Two different moieties of the molecule were modified: the thiazoline ring and the peptidic tail. As a result of minimum inhibitory concentration of Gram positive bacteria growth assessment of the library, different conclusions could be drawn from the results thus obtained. First, thiazoline was shown to be crucial to keep a broad activity profile against many strains; its substitution for a more rigid thiazole ring resulted in loss of activity towards most strains, while potency was only maintained against S. aureus. On the other hand, shortening of the peptidic tail had almost no effect in either activity or potency. Substitution of the peptidic tail with a cyclohexanoic acid moiety in the thiazole series resulted in recovery of activity against all strains and a potency increase against most of them.
The good results obtained are good evidence of the efficiency of the synthetic strategy developed during this thesis and demonstrate that chemical synthesis is a useful tool for both structure determination and structure-activity relationship studies.<br>En la presente tesis doctoral se ha llevado a cabo el desarrollo de una nueva estrategia sintética para la obtención de un nuevo miembro de la familia de antibióticos conocida como tiopéptidos, o tiazolil péptidos. Este nuevo miembro, la baringolina, fue aislado y caracterizado por la empresa farmacéutica española Biomar S.A., la cual no elucidó la estereoquímica del compuesto. Así, el propósito inicial de esta tesis es múltiple; por un lado se pretende desarrollar una estrategia que permita su obtención de forma directa y modular, facilitando la futura síntesis de análogos; por otro lado, la obtención de la baringolina sintética debe ofrecer una confirmación definitiva de su estructura y su estereoquímica.
La estrategia desarrollada se basó en reacciones de acoplamiento cruzado, lo cual requería la preparación de los fragmentos necesarios y la optimización de la metodología a utilizar. Además, se escogió utilizar amino ácidos de la serie L como única fuente de quiralidad en la molécula, la cual presumiblemente está formada a partir de estos, dado el origen ribosomal de los tiopéptidos.
Con la metodología puesta a punto y los fragmentos correspondientes preparados, se pudo llevar a cabo su ensamblaje, dando lugar a la baringolina sintética, la cual resultó ser idéntica a la natural, confirmándose así su estructura y estereoquímica.
Dado el éxito de la síntesis total, se procedió a la síntesis de una pequeña librería de análogos, en la cual se modificaron dos zonas diferentes de la molécula, el anillo de tiazolina y la cola peptídica. Como resultado de la evaluación de la capacidad de inhibición de cultivos de bacterios Gram positivo, se extrajeron diversas conclusiones relativas a las relaciones estructura-actividad de las partes modificadas. En primer lugar, la tiazolina demostró ser necesaria para mantener un amplio espectro de actividad frente a diversas cepas, ya que su substitución por un anillo de tiazol, más rígido, prácticamente solo mantuvo el mismo nivel de potencia frente a S.aureus. Por otro lado, el papel de la cola peptídica resultó ser limitado, ya que su acortamiento no causó grandes diferencias de actividad y potencia. Por último, se substituyó la cola por un grupo de ácido ciclohexanoico en la versión que poseía un anillo de tiazol en lugar de tiazolina, lo cual resultó en el restablecimiento de la actividad frente a todas las cepas y un aumento de potencia frente a la mayoría de estas.
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Tomita, Kenji. "Structure-activity Relationship Study on GPR54 Agonists." 京都大学 (Kyoto University), 2009. http://hdl.handle.net/2433/124039.
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Centani, Luyanda. "Structure activity and structure property relationships of antimalarial imidazopyridazines." Master's thesis, Faculty of Science, 2019. http://hdl.handle.net/11427/31315.
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Malaria is one of the most pressing human health issues. Despite being an ancient disease, it is estimated to have an annual death rate of 445 000 with out of 216 million malaria related cases in 2016. Malaria is most widespread in developing regions of the world. Forty percent of the world’s population is exposed to varying degrees of malaria. Malaria is caused by different species of the Plasmodium genus and the disease is vector-borne. The disease may be cured if diagnosed early. Most drugs that were once effective in the treatment of malaria have become ineffective due to the emergence of resistance, which has become the main driving force behind efforts to discover and develop new drugs able to circumvent the resistance. Imidazopyridazines have been shown to have potent antiplasmodium activity. The lead compound MMV652103 has been shown to display potent activity against the multidrug resistant K1 strain and the drug sensitive NF54 strain of the human malaria parasite Plasmodium falciparum. However, the majority of the antimalarial imidazopyridazine compounds evaluated to date have solubility and off-target human ether-a-go-go-related gene (hERG) potassium ion channel liabilities. Towards improving solubility and de-risking the hERG liability, a series of analogues was designed and synthesised. Structure-Activity Relationship (SAR) and Structure-Property Relationship (SPR) studies aimed at retaining the good antiplasmodium activity while improving solubility and reducing hERG channel inhibition, were conducted. Previous studies conducted on this series of imidazopyridazines have shown that incorporation of hydrogen bond donors or acceptors resulted in improving solubility and hERG channel inhibition. While the lead compound MMV652103 at pH 6.5 has a sub-optimal solubility of 5 µM, all target compounds showed an improvement in solubility. Five analogues 59, 78, 84, 85, and 86 exhibiting impressive in vitro asexual blood stage antiplasmodium potency (IC50< 100 nM) and aqueous solubility (> 200 µM) were identified from the study. The identified compounds also displayed good activity against the sexual late-stage gametocytes, the transmissible forms of the parasite.
