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1
Thornton, Stephen S. "Design, synthesis, and kinetics of novel acetylcholinesterase inhibitors." Thesis, Georgia Institute of Technology, 1989. http://hdl.handle.net/1853/26964.
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Matheson, Christopher. "Chemical and biological studies with Nek2 kinase inhibitors." Thesis, University of Newcastle upon Tyne, 2012. http://hdl.handle.net/10443/2024.
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The aim of modern cancer chemotherapy is to develop targeted drugs designed to exploit pharmacological differences between tumour cells and healthy tissues. One focus of this effort has been the identification of protein kinases that are expressed at elevated levels or in mutated forms, indicating a reliance of the tumour on specific kinase function. Nek2 is a human serine/threonine protein kinase related to the fungal protein NIMA, a critical mediator of mitosis. Interestingly, Nek2 is found to be upregulated in a variety of tumour cell lines derived from breast, cervical and prostate carcinomas, as well as lymphomas. Human Nek2 is implicated in the regulation of the centrosome and formation of a bipolar spindle, a framework that is vital for correct separation of sister chromatids during mitosis. It is proposed that Nek2 may complex with, and phosphorylate, proteins accumulated at the centrosome, possibly playing a role in intercentriolar linker cleavage during the centrosome cycle. Abnormalities in centrosome number and function are common in many cancers, indicating that loss of centrosome cycle regulation may be a major contributing factor in tumour progression. Overexpression of Nek2 may result in premature centrosome disjunction, and deregulation of this tightly controlled mitotic machinery leads to chromatid segregation errors, aneuploidy and chromosomal instability, common genetic abnormalities observed in tumour cells. This indicates a role for abnormal Nek2 function in tumourigenesis, and Nek2 depletion in a number of tumour cell lines has been shown to cause growth suppression and apoptosis. Nek2 is thus a potentially attractive cancer therapeutic target for small-molecule kinase inhibitors. Previous studies identified substituted purine derivatives as modest inhibitors of Nek2, leading to the discovery of two distinct inhibitor classes, exhibiting ATP-competitive and irreversible inhibition of the kinase, respectively. Purine-based compounds bearing substituents at the 8-position have emerged as modest competitive inhibitors of Nek2 that occupy the kinase ATP-domain through an unusual binding orientation (45; IC = 51.8 M). Additional possible interactions within the ATP- 50 binding site available to inhibitors of this class were explored, with the objective of developing tight-binding type II reversible inhibitors of Nek2. Structure-activity relationship studies resulted in a 10-fold improvement in activity over the initial hit compounds and a substantial improvement in drug-like properties (e.g. 129; IC = 5.1 M)). However, all 50 efforts to improve the potency of this series were unsuccessful. 6-Ethynylpurines have been identified as irreversible inhibitors of Nek2 through covalent modification of an active-site cysteine residue. The initial hit compound (147; IC = 0.14 50 M) was found to be a potent and selective inhibitor of the kinase in vitro, but with poor cellular activity attributed to limited permeability. Extensive structural modification of the 2- arylamino side-chain of this series afforded cell permeable analogues with improved potency, both in vitro and in vivo (e.g. 177; IC = 0.062 ± 0.01 M). 50 Biochemical studies using 177 suggested that inhibition of Nek2 resulted in an increase in mitotic abnormalities and a delay in mitotic progression, despite poor cellular growth inhibition being observed in initial tumour cell lines. Further cellular growth inhibition and cytotoxicity studies with selected compounds identified several sensitive tumour cell lines. However, kinase-inactive control compounds essentially devoid of Nek-inhibitory activity (e.g. 425; IC > 100 M) retained growth-inhibitory activity, indicating an alternative locus 50 of activity for the 6-ethynylpurine chemotype.
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Wong, Lai Hong. "Chemical genetic screen for inhibitors of human telomerase." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/9524.
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There remains a pressing need for the development of effective drugs that meet the clinical needs for cancer treatment, and inhibition of telomere length maintenance by disrupting human telomerase is a proven and tractable target for suppression of cancer cell growth. In response to the lack of currently available small molecules with efficacy against human telomerase, we developed a genetically and chemically tractable cell-based system in which S. cerevisiae is used to streamline the search for novel human telomerase inhibitors. Our results confirmed that yeast cell growth was rapidly inhibited upon induction of functional human telomerase at the telomere. This inducible growth arrest was used as a read-out for a high-throughput chemical screen for human telomerase inhibitors based on their ability to restore growth in the yeast system. From a library consisting of small, bioactive and cell-permeable compounds of diverse structure, we identified three novel “drug-like” compounds that inhibited the activity of native and recombinant telomerase complexes in vitro. “Validation assays” also confirmed the novel inhibitors were free of uncharacterized adverse effects against yeast and human cell models, thus confirming the specificity of these novel inhibitors against human telomerase target. This surrogate yeast model has therefore proven to be a cost-effective alternative to accelerate the search for human telomerase inhibitors, which we hope will serve to streamline the identification of further lead compounds effective against human cancer.
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Shirazi, Mehdi. "Surface application of yellowing inhibitors into paper." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38281.
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Papermakers are highly interested in upgrading mechanical paper by retarding or inhibiting the lignin color reversion. Yellowing can be prevented by screening UV light on the surface and adding yellowing inhibitors into papers. Surface treatment of paper in a size press by an inhibitor-starch mixture has more advantages compared to other methods. A novel microscopy technique using scanning electron microscopy is developed to identify and measure the polymer penetration into sized sheets.The kinetics of starch adsorption on wood fibers was elucidated. An initial high adsorption of cationic starch on pulp fibers is off set by high desorption rates. Furthermore the adsorption of hydroxyethyl ether starch increases smoothly with time due to polymer penetration into the macropores. At high salt concentrations, cationic starch does not make strong bonds with negatively charged fibers and as a result the desorption rate increases and the maximum adsorption approaches zero. The presence of salt has little effect on the adsorption of non-ionic hydroxyethyl ether starch.
Preferential adsorption of amyIose compared to amylopectin on cellulosic fibers is related to the size exclusion mechanism involved in polymer penetration into macropores.
The presence of cationic starch clusters is confirmed. The clusters initially adsorb on the fiber surface; however due to a higher desorption rate they are gradually replaced by individual polymers. The cluster size decreases with increasing shear in the presence of salt in cationic starch solutions. The cluster desorption rate for pulp fibers is higher than that for glass substrates. This might be due to different surface chemistry or roughness between pulp fibers and glass substrates. The maximum adsorption on glass substrates increases by increasing the cluster size. Hydroxyethyl ether starch does not form clusters and shear and the presence of salt have a minor effect on the polymer size.
Starch pickup by paper during surface sizing depends on the liquid absorption at the puddle and counter pressure of the trapped air in the pores. Starch viscosity, paper velocity and nip load have no effect on the thickness of the starch layer across the sized paper. However, for thick boards penetration increases by increasing the nip load due to lower sheet thickness at higher nip load. For sized board, the starch penetration is less for cationic starch than for hydroxyethyl ether starch due to higher viscosity and adsorption.
For the sized sheets with yellowing inhibitor/starch mixtures, the paper brightness after aging is affected by inhibitor concentration in the solution, since operating conditions have little effect on pickup. Using cationic starch slightly increases the brightness for boards, while it has little effect on paper brightness.
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Starks, Kenneth Maurice. "Novel pyridinium salts which inhibit acetylcholinesterase." Thesis, Georgia Institute of Technology, 1994. http://hdl.handle.net/1853/26950.
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Wilson, Jeanne E. "Deacylation rates of ortho-substituted derivatives of acylated HL elastase and PP elastase : electronically or sterically dependent." Thesis, Georgia Institute of Technology, 1987. http://hdl.handle.net/1853/27051.
