Дисертації з теми "Anti-novel"
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1
Gunnam, Mallikarjunareddy. "Novel anti-norovirus therapeutics." Thesis, Wichita State University, 2013. http://hdl.handle.net/10057/6818.
Повний текст джерелаАнотація:
Noroviruses are the most common cause of acute gastroenteritis, accounting for over 23 million cases annually in the U.S. alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this thesis, (a) structure-activity relationship studies were carried out using the acyclic sulfamide scaffold. Several derivatives based on this scaffold were found to inhibit norovirus in a cell-based replicon system and, (b) a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and ?-ketomides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED50 of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition inhibitors in the inhibition of norovirus 3CL protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as ?-ketoheterocycles and ?-ketoesters. Taken together, this thesis describes the discovery of two novel classes of inhibitors of noroviruses.Thesis (M.S.)--Wichita State University, Fairmount College of Liberal Arts and Sciences, Dept. of Chemistry
2
Calhoun, McKenzie L. "Novel Anti-Diabetic Medications." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/6885.
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3
Di, Francesco Angela Maria. "Anti-tumour properties of novel diaziridinylquinones." Thesis, University of Salford, 2001. http://usir.salford.ac.uk/26638/.
Повний текст джерелаАнотація:
This work is concerned with the synthesis and potential anti-tumour properties of novel Diaziridinylquinones. These types of compounds are usually activated by bioreduction to form cytotoxic species, which alkylate DNA and block cells in the G 2 /M phase of the cell cycle. However, the present studies have concentrated on compounds which appear to function by other mechanisms. Certain phenol/ester derivatives of PDZQ (2,5-diaziridinyl-3-phenyl-l,4-benzoquinone) were significantly more cytotoxic than PDZQ in all of the cell lines investigated (Chapter 3). The esters were cleaved by esterases to form a highly cytotoxic stable meta-phenol or an unstable para-phenol. The compounds were studied in detail using DNA cross-linking, clonogenic, apoptosis and flow cytometry assays. Preliminary studies on the protein tyrosine kinase (PTK) activity of the epidermal growth factor receptor (EGF-R) showed that the |iM concentrations of the meta-phenol can reduce the PTK activity of purified EGF-R by 50%. The overall proposed mechanism is that the cytotoxic esters are cleaved by esterases to form reactive phenols. However, the enhanced toxicities of these compounds are not simply due to the differences in DNA cross-linking efficiencies. It is proposed that the phenols cross-link DNA and inhibit one or more tyrosine kinases. Preliminary tumour xenograft studies suggest that some acridine derivatives of PDZQ have a very high therapeutic index (Chapter 4). These compounds cross-link DNA but there is no DNA-intercalation (from fluorescence, absorbance, DNA-unwinding and T m studies). It is proposed that these compounds can be reduced within a cell and interact with Topoisomerases. RH1 is scheduled for Phase I/II clinical trials and the final chapter of this thesis reports on the induction of apoptosis by this diaziridinylquinone. These studies used many different biochemical/visual techniques to measure apoptosis. The general conclusion from this study is that although RH1 can induce apoptosis, the extent is strongly dependent on the cell line and it is only significant at relatively high concentrations of drug.
4
Altaie, Ala. "Novel anti-oxidant properties of cobalamin." Thesis, University of Chester, 2009. http://hdl.handle.net/10034/128965.