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Kayastha, Shilva. "New methods of multiscale chemical space analysis : visualization of structure-activity relationships and structural pattern extraction." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF042/document.
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Cette thèse est dédiée à l’analyse systématique de l’espace chimique, et des relations structure-activité (SAR) en particulier. L’ouvrage présente des nouveaux protocoles d’analyse combinant des méthodes classiques et originales, dans le but d’analyser les SAR à l’échelle globale ainsi que locale. L’analyse globale des espaces chimiques repose sur la recherche des motifs structuraux privilégiés par cartographie topographique générative (GTM), ainsi que par analyse classique des « châssis » moléculaires. La cartographie a été ensuite couplée avec l’analyse de réseaux chimiques (CSN), permettant une transition de la vue globale vers l’analyse locale de SAR. L’optimisation mutiobjectif des propriétés de potentiels médicaments a été adressé par la méthode « star coordinates ». L’analyse locale des SAR inclut des nouvelles stratégies pour prédire les discontinuités dans le paysage structure-activité biologique, et une étude de l’impact de la structure sur l’ionisation des molécules. Des matrices SAR ont servi pour monitorer le progrès dans l’optimisation de nouveaux principes actifs<br>This thesis presents studies devoted to aid in systematic analysis of chemical spaces, focusing on mining and visualization of structure-activity relationships (SARs). It reports some new analysis protocols, combining both existing and on-purpose developed novel methodology to address both large-scale and local SAR analysis. Large-scale analysis featured both generative topographic mapping (GTM)-based extraction of privileged structural motifs and scaffold analysis. GTM was combined with chemical space network (CSN) to develop a visualization tool providing global-local views of SAR in large data sets. We also introduce star coordinates (STC) to visualize multi-property space and prioritize drug-like subspaces. Local SAR monitoring includes new strategies to predict activity cliffs using support vector machine models and a study of structural modifications on ionization state of compounds. The SAR matrix methodology was applied to objectively evaluate SAR progression during lead optimization
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Dimayuga, Mario Arnulfo De Leon. "Structure-activity relationship studies of biological activities of chemicals." Case Western Reserve University School of Graduate Studies / OhioLINK, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=case1055532031.
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Price, Craig Justin. "Structure-activity relationships in olefin polymerization catalysts." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-1678.
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Holmes, Victoria. "Structure activity relationships of cytochrome P450 4A1." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289361.
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Hargreaves, Martin Bernard. "Substrate structure activity relationships of cytochrome P4502E1." Thesis, University of Leicester, 1995. http://hdl.handle.net/2381/35247.
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Morsman, Janine M. "Structure-activity relationships (SAR) for cytochrome P4502C9." Thesis, University of Aberdeen, 1999. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU536139.
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In this project, an SAR approach was used to assess the putative active site interactions, using analogues of phenytoin (a co-regulated substrate), sulfaphenazole (CYP2C9-specific inhibitor) and bis-triazole antifungals (thought to exhibit less specific inhibition). <I>K</I><SUB>i</SUB> values were determined for the inhibition of tolbutamide methylhydroxylation. N2 of phenytoin is a postulated H-bond donor. Substitution (CH<SUB>3</SUB> or NH<SUB>2</SUB>), reduced inhibitory potency from 46 μM to 74 μM and 98 μM, respectively. Inhibition was competitive. Removal of a phenyl ring removed inhibitory potential, suggesting that an aromatic interaction (π-π stacking) is more influential than the H-bonding. Replacement with a fused-ring structure enhanced potency (<I>K</I><SUB>i</SUB> = 25 μM). Inhibition was non-competitive, which may be explained by the overall bulk of these analogues, together with less directional lipophilic/π-π stacking interactions. A putative active site model could feature a H-bond acceptor site, a lipophilic pocket, haem interaction with the site of oxidation, and π-π stacking with an appropriate phenyl ring. Sulfaphenazole and methysulfaphenazole (CH<SUB>2</SUB> instead of NH<SUB>2</SUB>) were the most potent analogues (<I>K</I><SUB>i</SUB> values of 0.82 μM and 0.39 μM). Removal of the pyrazole group reduced potency (<I>K</I><SUB>i<I> </I></SUB>= 91 μM), as a CYP2C9-haem interaction was prevented (type II difference spectra). Additionally, the N-phenyl function may undergo hydrophobic binding and/or π-π stacking. The bis-triazoles also produced type II spectra, which indicates a haem-ligand interaction (N4 triazole lone pair electrons). Inhibition was non-competitive. The triazole was the dominant determinant of potency, as seen by relatively small decreases in potency on substitution of a proposed H-bonding site. In conclusion, the above work indicates interactions consistent with previous CYP2C9 active site models. SAR data suggest a predominance of lipophilic and π-π stacking interactions, and CYP2C9-haem liganding (if appropriate). Hydrogen-bonding also has a significant role.