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Corredor, Sánchez Miriam. "Chemical Modulation of Identified Hit Compounds as Apoptosis Inhibitors." Doctoral thesis, Universitat Ramon Llull, 2013. http://hdl.handle.net/10803/117361.
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L’apoptosi és un procés biològic rellevant en moltes malalties. Un punt de regulació d’aquest procés és la formació d’un complex multiproteic anomenat apoptosoma; per tant, aquest complex té un gran interès per al desenvolupament de moduladors apoptòtics. El nostre grup ha descrit prèviament una piperazina-2,5-diona substituïda en posició 3 com a potent modulador apoptòtic. Estudis estructurals d’aquest compost han permès veure la presència dels isòmers cis / trans de l’enllaç de l’amida terciària exocíclica en un procés d’intercanvi lent, fet que pot ser important per a la interacció amb la diana biològica. Aquesta informació ens va animar a mimetitzar aquests isòmers a través d’una substitució isostèrica de l’enllaç amida amb unitats de 1,2,3-triazoles. La síntesi d’aquests anàlegs restringits es va dur a terme utilitzant una reacció Ugi multicomponent seguida d’una ciclació intramolecular. L’anàlisi completa per RMN (incloent les correlacions 1H-15N en abundància natural) d’aquests compostos han permès la caracterització inequívoca dels patrons de substitució corresponents. Finalment, l’increment de l’activitat inhibitòria d’aquests nous compostos en comparació amb el compost de partida ha proporcionat nova informació sobre la unió dels compostos a la diana terapèutica i ha fet possible la identificació de nous moduladors. Cal destacar que per a una de les estructures proposades, es va formar inesperadament una β-lactama que va resultar el compost amb una activitat inhibidora més alta. Els estudis computacionals realitzats també donen suport a la hipòtesi que el mecanisme d’inhibició de tots aquests nous derivats és a través de la unió amb la proteïna Apaf-1.
Degut a la formació d’aquest cicle, es va realitzar un estudi de reactivitat per explicar la manera de ciclació dels adductes de la reacció de Ugi. Per tal de modular aquesta reacció, s’ha sintetitzat una quimioteca de compostos que contenen els dos nuclis (β-lactama o dicetopiperazina) havent-se assajat les seves activitats com a inhibidores de l’apoptosis.
Finalment, per intentar millorar les propietats dels nostres compostos com a possibles candidats a fàrmac, s’han dut a terme uns acoblaments amb alguns dels inhibidors i glicodendrímers.
Com a conclusió, s’ha sintetitzat una nova família d’inhibidors de l’apoptosi amb una llibertat conformacional menor aconseguint mantenir valors d’activitat similars. Es confia que aquests compostos mostrin una selectivitat més gran, condició fonamental per regular un procés tan delicat.La apoptosis es un proceso biológico relevante en muchas enfermedades. Uno de los puntos de regulación de este proceso es la formación del complejo multiproteico llamado apoptosoma; por tanto, este complejo reviste gran interés para el desarrollo de moduladores apoptóticos. Previamente en nuestro grupo se ha descrito una piperazina-2,5-diona sustituida en posición 3 como potente inhibidor apoptótico. Estudios estructurales de este compuesto han permitido determinar la presencia de isómeros cis / trans del enlace de la amida terciaria exocíclica en un proceso de intercambio lento, hecho que puede ser importante en la interacción con la diana biológica. Ésta información nos animó a mimetizar éstos isómeros a través de una sustitución isostérica del enlace amida con unidades 1,2,3-triazólicas. La síntesis de éstos análogos restringidos se llevó a cabo usando una reacción Ugi multicomponente seguida de una ciclación intramolecular. El análisis completo por RMN (incluyendo las correlaciones 1H-15N en abundancia natural) de estos compuestos ha permitido la caracterización inequívoca de los patrones de sustitución correspondientes. Además, el aumento de la actividad inhibitoria de los nuevos compuestos ha proporcionado nueva información sobre el tipo de interacción de los compuestos con la diana terapéutica. La formación inesperada de una β-lactama en lugar de la dicetopiperazina para una de las estructuras propuestas y el hecho que este último compuesto fuera el que mostrara mayor actividad inhibidora, fueron hechos muy interesantes que dieron lugar a estudiar en mayor profundidad la reacción de ciclación intramolecular. Se realizó un estudio de la reactividad para explicar la ciclación de los aductos de la reacción de Ugi y para modular esta reacción, se sintetizó una quimioteca con los dos tipos de ciclo (β-lactama y dicetopiperazina), habiéndose ensayado sus actividades como inhibidores de la apoptosis. Finalmente, para intentar mejorar las propiedades de nuestros compuestos como posibles candidatos a fármaco, se llevaron a cabo acoplamientos entre algunos inhibidores y diferentes tipos de glicodendrímeros. Como conclusión, se ha sintetizado una nueva familia de inhibidores de la apoptosis con una libertad conformacional menor consiguiendo mantener valores de actividad similares. Se confía que estos compuestos muestren una selectividad mayor, condición fundamental para regular un proceso tan delicado.
Apoptosis is a biological process relevant to different human diseases stated that is regulated through protein-protein interactions and complex formation. In this context, one point of regulation is the formation of the multiprotein complex known as apoptosome. Consequently, this complex is of interest for the development of apoptosis modulators. In our group, it has been previously reported a peptidomimetic compound bearing a 3-substituted-piperazine-2,5-dione moiety as a potent apoptotic inhibitor. Structural studies of this compound showed the presence of cis/trans isomers of the exocyclic tertiary amide bond in slow exchange, which should be of high relevance for off-target interaction in front of the biological target. This information encouraged us to perform an isosteric replacement of the amide bond by a 1,2,3-triazole moiety, where different substitution patterns would mimic different amide rotamers. The syntheses of these restricted analogs have been carried out using the Ugi multicomponent reaction followed by an intramolecular cyclization. Unexpectedly, for one of the proposed structures, a novel β-lactam compound was formed. All synthesized compounds showed to efficiently inhibit apoptosis, in vitro and in cellular extracts, with slight differences for the corresponding regioisomers. Noticeably, the compound bearing the new β-lactam scaffold showed the highest inhibitory activity. On the other hand, computational studies also support the hypothesis that these new families of inhibitors exert their action by binding to Apaf-1, one of the components of the apoptosome complex. Due to the formation of the unexpected β-lactam scaffold, a reactivity study has been carried out to explain the course of the intramolecular cyclization of the Ugi adducts. In order to be able to modulate this cyclization, a small library of compounds bearing both heterocyclic scaffolds has been synthesized and their activities as apoptosis inhibitors have been evaluated. Moreover, couplings between some of the apoptosome inhibitors and different glycodendrimer moieties have been carried out to improve the properties of our compounds as drug candidates. As a conclusion, a new family of compounds has been designed, synthesized and characterized, and most of them showed good apoptosis inhibitory activities in vitro and in cellular extracts. We deem that the reduction of the conformational freedom achieved in this new family of inhibitors could be fundamental to increase the selectivity, which is a highly important condition when regulating such a delicate process.
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Mayhew, Maxine Eleanor. "Chemical inhibitors for biomass yield reduction in activated sludge." Thesis, Cranfield University, 1999. http://dspace.lib.cranfield.ac.uk/handle/1826/4547.