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Lock, Ruth E. "Structure-activity relationships (SAR) for cytochrome P4502C19." Thesis, University of Aberdeen, 1999. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU535752.
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Investigation of structure-activity relationships (SAR) for cytochrome P450 isoenzymes has implications for the prediction of drug-drug interactions. To date, the majority of research relating to the structure-activity relationships for P450 isoenzymes has concentrated on CYP2D6, CYP2E1, and CYP2C9. Knowledge of the likelihood of an interaction between a new chemical entity (NCE) and CYP2C19 is also of interest due to the existence of a genetic polymorphism in this enzyme. SAR for CYP2C19 were investigated in human liver microsomes (n=3) and CYP2C19 SUPERSOMES<SUP>TM</SUP> (n=2), by determining the inhibition of omeprazole 5-hydroxylation using benzodiazepine, phenytoin and fused-ring phenytoin analogues. (Fig. 8288). The inhibitory potency shown by the phenytoin and fused-ring phenytoin analogues appeared to be due to a combination of factors, including: a lipophilic group at R<SUB>1</SUB>, molecular length, surface area and volume of the compound (with the bulky fused-ring analogues showing greatest inhibitory potency), and lipophilicity (as indicated by calculated log P values and log D<SUB>7.4 </SUB>octanol values). A number of molecular features of the benzodiazepines proved important for the potent inhibition of CYP2C19-mediated omeprazole 5-hydroxylation. Again, a lipophilic group at R<SUB>1</SUB> was essential. QSAR (quantitative structure-activity relationship) studies showed binding of the benzodiazepines to the active site of CYP2C19 to be governed by this area of lipophilicity. The carbonyl group was important for a CYP2C19 interaction. Benzodiazepines missing the function were not inhibitory. By superimposing chemically similar groups of the inhibitors, an overlay was created from their 3D structures using (<I>S</I>)-mephenytoin as a template. From the preliminary pharmacophore generated, a number of interactions with the CYP2C19 active site seem to be necessary for inhibitory potency. Hydrogen bond formation is possible between particular amino acid residues within the active site and the carbonyl groups of the inhibitory analogues. The aromatic rings are capable of interacting (perhaps via π-stacking interactions) with a number of corresponding lipophilic areas, possibly "pockets" within the CYP2C19 active site.
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Howard, W. Brian. "Structure-Activity Relationships of Retinoids in Developmental Toxicology." DigitalCommons@USU, 1988. https://digitalcommons.usu.edu/etd/4042.
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The teratogenic potency of retinoid analogs was determined in Syrian hamsters and compared to the teratogenic potency of all-trans-retinoic acid (all-trans.-RA, ED50 = 10.5 mg/kg). A total of 15 analogs having variations in the cyclohexene ring were evaluated following various amounts of single oral doses on day 8 of gestation. Retinoids containing a five- or six-membered ring were as teratogenic as all-tmru.-RA, provided they had sufficient lipophilic substituents on the ring. The same pattern emerged for retinoids that had six-membered aromatic ring substitution for the natural cyclohexene ring of vitamin A. Incorporation of a supplementary aromatic ring in the side-chain adjacent to a gem-dimethyl-hexene ring resulted in an increase in teratogenicity by IS-fold compared to all-trans.-RA. Major modifications of the cyclohexene ring can be made without altering teratogenic activity. The ring need not be six-membered and can have decreased lipophilicity through the incorporation of polar groups compared to all-trans.-RA, but must have sufficient lipophilic substituents to provide the necessary mass for interaction with the retinoid receptor. Incorporation of a supplementary aromatic ring adjacent to a gem-dimethyl-hexene ring facilitated π-electron delocalization and restricts side-chain flexibility , thereby increasing teratogenic potency.
The pharmacokinetic disposition of 8 retinoids was investigated. Pregnant hamsters were dosed orally with all-trans-RA, 13-cis-retinoic acid, all-trans.-4- oxoretinoic acid, 9-cis-retinal, all-trans.-retinyl acetate, N-ethyl-all-trans- retinamide, N-ethyl-13-cis-retinamide, and arotinoid. The bioavailability of the retinamides was one-tenth that of the free acid retinoids. The plasma elimination half-life for all-trans-RA was 0.5 h. For 13-cis-retinoic acid and all-trans-4-oxoretinoic acid the elimination half-lives were 4.4 and 5.7 h, respectively.
The binding affinity of various retinoids to cellular retinoic acid-binding protein (cRABP) was determined in day-12 hamster fetuses. Fetal supernatants from the 105,000x g fraction were incubated with high specific-activity [3H]-all-trans-RA in the presence of various concentration of unlabeled retinoids with subsequent isolation of cRABP by size-exclusion HPLC. Teratogenic retinoids, or acidic metabolites of teratogenic retinoids bound to cRABP whereas nonteratogenic retinoids failed to bind.
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Dale, Clare Louise. "Fluorescent Aâ‚-adenosine agonists : a structure activity relationship." Thesis, University of Nottingham, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440124.
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Gabrielli, William Fullard. "Structure activity relationship studies of ochratoxin A analogues." Thesis, Stellenbosch : Stellenbosch University, 2002. http://hdl.handle.net/10019.1/53070.
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Thesis (MSc)--Stellenbosch University, 2002.<br>ENGLISH ABSTRACT: Mycotoxins have assumed worldwide importance due to the ubiquitous occurrence of
toxigenic fungi, their infestation of plant-based foods and feeds and the subsequent
economical and health impact it because of their contamination of commercial
products. Ochratoxin A (OA) is a nephrotoxic mycotoxin produced by isolates of
Aspergillus ochraceus and Penicillium verrucosum and occurs frequently in nature.
The major target for toxicity of OA in mammalian species is the kidneys and it has
been the major cause of Danish Porcine Nephropathy. OA has also been extensively
implicated in the aetiology of Balkan Endemic Nephropathy and Chronic Interstitial
Nephropathy in Northern-Africa. Furthermore, OA has been identified as a
carcinogen, an immunosuppressant and a teratogen with respect to the foetal central
nervous system.
Although a large amount of research has been conducted into the chemical nature of
the toxicity of OA, the exact molecular mechanism of action of OA is not yet
conclusive. Numerous structure activity relationship studies have suggested that the
toxicity of OA may be assigned to three major processes: (i) inhibition of ATP
production; (ii) inhibition of protein synthesis; and (iii) the disruption of hepatic
microsomal calcium homeostasis through the promotion of membrane lipid
peroxidation. It is the aim of this thesis to gain a better understanding, through the
synthesis ofOA analogues, of the chemical structure responsible for the toxic function
of the ochratoxins.
The halogen-group has extensively been implicated in the toxicity of the ochratoxins.
This is evident in ochratoxin B (OB), the dechloro analogue of OA, which is
approximately ten times less toxic than OA. Preliminary tests have indicated that
bromo-ochratoxin B(BrOB), the bromo analogue of OA, is more toxic than ochratoxin
A to renal cells. Fluoro-ochratoxin B and other analogues of OA, where other amino
acids are incorporated, should provide invaluable information on the structure-activity
relationships and the mode of action of the ochratoxins. Our research effort addresses
both these aspects (i) fluorination of the dihydroisocoumarin moiety and (ii) the coupling of different amino acids and dipeptides to the non-toxic hydrolysed product
of OA, ochratoxin a.
Chapter one includes a review of the important biological aspects of OA that has
served as a guideline to the synthesis of effective OA analogues. An overview of the
relevant chemistry involved in the modification of OA will conclude the chapter.
Chapter two entails a discussion of fluorine in bio-organic chemistry. This includes an
overview of the impact that fluorine substitution has on the biological reactivity of
molecules. A review on the synthesis of organofluorine compounds, which forms the
emphasis of this study, concludes the chapter.
Chapter three elaborates on the different methodologies used in our attempts to
synthesise fluoro-ochratoxin B and other analogues. These included the direct
electrophilic fluorination of OB and different analogous aromatic model compounds
by xenon difluoride, N-fluorobenzenesulfonimides and Selectfluor™ as fluorinating
agents. Also involved is an investigation into an alternative route for the synthesis of
fluoro aromatic compounds from bromo and chloro analogues by means of palladium
catalysed trimethyl- and tributylstannyl and trimethylsilylation which in tum may be
substituted with fluorine by means of xenon difluoride. Efforts towards the direct
catalytic fluorosubstitution of aryl halides are also investigated. The synthesis of a key
intermediate, fluoroacetoacetaldehyde, in a de nova synthetic route to fluoroochratoxin
B is also discussed.