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Increasing legislation and rising treatment and disposal costs have promoted optimisation of the activated sludge process to encompass reduction of waste biomass. Manipulation of process control such as increasing sludge age and decreasing food to microorganism ratio can lower waste sludge production, but capital works as well as increased operating costs in the form of power requirement for oxygen supply may be required. The need for a cost effective method of biomass reduction without capital expenditure has prompted research into methods beyond process control. The use of chemicals capable of disrupting microorganism metabolic pathways can theoretically allow continuation of catabolic (degradative) paths whilst halting some or all of the anabolic (growth) pathways. This project explored the use of metabolic inhibitors (uncouplers, tricarboxylic acid cycle inhibitors and antibiotics) to reduce the yield of the activated sludge process. Initial respirometric studies identified many chemicals capable of interacting with the activated sludge microorganisms. Increased oxygen uptake rate was taken as an indication of a good uncoupler, and tests highlighted 4 chemicals with significant potential for achieving biomass reduction (trypan blue, rotenone, 2,4 DNP and 4 NP). These chemicals were then tested at a laboratory scale and at bench scale in both batch and continuous simulations. Simulations were carried out using activated sludge and settled sewage feed to obtain as realistic conditions as possible. In batch tests, trypan blue, rotenone and 2,4 DNP successfully reduced mixed liquor suspended solids accumulation with little effect on COD removal compared to controls. In continuous simulations, 2,4 DNP and 4 NP both lowered yield with respect to their relative controls. Rotenone addition did not result in lowered yield. In all cases, any yield reduction was not at the expense of process efficiency in terms of COD and BOD removal. At pilot scale, 2,4 DNP almost halved the observed yield compared to the control whilst having no significant effect on BOD, COD or ammonia removal, nitrite and nitrate production, SVI or CST. Addition of chemical uncouplers had little effect on the species diversity of the activated sludge though a reduction in the floc size was observed in treated samples. Selection of a suitable chemical can result in reduced yield without detrimental effect to process efficiency in the activated sludge process. An increase in oxygen consumption occurred which has an associated cost implication, but this was not found to be significant compared to the savings made by reducing the yield.
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Zhou, Linna. "Chemical biology studies on 5-nitrofurans and sirtuin inhibitors." Thesis, University of St Andrews, 2012. http://hdl.handle.net/10023/3407.
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Part I: Target identification studies are one of the most difficult but rewarding challenges in chemical biology. Part I of this thesis describes target identification studies for 5-nitrofuran containing hits. The 5-nitrofurans used in this study were identified in a phenotypic screen for compounds that induced melanocyte cells death in zebrafish. Chapter 1 provides brief overviews on three related areas of the project: 1) the use of zebrafish as a model organism in drug discovery; 2) phenotypic screening using zebrafish and 3) the strategies used in target identification studies. Chapter 2 describes the synthesis of and SAR studies on two series of 5-nitrofuran containing analogues. The design and preparation of biotinylated chemical probes based on the SAR data is also described. These chemical tools are then used in affinity chromatography studies and genetic validation of a potential target (zebrafish Aldh2) of the 5-nitrofuran compounds is reported. Chapter 3 provides a review of the biological and chemical processes that human ALDHs are known to mediate. In addition, small molecules that modulate ALDH2 activity are reviewed. A detailed study of the interaction between 5-nitrofurans and human ALDH2 including in vitro enzymatic assays is described leading to the conclusion that the 5- nitrofurans under study are substrates of human ALDH2. Further mechanism of action investigations using model reactions are also presented. Chapter 4 introduces the use of 5-nitrofuran containing drugs in the clinic and highlights the reported side-effects. Further investigation of the interaction between ALDH2 and 5- nitrofurans in zebrafish and yeast using ALDH2 inhibitors is described. Based on these results, a combination therapy strategy is proposed. Finally, the trypanocidal activity of the newly synthesised 5-nitrofurans is discussed. Experimental details and future work for Part I are presented in Chapters 5 and 6 respectively. Part II: Human sirtuins are associated with various biological functions and diseases, including cancer and neurodegeneration. Previous work from the Westwood Lab has led to the discovery of the tenovins that act as inhibitors of SIRT1 and SIRT2. Part II of the thesis reports the development of potent fixed ring tenovin analogues with high SIRT2 selectivity. Chapter 7 provides a brief review of the biology of human SIRT2 and the reported SIRT2 inhibitors available to date. This is followed by a short summary of the previous work on the tenovins in the Westwood Lab and the design of the fixed ring tenovin analogues. Chapter 8 describes the synthesis of three series of fixed ring tenovin analogues. SAR data is generated based on in vitro enzymatic assays against both SIRT1 and SIRT2 and the prepared analogues showed relatively high potency and selectivity against SIRT2. Further cell-based deacetylation assay are also discussed. All the experimental details are reported in Chapter 9 and Chapter 10 provides with conclusions and proposed future work.
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Fraser, Rebecca Dawn. "Isolation of natural product inhibitors and synthesis of inhibitors of signal transduction : Part II structure-activity relationship for a series of glycosidase inhibitors." Diss., Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/30508.
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Silveira, Alvito J. "Synthesis of 6-guanidinobenzoxazinones as potential inhibitors of trypsin-like enzymes." Thesis, Georgia Institute of Technology, 1989. http://hdl.handle.net/1853/26914.
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李鵬. "Chemical and pharmacological studies on angiogenesis inhibitors from Salvia miltiorrhiza." Thesis, University of Macau, 2008. http://umaclib3.umac.mo/record=b2150645.
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Sharifi, Hassan. "Laboratory evaluation of chemical and biological kinetic gas hydrate inhibitors." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/51514.
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For practical purposes, kinetic hydrate inhibitors must perform in a predictable manner in the field. However, the complexity of the petroleum fluid composition, the presence of dissolved electrolytes, and high driving force (overpressure or sub-cooling), make it difficult to impossible task to achieve. In this thesis, the performance of two chemical kinetic inhibitors, polyvinylcaprolactam (PVCap) and polyvinylpyrrolidone (PVP), and two biological ones, type I and III antifreeze proteins (AFP I and III) were evaluated under conditions mimicking oil and gas filed ones. The evaluation was done by using a double high pressure stirred vessel (crystallizer), a high-pressure cell in conjunction with a rotational rheometer and a high pressure micro differential scanning calorimeter. Although the above noted inhibitors were found to prolong the hydrate induction time and reduce the initial hydrate growth in saline solutions, the rate was found to increase when hydrate crystals started to form in the gas phase of the crystallizer.
Circular dichroism experiments suggested that the saline solution does not perturb the structure of AFP I and III. However, in the presence of NaCl, the inhibitory activity of AFP I to prolong induction time decreased while AFP III was more active. Here, increase in induction time was ordered: no inhibitorChemical and Biological Engineering, Department of
Graduate
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Frost, Julianty. "VHL inhibitors as chemical probes of the hypoxia signalling pathway." Thesis, University of Dundee, 2018. https://discovery.dundee.ac.uk/en/studentTheses/2885a480-4372-426c-8cab-45b74d1a5b7e.
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Von Hippel–Lindau (VHL) is the E3 ubiquitin ligase targeting hypoxia-inducible transcription factor-alpha (HIF α) for proteasomal degradation. The crucial function of VHL in response to hypoxia and cellular oxygen sensing are well established, owing to the use of genetic tools through knockout and knockdown that inactivate VHL. However, the functional consequences of specifically interrupting the interaction between VHL and HIF α remain to be elucidated. The development of a chemical probe that unambiguously blocks the VHL:HIF α interaction downstream of HIF α hydroxylation by prolyl hydroxylase domain (PHD) enzymes, would address biological questions about VHL molecular targets and functional consequences of disrupting the interaction. Here, small molecules inhibiting the VHL:HIF α interaction were shown for the first time to stabilise HIF α and elicit HIF transcriptional activity in cells. The most potent VHL inhibitor identified is VH298. VH298 is potent, cell-permeable, selective, and not toxic at the concentration required for HIF α stabilisation. Further characterisation shows that VHL inhibitor exclusively induces HIF-dependent changes in global gene and protein expression, demonstrating the specificity of the inhibitor. VHL protein level was found to increase in the presence of VHL inhibitor, which in turn promotes the degradation of HIF α in prolonged inhibition. The work herein characterises the VHL inhibitor as a chemical probe of the hypoxia signalling pathway with great potential to address biological questions regarding the roles and regulation of VHL. The VHL inhibitor is a unique tool due to its on target selectivity and specificity in inducing HIF activity, without affecting HIF-independent response, and exerts its effect further downstream than PHD hydroxylation. This work provides a foundation and cellular proof of concept for future studies evaluating therapeutic potential of VHL inhibitor in diseases, such as chronic anaemia, ischaemia, and inflammation-driven diseases.