Furthermore, the synthesis of novel OA analogues with respect to the replacement of
the L-phenylalanine moiety is addressed. This includes the conversion of OA to Oa,
by acid hydrolysis, followed by the coupling of ortho-, meta- and para- substituted
DL-fluorophenylalanine to the lactone acid. This is followed by the synthesis of
histidylhistidine methyl ester and attempted coupling to Oa. The coupling of
halosalicylic acids and salicylic acid to L-phenylalanine, for use as model aromatic
substrates for fluorination, IS discussed. Peptide coupling by
dicyclohexylcarbodiimide carboxyl activation, with reference to the protection of the
phenolic hydroxyl group in 5-chlorosalicylic acid for application to Oa, concludes
this work.<br>AFRIKAANSE OPSOMMING: Mikotoksiene is van wêreld-wye belang as gevolg van die alomteenwoordige
voorkoms van toksigeniese fungi, hul besmetting van plantaardige kossoorte en
voerstowwe en die gevolglike ekonomiese en gesondheidsimpak deur die
besoedeling van kommersiële produkte. Ochratoksien A (OA) is 'n nefrotoksiese
mikotoksien wat geproduseer word deur isolate van Aspergillus ochraceus en
Penicillium verrucosum en kom algemeen in die natuur voor. Die niere is die hoof
teiken vir vergifiting deur OA in soogdierspesies en is as die vername oorsaak van
"Danish Porcine Nephropathy" aangewys. OA word verder aangedui as die oorsaak
vir "Balkan Endemic Nephropathy" en "Chronic Interstitial Nephropathy" in Noord-
Afrika. OA is verder geïdentifiseer as 'n karsinogeen, immuno-onderdrukker en is
teratogenies ten opsigte van die sentrale senuweestelsel van fetusse.
Alhoewel aansienlike navorsing alreeds gewei is aan die chemiese natuur van die
toksisiteit van OA, is die presiese molekulêre meganisme van OA reaktiwiteit
onbeslis. Verskeie struktuur-aktiwitweit verwantskaps studies dui daarop dat die
toksisiteit van OA hoofsaaklik toegeskryf kan word aan drie hoof prosesse: (i)
inhibisie van ATP produksie; (ii) inhibisie van proteïen sintese; en (iii) die
ontwrigting van hepatiese mikrosomale kalsiumhomeostase deur die bevordering van
membraanlipiedperoksidasie. Hierdie tesis het ten doel, deur die sintese van OA
analoë, om 'n beter insig oor die chemiese struktuur wat verantwoordelik is vir die
toksiese funksionaliteit van ochratoksiene te verkry.
Die halogeen substituent is grootliks geïmpliseer in die toksisiteit van OA. 'n Bewys
hiervan is ochratoksien B (OB), die dechlooranaloog van OA, wat ongeveer tien maal
minder toksies is as OA. Voorlopige ondersoeke het aangetoon dat bromoochratoksien
B (BrOB), die broomanaloog van OA, meer toksies is vir nierselle as
OA. Fluoorochratoksien B en ander analoë van OA, waar ander aminosure
geïnkorporeer word, behoort waardevolle inligting te voorsien met betrekking tot die
struktuur-aktiwiteitsverwantskappe en die wyse waarop ochratoksiene funksioneer.
Hierdie navorsingspoging spreek beide aspekte aan; (i) die fluorering van die dihidroïsokumarien gedeelte en, (ii) die koppeling van verskillende armnosure en
dipeptiede aan die nie-toksiese hidrolieseproduk van OA, nl. ochratoksien a.
Hoofstuk een vervat 'n oorsig van die belangrike biologiese aspekte van OA wat dien
as riglyn vir die sintese van doeltreffende OA analoë. Die hoofstuk word afgesluit met
'n oorsig van die relevante chemie betrokke by die modifisering van die struktuur van
OA.
Hoofstuk twee bevat 'n bespreking van die aanwending van fluoor in bio-organiese
chemie. Dit bevat 'n oorsig van die impak wat fluoorsubstitusie het op die biologiese
reaktiwiteit van molekules. 'n Opsomming oor die sintese van
organofluoorverbindings, wat die essensie van hierdie studie is, beëindig die hoofstuk.
Hoofstuk drie handeloor die veskillende metodes wat toegepas is in pogings om
fluoorochratoksien B en ander analoë te sintetiseer. Dit sluit in die direkte
elektrofiliese fluorering van OB en ander verwante aromatiese modelverbindings deur
gebruik te maak van xenondifluoried, N-fluoorbenseensulfonimied en Selectfluor™ as
fluoreringsreagense. Dit behels verder ook 'n ondersoek na 'n alternatiewe roete tot
die sintese van fluooraromatiese verbindings vanaf broom- en chlooranaloë. Vir die
doel word palladiumgekataliseerde trimetiel- en tributielstannilering, en
trimetielsililering wat vervolgens deur middel van xenondifluoried met fluoor
gesubstitueer kan word, aangewend. Pogings tot die direkte katalitiese
fluoorsubstitusie van arielhaliede word ook bespreek. Die sintese van 'n sleutelintermediêr,
fluoroasetoasetaldehied, in 'n de nova sintese roete tot fluoorochratoksien
B word bespreek.