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Saint-Cyr, Karine. "Adsorption kinetics of dyes and yellowing inhibitors on pulp fibers." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0019/MQ55028.pdf.
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Gutierrez, Jemy A. "Inhibition and functional characterization of asparagine synthetase." [Gainesville, Fla.] : University of Florida, 2006. http://purl.fcla.edu/fcla/etd/UFE0015619.
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Wilson, Lois Kathryn. "A probe of the rotenone-piericidin a-amytal binding site of NADH-coenzyme Q reductbase by structure-activity relationships between the new natural benzofuran inhibitor hydroxytremetone and related ben." Thesis, Georgia Institute of Technology, 1989. http://hdl.handle.net/1853/26005.
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Roberts, Steven F. "Investigation of the enzymology and pharmacology of novel substrates and inhibitors of dopamine beta-monooxygenase." Diss., Georgia Institute of Technology, 1987. http://hdl.handle.net/1853/27141.
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Lauro, Andrea Marie. "The design and synthesis of novel serine proteinase inhibitors." Diss., Georgia Institute of Technology, 1989. http://hdl.handle.net/1853/30032.
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Hall, John Jacobs Pinney Kevin G. Trawick Mary Lynn. "Inhibitors of tubulin, nitric oxide synthase, and HIF-1 alpha synthesis, biological, and biochemical evaluation /." Waco, Tex. : Baylor University, 2008. http://hdl.handle.net/2104/5193.
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Dagia, Nilesh M. "Transcription Inhibitors as Anti-Adhesion Agents." Ohio University / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1089820343.
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Ciobanu, Liviu Constantin. "Chemical synthesis and biological activity of new inhibitors of steroid sulfatase." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0021/MQ47185.pdf.
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Jiang, Jingqian. "Development of uncharged galactosyltransferase inhibitors : chemical tools for applications in cells." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/development-of-uncharged-galactosyltransferase-inhibitors(f0f8fadc-7b4d-417c-8ce7-995d5c157e6d).html.
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β-1,4-Galactosyltransferases (β-1,4-GalTs) catalyse the transfer of D-galactose from a uridine diphosphate galactose (UDP-Gal) donor to an N-acetylglucosamine (N-GlcNAc) or glucose (Glc) acceptor, forming a β-1,4-glycosidic linkage. β-1,4-GalTs are required for the formation of important glycan epitopes, such as terminal tetrasaccharide Sialyl Lewis X (sLex), which is present in P-selectin glycoprotein ligand 1 (PSGL-1) and other cell adhesion molecules. Therefore, small molecular β-1,4-GalT inhibitors are of great interest as chemical tool compounds to study sLex- and PSGL-1-dependent processes. A UDP-Gal derivative, 5-(5-formylthien-2-yl) UDP-galactose (5-FT UDP-Gal), has previously been described as a potent, broad-spectrum GalT inhibitor; however, the application of 5-FT UDP-Gal in cell assays is compromised by its limited stability and membrane permeability, due to the presence of pyrophosphate and sugar moieties. Therefore, the main aim of this thesis was to develop uncharged β-1,4-GalT inhibitors based on 5-FT UDP-Gal, but with more suitable properties for cellular applications. Several approaches were explored to achieve this goal. In chapter 2, attempts to apply the pro-drug concept using phosphate esters of 5-FT UDP-Gal are described. A series of 5-substituted nucleoside derivatives derived from 5-FT UDP-Gal was also prepared. The inhibitory activities of these derivatives against β-1,4-GalT were assessed in biochemical assays. Direct comparison with the corresponding complete UDP-sugar derivatives allowed the identification of structural factors that determine activity. The effects of the most active nucleoside derivative and its ester prodrug were also investigated in a PSGL-1 expression assay. Attempts to overcome the relative loss of activity from the absence of pyrophosphate and sugar moieties in nucleoside inhibitors using dynamic combinatorial chemistry are described in Chapter 3. A hydrazone dynamic combinatorial library (DCL) was generated from the most potent nucleoside fragment and a series of hydrazides to identify mimics of pyrophosphate and sugar moieties to develop potent inhibitors. A suitable hydrazide was identified from the library and the corresponding nucleoside derivatives were generated and evaluated in the biochemical assay as well as the PSGL-1 expression assay. A known, substrate-based -1,4-GalT inhibitor was prepared as a positive control in the DCL experiments. However, this N-GlcNAc derivative unexpectedly behaved as an acceptor substrate rather than an inhibitor in our phosphatase-coupled assay. These unexpected finding, including attempts to rationalise the discrepancy between these results and reported in previous literature describing this compound as a β-1,4-GalT inhibitor, are described in Chapter 4.
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Leung, Ka Kay. "Analysis of yeast resistance to lignocellulosic-derived inhibitors." Thesis, University of Nottingham, 2015. http://eprints.nottingham.ac.uk/32589/.
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The rapid depletion of fossil fuel reserves and concurrent increase in global temperatures has resulted in global demand for the production of alternative environmentally friendly fuels. First-generation biofuels that utilise cash crops for the extraction of fermentable sugars currently exist, but are highly controversial due to socioeconomic and environmental reasons such as diverting food production or deforestation. Therefore, second-generation biofuels that utilise lignocellulosic waste materials are a more attractive prospect. In Europe, lignocellulosic biomass wastes such as wheat straw, display great potential for the production of alternative energy sources such as bioethanol for transportation. Conversion to this biofuel requires microorganisms that will effectively utilise the constituent sugars to produce a high yield of product. Saccharomyces cerevisiae (S. cerevisiae) strains possess the most desirable phenotypes for this objective. However, the components of wheat straw are difficult to break down, therefore pretreatment is required. Pretreatment methods vary but often utilise various chemicals that produce compounds that are inhibitory to yeast. This affects the efficiency of fermentations. The focus of this work is on formic acid and a synthetic media containing the main inhibitor compounds released during pre-treatment of steam exploded wheat straw. Six pair-wise F1 crosses between four distinct parental S. cerevisiae clean lineage populations have been generated previously by Cubillos et al., 2009. The 96 F1 progeny from each cross have been assayed for tolerance phenotypes in order to determine QTLs (Quantitative Trait Loci), which will enable us to map genes contributing to the multi-genic trait of inhibitor tolerance. Overall, three QTLs were identified for formic acid and five QTLs were identified from the synthetic inhibitor mix. Candidate genes were selected from the QTL analysis and were tested by performing reciprocal hemizygosity assays to determine which genes are responsible for inhibitor resistance to enable the development of yeast strains suitable for second-generation biofuel production.
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Liu, Yonglan. "DATA-DRIVEN COMPUTATIONAL DESIGN AND DISCOVERY OF ANTIFOULING MATERIALS AND AMYLOID INHIBITORS." University of Akron / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=akron1619464202390549.
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Ren, Baiping. "Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides." University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697.
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Chen, Shen-En Trawick Mary Lynn. "Modeling, design, and development of potential inhibitors of [gamma]-glutamylamine cyclotransferase and inhibitors of cruzain as therapeutic agents for Chagas' disease." Waco, Tex. : Baylor University, 2008. http://hdl.handle.net/2104/5189.
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Al-Adel, Shadi. "The effect of biological and polymeric inhibitors on methane gas hydrate growth kinetics." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18439.
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Gas hydrates, also known as clathrate hydrates, are non-stoichometric crystalline compounds that have an "ice-like" appearance. They occur when water molecules hydrogen bond to form cavities that can be occupied by a gas or volatile liquid. The inclusion of these guest molecules stabilizes the water network. Hydrates are a nuisance to the gas processing industry as they plug pipelines and equipment which can upset daily operations and add unnecessary maintenance costs. In this work, kinetic experiments were performed on a methane-water system in the presence of Antifreeze Proteins (AFP`s) in order to elucidate their effectiveness as a kinetic hydrate inhibitor. The results were compared to experiments done with a classical polymeric hydrate inhibitor, N-vinylpryrrolidone-co-N-vinylcaprolactam [poly(VP/VC)] at the same pressure, temperature and weight percent conditions. As well, a series of experiments was conducted on poly(VP/VC) to examine the effect of concentration on hydrate growth inhibition. Experiments were performed at temperatures between 275.15-279.15 K and pressures between 5800-7200 kPa. The effect of the kinetic inhibitors on the hydrate growth profile was examined as well as the effect of temperature and pressure on the performance of the inhibitors. Two other polymers were tested for hydrate growth for the first time to discover their effect on the kinetics of hydrate formation. The results showed that they promoted the growth of clathrate hydrates.Les hydrates gazeux, aussi connus comme des «clathrates d'hydrate », sont des complexes crystallins non-stœchiométriques ayant l'apparence de la glace, mais composés d'une structure différente. Ils se forment quand des molécules d'eau se lient grâce aux liens hydrogène pour former des cavités qui peuvent être occupés par un gaz ou un liquide volatil. L'introduction de ces molécules «invités» stabilise la structure formée par les molécules d'eau. Les hydrates sont une nuisance pour l'industrie de développement de gaz parce qu'ils peuvent obstruer les pipelines et équipements, ce qui interromperait les opérations quotidiennes et ajouterait aux coûts de maintenance. Dans cette étude, des expériences cinétiques ont été effectuées sur des systèmes méthane-eau en présence de protéines antigel (AFP's) pour déterminer leur efficacité comme inhibiteurs cinétiques d'hydrates. Les résultats ont été comparés aux résultats obtenus avec des polymères inhibiteurs d'hydrates classiques, N-vinylpryrrolidone-co-N-vinylcaprolactam [poly(VP/VC)], avec la même pression, température et pourcentage de masse en inhibiteur. De plus, une série d'expériences a été conduite avec le poly (VP/VC) afin d'examiner l'effet de la concentration du polymère sur l'inhibition de la croissance d'hydrates. Les températures et pressions examinées variaient respectivement de 275.15 à 279.15K et de 5800 à 7200 kPa. L'effet des inhibiteurs cinétiques sur le profil de la croissance d'hydrates a été examiné ainsi que l'effet de la température et de la pression sur la performance des inhibiteurs. Deux autres polymères ont été testés pour la première fois pour étudier la croissance d'hydrates et découvrir leurs effets sur la cinétique de formation des hydrates gazeux. Les résultats obtenus ont démontré que ces polymères favorisent la croissance d'hydrates. fr
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Ghareba, Saad. "Inhibition of carbon steel corrosion by long alkyl-chain amino acid corrosion inhibitors." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104608.
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Carbon steel (CS) is the most commonly used material for equipment and pipes in the oil production processes. However, presence of water/salts and carbon dioxide, among other gases, in the oil is a serious problem due to increased corrosion rate of the material. The most common way of mitigating this problem is by using corrosion inhibitors. However, many common corrosion inhibitors that are in use today are health hazards. Therefore, there is a need to develop more environmentally compatible and biodegradable corrosion inhibitors. Bioorganic and naturally occurring molecules, such as amino acids, are the most obvious candidates. This work was aimed at studying the influence of some amino acids, 11-aminoundecanoic acid (11AA) and 12-aminododecanoic acid (12AA), as corrosion inhibitors for carbon steel (CS) in hydrochloric acid and some other electrolytes that might be used in certain industries.In this study the inhibiting effect of 12AA on corrosion of CS in CO2-free and CO2-saturated 0.5 HCl was investigated as a function of various parameters: inhibitor concentration, electrolyte pH, temperature, treatment time, CS surface roughness, electrolyte flow rate and pattern, effect of electrolyte type. In addition, the interaction of 11AA with the CS surface under selected experimental conditions was also investigated. It was found that 12AA inhibits both partial corrosion reactions, with a slightly stronger inhibition of the anodic corrosion reaction which indicated that 12AA acts as a mixed-type inhibitor. The corrosion protection mechanism is by formation of a surface-adsorbed 12AA monolayer that offers a hydrophobic barrier to transport of solvated corrosive ions to the surface yielding a maximum inhibition efficiency of ~98%. The adsorption of 12AA onto the CS surface was described by the Langmuir adsorption isotherm. The corresponding Gibbs energy of adsorption was calculated to be −26 and −28 kJ mol−1 in the CO2-free and CO2-saturated 0.5 M HCl, respectively. This indicated that the self assembled monolayers (SAM) formation process is spontaneous and reversible. PM-IRRAS measurements revealed that the SAM is amorphous, which could be attributed to the repulsion between the neighboring positively charged amine groups and also to a high heterogeneity of the CS surface. The study showed also that the 12AA can be used as an effective inhibitor of CS general corrosion in several other electrolytes including; acetic acid, perchloric acid and sodium chloride, but its application in nitric and sulfuric acid should be avoided. The corrosion inhibition of the CS surface by 12AA is also effective at higher pH values, although the corresponding corrosion inhibition efficiency decreased due to a decrease in 12AA solubility. 12AA was also confirmed to be an efficient corrosion inhibitor of a CS surface of different roughness.The effect of flow and flow pattern of CO2-saturated HCl on the corrosion inhibition of CS by 12AA was also investigated in a square duct, rotating disk electrode (RDE) and jet impingement cell configuration. 3 mM 12AA provided high corrosion inhibition efficiency in the square duct and RDE configuration. However, in 1 mM 12AA solution, the inhibition efficiency decreased with an increase in Reynolds number (Re), due to desorption of 12AA from the CS surface. 12AA was found to poorly protect CS in the impingement-jet configuration at low Re, while at high Re, acceleration of CS corrosion was recorded.Similar results were also obtained for inhibition of CS corrosion by 11AA. In fact, this molecule was found to better protect CS from corrosion than 12AA. This was attributed to the higher surface coverage of 11AA on the CS surface, i.e. the formation of a more compact 11AA monolayer.L'acier au carbone est le matériel le plus couramment utilisé pour les équipements et les pipelines reliés aux processus de production pétrolière. Toutefois, la présence de certains éléments comme l'eau, les sels and le dioxyde de carbone dans l'huile pose plusieurs problèmes reliés à l'augmentation du taux de corrosion du matériel. La façon la plus répandue d'éliminer ce problème est l'utilisation d'inhibiteurs de corrosion. Il est cependant important de mentionner que la majorité de ces inhibiteurs sont nocifs pour l'être humain. Il est donc nécessaire de développer des composés compatibles avec l'environnement et biodégradables et ceci peut être fait avec l'utilisation d'acides aminés.Ce projet a pour but d'étudier l'influence des acides aminés "11-aminoundecanoic acid" (11AA) et "12-aminododecanoic acid" (12AA) en tant que qu'inhibiteurs pour l'acier carbone dans l'acide chlorhydrique et plusieurs autres électrolytes utilisés dans certaines industries.Dans cette étude, l'effet inhibiteur du 12AA sur la corrosion de l'acier carbone dans une solution sans ou saturée en dioxyde de carbone et avec 0.5 M d'acide chlorhydrique a été étudié. Différents paramètres tels que la concentration des inhibiteurs, la concentration des électrolytes, le pH, la température, le temps de traitement, la rugosité de surface, le taux de flux et les différents types d'électrolytes furent analysés pour mieux comprendre le mécanisme de fonctionnement. De plus, l'interaction du 11AA avec la surface de l'acier à certaines conditions fut également prise en considération.Il fut démontré que le 12AA inhibait les corrosions partielles et démontrait une corrosion anodique légèrement plus inhibée. Ceci nous a donc indiqué que cet inhibiteur était de type mixte. Le mécanisme de protection de la corrosion se faisait par adsorption de l'inhibiteur 12AA et cela procurait une protection hydrophobique contre les ions corrosifs avec une efficacité de 98%. L'adsorption de 12AA à la surface de l'acier suit le modèle de l'isotherme de Langmuir. L'énergie de Gibbs correspondante de cette adsorption a été calculée comme étant environ −26 (sans CO2) et −28 kJ mol−1 (saturée en CO2 et 0.5 M HCl). Ceci a indiqué que la formation de la couche (composée d'une épaisseur) est amorphe et que cela est causé par la répulsion engendrée avec les groupes voisins de même charge positive et par le caractère très hétérogène de la surface. L'étude a aussi démontré que le 12AA peut être très efficace contre la corrosion de l'acier carbone et ce avec une grande variété d'électrolytes et d'acides. Il est important de mentionner que l'inhibiteur est inefficace contre l'acide nitrique et sulfurique. L'inhibiteur peut aussi réduire la corrosion lorsque le pH est élevé, mais voit son efficacité réduite dans ces conditions en raison de l'augmentation de sa solubilité. Finalement, le 12AA semble aussi performant avec toutes les rugosités. L'effet et le type de flux d'une solution de HCl saturée en dioxyde de carbone fut aussi étudié avec l'aide d'une électrode à disque rotatif. L'inhibiteur 12AA (3mM) se démontra très performant à contrer la corrosion dans un espace carré et avec un électrode à disque rotatif. Cependant, lorsque la concentration fut réduite à 1mM la performance de l'inhibiteur diminua et son nombre de Reynolds fut augmenté. Ceci fut causé par désorption de 12AA de la surface de l'acier. Cet inhibiteur ne fut donc pas efficace à protéger l'acier carbone dans ces conditions.L'étude de l'inhibiteur 11AA donna des résultats similaires. Cependant, la protection de l'acier carbone fut plus efficace qu'avec le 12AA à cause que le 11AA est capable de couvrir une surface plus importante tout en faisant une couche plus compacte.