Die sintese van nuwe OA analoë, met betrekking to die vervangmg van die Lfenielalanien
(L-Phe) groep word ondersoek. Dit bevat die omsetting van OA na Oa,
deur suurhidrolise, gevolg deur die koppeling van orto-, meta- en paragesubstitueerde
DL-fluoorfenielalanien aan die laktoonsuur, Oa. Daarna word die
sintese van histidielhistidienmetielester en die verdere pogings aangaande koppeling
met Oa bespreek. Die koppeling van halosalisielsure en salisielsuur aan L-Phe wat
dien as model aromatiese verbindings vir fluorering, word behandel. Peptiedkoppeling
met behulp van disikloheksielkarbodiimied-karboksielaktivering, met inbegrip van die beskerming van die fenoliese hidroksiel groep m 5-chloorsalisielsuur Vir die
toepassing op Oa, beëindig hierdie werk.
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Li, Ju-Yun. "Quantitative structure-activity relationship studies in medicinal chemistry." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062596938.
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Oosting, Peter. "Bicyclic Tramadol analogues : towards a structure-activity relationship." Bordeaux 1, 2007. http://www.theses.fr/2007BOR13413.
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Le traitement de la douleur est un domaine d'importance croissante dans la médecine. Pour les douleurs sévères, les opiacés restent parmi les médicaments les plus utilisés, mais ils présent cependant des effets secondaires sérieux, c'est pourquoi les chercheurs continuent à développer de nouveaux analgésiques. Le Tramadol, un opiacé partiel avec un mécanisme particulier, n'induit pas les effets secondaires associés avec la plupart des opiacés. Il a été utilisé durant des années pour le traitement des douleurs modérées et sévères. Cette thèse décrit la synthèse de composés dérivés du Tramadol, ainsi que leur activité biologique. Plus précisément, des dérivés bicycliques possédant les mêmes groupements pharmacophores que le Tramadol ont été synthétisés. Des composés possédant des cycles de taille différente ont été obtenus. Certains dérivés ont été davantage fonctionnalisés en utiliant des réactions d'hydrogénation, de dihydrowylation et d'owygénation. En outre, certains produits ont été soumis à des réactions utilisant l'approche combinatoire. Ainsi, des réactions de type Grignard ont été effectuées avec un robot, dans le but de découvrir, par hasard, des composés intéressants. Les deux approches ont mené à des produits qui possèdent une activité biologique. Ces données biologiques ont été utilisées dans une étude de modélisation moléculaire afin de découvrir de nouvelles cibles. Les expériences de "Docking" sur le récepteur u ont permis d'identifier quelques composés intéressants, malheuresement la synthèse de l'un de ces composés a échoué en raison de problèmes d'hydrolyse d'une fonction cétal. A la fin de ces travaux, une synthèse a été proposée qui permettra vraisemblablement d'obtenir le composé désiré.
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Musa, Muftah Miloud A. "Structure activity relationship studies of new ethylene antagonists." Thesis, Curtin University, 2016. http://hdl.handle.net/20.500.11937/77805.
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Ethylene antagonists provide one of the most effective methods to reduce postharvest losses of horticulture produce. The understanding of the mode of action of 1-methylcyclopropene led to the discovery of a new class of ethylene antagonist. Cycloproparenes, benzocyclopropene and 1H-naphtho[b]cyclopropene were prepared and showed excellent inhibition of the effect of ethylene on some fruits and waxflowers.
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Hattotuwagama, Channa Karunadasa. "Computational studies of sweet-tasting molecules." Thesis, University of Reading, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270841.
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Barber, Megan Marie. "2,4-Disubstituted Quinazolines with Antileishmanial or Antibacterial Activity." Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5840.
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Herein 47 2,4-disubstituted quinazolines were synthesized and tested against Leishmania donovani intracellular amastigotes. A structure-activity relationship was conducted and lead to the identification of quinazolines with EC50s in the single digit and high nanomolar range with favorable antileishmanial selectivity indexes. Quinazoline 2.6 and 2.31 underwent in vivo efficacy studies in murine models of visceral leishmaniasis, reducing liver parasitemia by 12 % and 24 %, respectively, when given by the intraperitoneal route at 15 mg/kg/day x 5 days. The antileishmanial efficacy and easy of synthesis make the 2,4-disubstituted quinazoline compound series a suitable platform for the future development of antileishmanial agents.
A similar series of 50 N2,N4-disubstituted quinazoline-2,4-diamines has also been synthesized and tested against multi-drug resistant strains of Acinetobacter baumannii. Quinazolines with MICs in the single digit micromolar range were identified within the structure-activity relationship. The observed potencies of the top compounds and the easy of synthesis lend to the further investigation of in vivo efficacy studies and could be considered a suitable platform for the future development of anti-bacterial agents against A. baumannii.