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Alizadehbirjandi, Atefeh. "Polymeric drug delivery vehicles for encapsulation and release of SAHA histone deacetylase inhibitors." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1546447766963075.
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Stangner, Konstanze. "Development of Indole-Based Inhibitors of Acetylcholinesterase to Combat Mosquito-Borne Diseases." Thesis, Umeå universitet, Kemiska institutionen, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-160177.
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Kauppi, Anna. "Chemical attenuation of bacterial virulence : small molecule inhibitors of type III secretion." Doctoral thesis, Umeå : Department of Chemistry, Umeå University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-936.
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Lau, Lai-shan. "Identification of small molecule inhibitors of influenza A virus by chemical genetics." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39634413.
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Lau, Lai-shan, and 劉麗珊. "Identification of small molecule inhibitors of influenza A virus by chemical genetics." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39634413.
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Yamamoto, Masaru. "Synthesis and oxidation studies of sulfur containing inhibitors for human leukocyte elastase : (2) synthesis of cyclic peptide analogs for tissue factor pathway inhibitor (TFPI) : Part 2 synthesis and evaluation of aziridinecarboxylic acid analogs as a new family of cysteine proteinase inhibitors." Diss., Georgia Institute of Technology, 1993. http://hdl.handle.net/1853/25953.
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Sigtryggsson, Sigtryggur Bjarki. "Design and Synthesis of Novel Small-Molecule Inhibitors of the Keap1-Nrf2 PPI." Thesis, Uppsala universitet, Organisk kemi, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-396049.
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Cot, Emilie. "Inhibition chimique des Cdk : mécanisme biochimiques et conséquences cellulaires." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20054.
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Les kinases dépendantes des Cyclines (Cdk) contrôlent le déroulement du cycle cellulaire, mais leur étude est difficile car des mécanismes de compensation se développent lorsqu'une Cdk est absente. Cdk2 est principalement impliquée dans la phase de réplication de l'ADN, cependant l'ablation génétique de Cdk2 chez la souris n'a pas d'effet sur leur développement: les fonctions de Cdk2 sont compensées par d'autres Cdk. L'inhibition chimique permet de bloquer une Cdk et de limiter les compensations. Pour étudier les rôles de Cdk2, nous l'avons inhibé avec NU6102 qui sélectif pour Cdk2 dans le modèle xénope. Nous avons aussi développé des mutants de Cdk2 résistants à NU6102 pour vérifier sa sélectivité et avons cherché à mieux comprendre les paramètres qui déterminent l'affinité entre Cdk2 et un ligand. D'autre part, nous déterminons in vitro que NU6102 serait plus sélectif pour Cdk2 que pour les autres Cdk chez l'humain, et avons décrit les phénotypes induits par cet inhibiteur dans les cellules humaines en cultures. Ces résultats ne permettent pas de confirmer la sélectivité de NU6102 mais montrent que NU6102 a des caractéristiques intéressantes pour être utilisé dans le traitement contre le cancer. L'activité des Cdk est essentielle à l'initiation de la réplication de l'ADN, mais aucun substrat essentiel n'a été identifié chez les métazoaires. Nous avons réalisé un crible des protéines chargées sur la chromatine en présence et en absence d'activité Cdk dans le modèle xénope, afin d'identifier des substrats qui pourraient être impliqués dans la réplication. Ces résultats suggèrent que l'activité Cdk, qui initie la réplication au niveau des origines de réplication de l'ADN, pourrait être impliquée dans d'autres fonctions cellulairesCycline Dependant Kinases (Cdk) control cell cycle progression. The study of their roles is often difficult because of functional redundancy; when a given Cdk is absent, others may compensate. The main role of Cdk2 in the cell cycle is in the initiation of DNA replication, but absence of Cdk2 is compensated for by Cdk1. For example, mice with a genetic knockout of Cdk2 are viable. The chemical inhibition of Cdks may limit compensation by other Cdks. Therefore, to study Cdk2 roles, we have studied chemical inhibition by NU6102, which seems to be selective for Cdk2 in the Xenopus model. To verify the selectivity and study parameters that determine selectivity, we have designed and produced mutants of Cdk2 which are resistant to NU6102, allowing restoration of function in the presence of inhibitor. Moreover, we demonstrate in vitro that NU6102 is selective for Cdk2 compared to other human Cdks, and we describe phenotypes induced by NU6102 in cultured cells, which are interesting in the light of potential applications of NU6102 in cancer chemotherapy. Cdk activity is essential for initiation of DNA replication, but in metazoans no essential substrates are known. To identify potential Cdk substrates during DNA replication, we have performed a proteomics screen of the proteins loaded onto chromatin in the presence or absence of Cdk activity, in the Xenopus model. The results suggest that Cdk activity is not only required for assembling DNA replication complexes onto origins of replication, but may also be implicated in other cellular functions
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Hudson, Christine Cecilia. "Isolation of signal transduction inhibitors by bioassay-directed fractionation of plant extracts." Diss., Georgia Institute of Technology, 1996. http://hdl.handle.net/1853/30636.
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Arora, Ishan. "Identification of features contributing to binding promiscuity of small-molecule inhibitors for rapidly mutating targets." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/114313.
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Thesis: S.M., Massachusetts Institute of Technology, Department of Chemical Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 21-27).
HIV infection has become a persistent worldwide epidemic despite the continuous development of novel inhibitors. A key challenge in combating HIV and other pandemic viral infections is the ability of the virus to mutate at an enormous rate and rapidly develop resistance to existing drugs. Among the various strategies that have been explored for the design of broadly binding HIV protease inhibitors, the substrate envelope hypothesis which is based on the idea of designing drugs that mimic the structural features of substrates has proved particularly effective. However, studies aimed at probing the substrate envelope hypothesis have found that the substrate envelope is a contributory but not sufficient property for robust binding and hence it is important to develop a better understanding of the other factors that contribute to binding promiscuity. This study investigated the key features which differentiate robust HIV protease inhibitors from susceptible HIV protease inhibitors by examining the interactions of certain known flat and nonflat binders with the different residues of HIV protease in terms of binding energy and number of contacts and correlating this analysis with the information about the mutational space of the virus. It was found that the promiscuous inhibitors, susceptible inhibitors and substrates all interact with the same set of HIV protease residues, some of which are vulnerable to primary mutations. The total contribution to the binding of an inhibitor/substrate to HIV protease from the HIV protease residues that are associated with primary mutations was observed to be a vital attribute separating flat binders from susceptible binders, with a greater contribution to binding from these residues translating into a higher susceptibility of the inhibitor to primary mutations. Certain strategies were proposed for incorporating these inferences in the computational drug design framework in order to generate robust HIV protease inhibitors. Although the analysis in this project was carried out using HIV protease as the model system, it is envisaged that the results obtained here would be generalizable to other rapidly mutating targets and hence these insights would facilitate drug design in the case of the outbreak of new epidemics of highly mutable infectious agents.
by Ishan Arora.
S.M.
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Njuguna, Nicholas M. "Investigating the chemical space and metabolic bioactivation of natural products and cross-reactivity of chemical inhibitors in CYP450 phenotyping." Doctoral thesis, University of Cape Town, 2014. http://hdl.handle.net/11427/12927.
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Includes bibliographical references.Natural products have been exploited by humans as the most consistently reliable source of medicines for hundreds of years. Owing to the great diversity in chemical scaffolds they encompass, these compounds provide an almost limitless starting point for the discovery and development of novel semi-synthetic or wholly synthetic drugs. In Africa, and many other parts of the world, natural products in the form of herbal remedies are still used as primary therapeutic interventions by populations far removed from conventional healthcare facilities. However, unlike conventional drugs that typically undergo extensive safety studies during development, traditional remedies are often not subjected to similar evaluation and could therefore harbour unforeseen risks alongside their established efficacy. A comparison of the ‘drug-like properties’ of 335 natural products from medicinal plants reported in the African Herbal Pharmacopoeia with those of 608 compounds from the British Pharmacopoeia 2009 was performed using in silico tools. The data obtained showed that the natural products differed significantly from conventional drugs with regard to molecular weight, rotatable bonds and H-bond donor distributions but not with regard to lipophilicity (cLogP) and H-bond acceptor distributions. In general, the natural products were found to exhibit a higher degree of deviation from Lipinski’s ‘Rule-of-Five’. Additionally, these compounds possessed a slightly greater number of structural alerts per molecule compared to conventional drugs, suggesting a higher likelihood of undergoing metabolic bioactivation.
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Young, Frederick Kwai. "An investigation into the effects of novel DBM and PAM effectors on catecholamine metabolism and amidation in adrenal chromaffin cell culture : (2) Microbial production of poly-β-hydroxybutyric acid from D-xylose and lactose using pseudomonas cepacia." Diss., Georgia Institute of Technology, 1995. http://hdl.handle.net/1853/26247.
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Mosley, Sylvester L. "Base-modified carbocyclic nucleosides as medicinal agents." Thesis, Georgia Institute of Technology, 2001. http://hdl.handle.net/1853/27041.
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Bortone, Kara Michelle. "Structural analysis of Coccidioides immitis chitinase activity and inhibition /." Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3008282.
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Deller, Robert C. "The investigation and application of ice recrystallization inhibitors as cryoprotectants." Thesis, University of Warwick, 2013. http://wrap.warwick.ac.uk/61919/.
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There is a continuing need for improvements in the cryopreservation of clinically relevant cells, tissues and organs as advances in transplantation science and regenerative medicine rise alongside an aging populace that intensifies demand. Antifreeze (glyco)proteins (AF(G)Ps) and antifreeze proteins (AFPs) are classes of proteins found in cold acclimatized species. Ice recrystallization is a highly damaging process that occurs upon the thawing of frozen specimens with AF(G)Ps and AFPs limiting this effect in a process termed ice recrystallization inhibition (IRI). However AF(G)Ps and AFPs largely fail to improve in vitro and ex vivo cryopreservation due to their secondary property of dynamic ice shaping. The biocompatible and synthetically accessible polymer poly(vinyl alcohol) (PVA) has been shown to process a strong IRI activity. The IRI property of PVA along with numerous other polymers and polyols is investigated to highlight the uniqueness of PVA (Chapter 2). PVA is then explored as a cryoprotectant with red blood cells (Chapter 3), immortalized mammalian cell lines (Chapter 4) and primary cells (Chapter 5) with a significant advantageous effect observed with each cell type in terms of the number of cells recovered post thaw. However, this is despite the use of proportionately low concentrations of PVA compared to traditional membrane permeable cryoprotectants. The application of PVA as a cryoadjuvant could therefore improve the cryopreservation of cells, tissues and organs resulting in widespread clinical benefits.
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Collins, James Charles. "Inhibitors of Cdc25 phosphatases : potential anti-cancer drugs and tools for chemical genetics." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/11189.
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Cdc25 phosphatases play a crucial role in the regulation of the cell cycle, and overexpression of the three known isoforms has been directly correlated with poor cancer prognosis. Inhibition of this enzyme could prove to be an effective therapeutic strategy, but the most potent reported inhibitors lack specificity and an appropriate mechanism of action. Furthermore, more basic research is needed into the structure and precise cellular function of the different cdc25 isoforms. Following a literature survey, panels of novel inhibitors modelled on the natural product dysidiolide and reported quinonoid compounds were synthesised. Initial phosphatase assay results with cdc25A discouraged any further synthesis of related inhibitors. The untagged catalytic domain of each isoform was prepared, expressed and purified to carry out NMR structural studies. However, preliminary spectra showed a high degree of conformational flexibility that made further analysis prohibitively difficult. Extensive screening of crystallisation conditions also did not prove successful. As an alternative strategy, a ligand-based virtual screening approach using an optimised selection of reported inhibitors resulted in discovery of diarylthiazoles as novel, potent and drug-like inhibitors of cdc25 and the related phosphatase VHR. Some of these compounds also demonstrated potent anti-proliferative activity against a panel of cell lines. Parallel synthesis of a wide range of diarylthiazole analogues using a regioselective, sequential Pd-coupling approach proved moderately successful, identifying promising novel inhibitors for further development, although without significantly increasing the binding affinity. Screening of a wide range of commercially-available compounds chosen by a substructure analysis identified further promising inhibitors, which compare favourably with the best literature compounds. Attempts to develop novel methodology for the rapid and divergent synthesis of aminothiazoles ultimately proved unsuccessful with respect to various approaches to the difficult C-N bond formation, but simple conditions were found for the synthesis and Suzuki coupling of a highly electron-rich aminothiazole C4-triflate.
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ANGIONI, MARIA MADDALENA. "Response to treatment with chemical and biological inhibitors of c-met mutated form." Doctoral thesis, Università degli Studi di Cagliari, 2012. http://hdl.handle.net/11584/266057.
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c-MET is a receptor tyrosine kinase that, after binding with its ligand, hepatocyte growth factor (HGF), activates many signaling pathways, driving proliferation, motility, migration and invasion. Although c-MET is important in the control of tissue homeostasis under normal physiological
conditions, it has also been found to be aberrantly activated in human cancers via mutation, amplification or protein overexpression. Activating point mutations were identified in the kinase domain of MET, either in the germline of patients affected by hereditary papillary renal carcinoma (HPRC) or in spontaneously occurring tumors; in particular, nine missense mutations (defined METPRC mutations), leading to constitutive activation of MET protein, have been identified in HPRC families. Given the importance of MET as a target for cancer therapies, clinical trials aimed at inhibiting it through the use of tyrosine kinase inhibitors (TKIs) have recently been started. The aim of project was: (i) to evaluate if METPRC mutants are sensitive to PHA-665752 (a small kinase inhibitor of MET), (ii) if some mutants are insensitive to the inhibitor, to investigate the mechanisms responsible for resistance, (iii) to check if the resistant mutants are still sensitive to other chemicals inhibitors or monoclonal antibodies against MET, (iv) to identify activating point
mutations in human surgically resected lung cancers.