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Bourin, Marie-Claude. "Thrombomodulin: a novel proteoglycan : studies on structure-function relationships /." Uppsala : Sveriges lantbruksuniv, 1990. http://epsilon.slu.se/avh/1990/91-576-4149-8.gif.
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Srivastava, Sanjay. "Structure-activity relationship studies in medicinal chemistry and drug design." Case Western Reserve University School of Graduate Studies / OhioLINK, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=case1056054628.
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Simonsen, Shane M. "Diversity and structure-activity relationships of the cyclotides /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19079.pdf.
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Nilsson, Ulrika K. "Lysophosphatidic acid : Physiological effects and structure-activity relationships." Doctoral thesis, Linköping : Univ, 2002. http://www.ep.liu.se/diss/med/07/51/index.html.
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Bruce, Craig L. "Classification and interpretation in quantitative structure-activity relationships." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11666/.
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A good QSAR model comprises several components. Predictive accuracy is paramount, but it is not the only important aspect. In addition, one should apply robust and appropriate statistical tests to the models to assess their significance or the significance of any apparent improvements. The real impact of a QSAR, however, perhaps lies in its chemical insight and interpretation, an aspect which is often overlooked. This thesis covers three main topics: a comparison of contemporary classifiers, interpretability of random forests and usage of interpretable descriptors. The selection of data mining technique and descriptors entirely determine the available interpretation. Using interpretable approaches we have demonstrated their success on a variety of data sets. By using robust multiple comparison statistics with eight data sets we demonstrate that a random forest has comparable predictive accuracies to the de facto standard, support vector machine. A random forest is inherently more interpretable than support vector machine, due to the underlying tree construction. We can extract some chemical insight from the random forest. However, with additional tools further insight would be available. A decision tree is easier to interpret than a random forest. Therefore, to obtain useful interpretation from a random forest we have employed a selection of tools. This includes alternative representations of the trees using SMILES and SMARTS. Using existing methods we can compare and cluster the trees in this representation. Descriptor analysis and importance can be measured at the tree and forest level. Pathways in the trees can be compared and frequently occurring subgraphs identified. These tools have been built around the Weka machine learning workbench and are designed to allow further additions of new functionality. The interpretability of a model is dependent on the model and the descriptors. They must describe something meaningful. To this end we have used the TMACC descriptors in the Solubility Challenge and literature data sets. We report how our retrospective analysis confirms existing knowledge and how we identify novel C-domain inhibition of ACE. In order to test our hypotheses we extended and developed existing software forming two applications. The Nottingham Cheminformatics Workbench (NCW) will generate TMACC descriptors and allows the user to build and analyse models, including visualising the chemical interpretation. Forest Based Interpretation (FBI) provides various tools for interpretating a random forest model. Both applications are written in Java with full documentation and simple installations wizards are available for Windows, Linux and Mac.
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McNeany, T. John. "Non-parametric approaches to quantitative structure-activity relationships." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431188.
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Boyd, Gary William. "Cyclopenta[a]phenanthren-17-ones : structure/activity relationships." Thesis, University of Surrey, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.334403.
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Hutchinson, Francis. "Structure and energetics of trivalent metal halides." Thesis, University of Oxford, 1999. http://ora.ox.ac.uk/objects/uuid:0fdaf43d-0414-491c-a3dc-04414b84a164.
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Metal trihalide (MX<sub>3</sub>) systems represent a stern challenge in terms of constructing transferable potential models. Starting from a previously published set of potentials, 'extended' ionic models are developed which, at the outset, include only anion polarization. Deficiencies in these models, particularly for smaller (highly polarizing) cations, are shown to be significant. For example, crystal structures different to those observed experimentally are adopted. The potentials are improved upon by reference to ab initio information available for alkali halides with the 'constraint' that the parameters transfer systematically in a physically transparent manner, for example, in terms of ion radii. The possible influence of anion compression ('breathing') and the relative abundance of anion-anion interactions are considered. Simulation techniques are developed to allow for the effective simulation of any system symmetry and for the study of transitions between different crystals (constant stress). The developed models are fully tested for a large range of metal trichloride (MCl<sub>3</sub>) systems. Particular attention is paid to the comparison with recent neutron and X-ray diffraction data on the liquid state. Polarization effects are shown to be vital in reproducing strong experimental features. The excellent agreement between simulation and experiment allows for differences in experimental procedures to be highlighted. The transferability is further tested by modelling mixtures of the lanthanides with alkali halides with potentials unchanged from the pure systems. The complex evolution of the melt structure is highlighted as the concentration of MCl<sub>3</sub> increases. The effectiveness of the models is tested by reference to dynamical properties. Particular attention is paid to the comparison with Raman scattering data available for a wide range of systems and mixture concentrations. The simulated spectra are generated both by a simple molecular picture of the underlying vibrations and by a more complex (fluctuating polarizability) model in which the spectra are broken down into contributions from different mechanisms. This comparison allows for the validity of treating network-like systems as a series of 'isolated' molecules to be assessed. The transferability of the potentials is pushed to the limits by modelling metal tribromides, in which the parameters are obtained from the trichlorides by the same simple scaling arguments.