We have found that some METPRC mutants cannot be inhibited by PHA-665752. Treatment with this TKI does not alter either receptor phosphorylation or MET mutants-induced biological activities (migration, invasion, anchorage-independent growth). We showed that these mutants are
insensitive also to JNJ-38877605, a multitargeted tyrosine kinase inhibitor.. When we performed the mutational analysis on lung cancer samples, in one tumor we found the presence of one of the identified“resistant” mutations.
To determine whether the mutants resistant to PHA-665752 could be inhibited with other strategies, we treated the mutant-expressing cells with the monoclonal antibody DN30, directed against the extracellular portion of the receptor. Our results showed that DN30 was indeed able to inhibit all the METPRC mutants. In conclusion, we have identified some METPRC mutants which do not respond to the ATP competitive kinase inhibitors. Since the identified METPRC mutations are located in the kinase domain and alter its conformation; it is likely that the competitive inhibitors are unable to interact with the ATP binding site in the context of the mutated receptors; this would render these mutants "resistant" to the action of tyrosine kinase inhibitors. However, these mutated forms still remain
responsive to treatment antibodies directed against the MET extracellular portion: This observation is important since the use of monoclonal antibodies represent a therapeutic alternative for patients with tumors carrying MET mutants resistant to TKIs.
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Muto, Yukiyo. "The synthesis and mode of action of NPPB and related compounds." Thesis, University of Canterbury. Biological Sciences, 2006. http://hdl.handle.net/10092/1522.
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5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) was normally recognised as a Cl- channel inhibitor, but its specificity is in question, since an inhibitory effect against K⁺ channels has been reported. To identify the significance of the molecules structural components, NPPB and related compounds, such as 2-(3-phenylpropylamino) benzoic acid (PPAB), 5- nitro-2-heptylamino benzoic acid (HANB) and 2-nitro-5-heptylamino benzoic acid (HANB-2) were synthesised by reductive amination using various aldehydes and amines. Using internodal cells of the giant green Characean algae, Nitella hookeri, the effects of NPPB and related compounds on cytoplasmic streaming and turgor regulation were determined. Previous experiments stated that cytoplasmic streaming was sensitive to NPPB, PPAB and HANB with IC₅₀ values of 24µmol/L, 455µmol/L, and 6.4mmol/L, respectively. In this report, the IC₅₀ values of purchased NPPB and niflumic acid were found to be 88.65µmol/L and 121.82µmol/L, respectively. Although the IC₅₀ value of purchased NPPB showed a slight difference from that of synthesised NPPB, the results of the cytoplasmic streaming experiment indicated the possibility of this analysis to be a simple assay system for analysing the effects of structural modification to ion channel inhibitors on their biological activity. Moreover, NPPB and PPAB seem to stimulate regulation of turgor pressure under hyperosmotic shock, which can be explained by a blockage of K⁺ efflux during osmotic stress leading to faster recovery of turgor regulation. Additionally, the results of cytosolic free Ca²⁺ analysis using aequorin technology also suggested that the possibility of this analysis to be used as a more direct measure of the inhibitory effect, while the cytoplasmic streaming analysis is a more indirect method. The preliminary results from this research suggest the significance of the simple assay systems for analysing the effects of structural modification ion channel inhibitors, which can be used for future study regarding ion channel structures.
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Lessard, Lindsay Dianne. "Morphology study of structure I methane hydrate formation on water droplets in the presence of kinetic inhibitors." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=99520.
Full textAbstract:
Gas hydrates are non-stoichiometric crystalline compounds that occur when water molecules hydrogen bond to form cavities which can be stabilized by the presence of a guest molecule such as a gas or volatile liquid. Hydrates have been problematic in the oil and gas industry for several years as they may block pipelines and damage equipment. It is therefore of great interest to find environmentally safe inhibitors which can prevent hydrates from forming or from growing large enough to block pipelines.The purpose of my study was to observe the effect of kinetic inhibitors on the morphology of methane structure I hydrate using a high pressure crystallizer. Two kinetic inhibitors were studied, poly(VP/VC), a lactam ring copolymer, and antifreeze protein.
Experiments were carried out on droplets with and without memory at pressures ranging from 5000 kPa to 10,000 kPa. There was no evident trend in induction times since nucleation is a stochastic process. Surface coverage time of each droplet was measured and found to be fastest on the water droplet followed by that of the poly(VP/VC) droplet and finally the AFP droplet, confirming that the two kinetic inhibitors studied were in fact effective at inhibiting hydrate growth. Since hydrate growth, unlike nucleation, can reliably be measured we can definitively conclude that AFP has a greater kinetic inhibiting effect on hydrate growth.
During hydrate decomposition, it was observed in all experiments that the water droplet decomposed first followed by the poly(VP/VC) droplet and the AFP droplet. It is proposed that since the polymer chains and protein molecules bind to the hydrate crystals, this reduces the surface area of hydrate skin exposed, slowing the rate of decomposition.
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Hirao, Maki. "A chemical genetic approach for the identification of selective inhibitors of NAD(+)-dependent deacetylases /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/8534.
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Badiani, Kamal. "Synthesis and evaluation of enzyme inhibitors based on amino- and cyclopropane carboxylic acids." Thesis, University of St Andrews, 1997. http://hdl.handle.net/10023/14052.
Full textAbstract:
The coenzyme B12-dependent enzyme, glutamate mutase (E. C. 5.4.99.1), catalyses the reversible carbon-skeleton rearrangement of (2S)-glutamic acid to (25.35)-3-methylaspartic acid. Glutamate mutase is the first enzyme on the mesaconate pathway. A variety of glutamate and 3-methylaspartate analogues (which also include isotopically labelled molecules), were synthesised as molecular probes of the enzyme. Synthesis of stereospecifically labelled 3-ethylaspartic acid: (2S,3S)-[3'-C2H3], and (2S,3S)-[C2H2C2H3]-ethylaspartic acids were constructed using appropriately labelled iodoethane. (2S,3S)-2-Bromo-3-methylsuccinic acid was synthesised via the diazotization of (2S,3S)-3-methylaspartic acid, in the presence of bromide ion. (2S)-Methylsuccinic acid was synthesised by the catalytic hydrogenation of (2S,3S)-2-bromo-3-methylsucdnic acid. Biological studies of the synthesised compounds (including the labelled isotopomers) displayed no activity against glutamate mutase. 3-Methylaspartate ammonia-lyase, the second enzyme in the mesaconate pathway, catalyses the deamination of (2S,3S)-3-methylaspartic acid to mesaconic acid. A range of 1-substituted cyclopropane 1,2-dicarboxylic acids were synthesised using short efficient routes and were found to be good to potent inhibitors of 3-methylaspartase. X-ray crystallographic studies have determined the absolute stereochemistry. The mode of action of the most potent inhibitor, (1S,2S)-1-methylcyclopropane 1,2-dicarboxylic acid (20 mumol dm-3), is consistent with it acting as a transition state analogue for the central substrate deamination reaction catalysed by the enzyme. beta-Amino acids are constituents of many biologically active peptides. A general procedure for the synthesis of alpha-substituted-beta-amino acids has been developed. The synthesis involves a Baylis-Hillman amine catalysed conversion of methyl acrylate, with an appropriate aldehyde, to give the alpha-(hydroxyalkyl) acrylate. Bromination and subsequent azide displacement furnishes the azido alkene, which is catalytically hydrogenated, to furnish the beta-amino ester.