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Gupta-Ostermann, Disha [Verfasser]. "Computational Methods for Structure-Activity Relationship Analysis and Activity Prediction / Disha Gupta-Ostermann." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1080561277/34.
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Malet, Nicolas. "Structure-activity relationship and biosynthesis of the methylenomycin furans." Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/54119/.
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Today, more than 70 % of clinically-used antibiotics are produced by Streptomyces species. However, it is estimated that only 1 % of secondary metabolites produced by these bacteria have been discovered to date. Chemical communication in bacteria is defined as producing and responding to signalling molecules, which govern physiological processes, including antibiotic production and morphological differentiation. By understanding the signalling mechanisms of such molecules, new bioactive metabolites, of value to society, can be discovered. Examples of well characterized signalling molecules include acylhomoserine lactones (AHLs) and γ-butyrolactones (GBLs). A recently-discovered novel class of signalling molecules, 2-alkyl-4-hydroxymethylfuran-3- carboxylic acids (AHFCAs), which induce methylenomycin antibiotic biosynthesis in S. coelicolor is being studied in our group. We have investigated the structure-activity relationship of AHFCAs with respect to induction of methylenomycin production. The methodology of Davis et al. has been applied and extended to synthesise a range of AHFCA analogues with different alkyl chains, as well as modifications to the hydroxymethyl and carboxyl groups and the heterocycle (Figure 2). The ability of the resulting library of compounds to induce methylenomycin production was investigated. Structural features that are important for the biological activity of the AHFCAS were identified. Surprisingly, several analogues had very similar biological activity to the natural products. In 2007, a biosynthetic pathway to γ-butyrolactones was proposed and AfsA was shown to be a key enzyme in this process. mmfL encodes an AfsA-like protein, which is hypothesised to catalyse the formation of a butenolide intermediate in methylenomycin furan biosynthesis. mmfH and mmfP encode a flavin-dependent monooxygenase and a phophatase, respectively. Here, we report biochemical characterisation of the MmfL, MmfP and MmfH enzymes as well as attemps to reconstitute the methylenomycin furan biosynthetic pathway in vitro.
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Reddy, Badinehal Asrith. "COMMERCIALIZATION OF A QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP TOOL - SARCHITECT." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1295637833.
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FAN, WEIGUO. "USING MOLECULAR SIMILARITY ANALYSIS FOR STRUCTURE-ACTIVITY RELATIONSHIP STUDIES." Kent State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=kent1353964351.
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Longworth, Mitchell Francis. "Structure Activity Relationship Study of Cannabinoid Receptor 1 Ligands." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/18242.
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This thesis describes the design, synthesis and pharmacological evaluation of a library of CB1 orthosteric and allosteric ligands. Synthetic cannabinoids (SCs) have emerged in the public domain as a ‘legal’ alternative to cannabis. These drugs are based on experimental cannabinoid 1 receptor (CB1) agonists that were investigated as potential treatments for neuropathic pain. As these compounds have not gone through any formal human testing, they have been associated with an array unpredictable, and often serious, adverse effects. The initial focus of this work was to synthesise recent high concern SCs and their major phase 1 metabolites, and access their cannabimimetic activity in vitro and in vivo. An efficient, divergent synthesis was utilised to access a library of SCs. Using a FLIPR assay with AtT20 cells transfected with either hCB1 or hCB2, the series of SCs synthesised proved to be some of the most potent and efficacious cannabinoid ligands recorded to date. Their cannabimimetic activity was verified in vivo, where select SCs caused a characteristic hypothermic and bradycardic response in a rat model. In contrast to the phytocannabinoids, the major metabolites of SCs retain activity at both cannabinoid receptors, and also have activity at key off-site receptors TRPA1 and TRPV1, potentially contributing to the overall pharmacological profiles of the drugs. With limited potential as therapeutics, classes of compounds beyond CB1 agonists are being investigated to modulate the endocannabinoid system. ZCZ-011 has shown promising in vivo and in vitro results as a positive allosteric modulator (PAM) at CB1. As there was insufficient structure activity analysis conducted on this compound, modifications were made to the lead structure to investigate the key binding requirements of CB1 allosteric binding, incorporating key features of other CB1 PAMs. These compounds are currently undergoing in vitro evaluation.