Повний текст джерелаАнотація:
Oxidative stress has been associated with a wide range of diseases, including cardiovascular diseases, Alzheimer's disease, atherosclerosis, Parkinson's disease and cancer. It also plays a role in the ageing process. Hyperhomocysteimia is commonly found to be associated with these diseases. The hyperhomocysteimia is a result of a deficiency in both folate and cobalamin Folate is known to reduce Hey and protect cells from apoptosis, but there are no studies investigating the impact of cobalamin on apoptosis induced by oxidative stress or the mechanism(s) of the protection. The aims of the research are to investigate the protective role of cobalamin and the possible mechanism(s) for this protection. It also examines the protective role of novel cobalamin and investigates their superior protection. The methods used in this research for apoptosis detection we used caspase-3 and the annexin-V, while for necrosis we used PI staining, where cell viability were detected using MTS assay. We also measured the generation of superoxide by Lucigenin-enhanced chemiluminescence and reactive oxygene species by using the redox active prob DCFH-DA. Moreover, the intracellular proteins were measured via staining with specific fluorescent-conjugated antibodies were detected using flowcytometry. Our result demonstrated that 25|iM of cobalamin protects cells from apoptosis. The protection by cobalamin was associated with induction of iHsp72 and iHO-1, and these are shown to be essential for the protection. Furthermore, our research demonstrated a novel mechanism of cobalamin-apoptosis protection involving induction of NfkB, ERK1/2 and AKT signal transduction pathways. In order to protect cells from apoptosis induced by oxidative stress, cobalamin induces the pNfkB which in turn regulate the iNOS and HO-1 induction. Cobalamin also induces thepERK1/2 which regulates the induction of Hps72 and Nrf2. And finally, pAKT induced by cobalamin which regulate the Nrf2 and HO-1 induction. The inhibition of any of theses pathways leads to loss the protection. The GSCbl and NACCbl provide a superior protection against oxidative stress, this protection involved induction of the signal transduction pathways and Hsps. To conclude; cobalamin provides protection against cells death induced by oxidative stress. Cobalamin achieves this by multiple pathways which include direct antioxidant stimulation and induction of signal transduction pathways. Different cobalamin derivatives have superior protections. These finding are a useful pharmaceutical tool in the treatment of the oxidative stress related diseases.
5
Fu, Yu. "Baicalein, a novel anti-diabetic compound." Thesis, Virginia Tech, 2012. http://hdl.handle.net/10919/76854.
Повний текст джерелаАнотація:
Both in type 1 (T1D) and type 2 diabetes (T2D), the deterioration of glycemic control over time is primarily caused by an inadequate mass and progressive dysfunction of ?-cells, leading to the impaired insulin secretion. Thus, the search for agents to protect b-cell and enhance its function is important for diabetes treatment. Studies have reported that baicalein, a flavone originally isolated from the roots of Chinese herb Scutellaria baicalensis, has various claimed beneficial effects on health, such as anti-oxidant, anti-viral, anti-thrombotic, and anti-inflammatory effects. However, it is unclear whether it exerts an anti-diabetic action. Here, we present evidence that baicalein may be a novel anti-diabetic agent. Specifically, dietary intake of baicalein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in high-fat diet (HFD)-fed middle-aged diabetic mice, which was associated with the improved isle t?-cell survival and mass. Baicalein treatment had no effect on food intake, body weight gain, circulating lipid profile, and insulin sensitivity in HFD-fed mice. In in-vitro studies, baicalein significantly augmented glucose-stimulated insulin secretion in insulin-secreting cells (INS1) and promotes viability of INS1 cells and human islets. These results demonstrate that baicalein may be a naturally occurring anti-diabetic agent by directly modulating pancreatic?-cell function.Master of Science
6
Bennett, Andrew Richard. "Novel anti-corrosion coatings on steel." Thesis, Swansea University, 2009. https://cronfa.swan.ac.uk/Record/cronfa42310.
Повний текст джерелаАнотація:
The primary objective of the work detailed in this thesis was to further explore the inhibitory performance of polyaniline for the prevention of corrosion-driven cathodic disbondment on steels and zinc-alloy coated steels. Polyaniline was investigated under atmospheric conditions so as to make possible further elucidation of the mechanisms by which it would provide this inhibition. Accordingly it is suggested that the positive performance of polyaniline indicated within this report, in addition to further mechanistic understanding, paves the way for industrial use of polyaniline as an inhibitor. To provide further mechanistic support to the inhibitory performance of polyaniline, polyaniline micro-films were applied to the metal substrate surfaces, allowing the visualisation of electrochemical and acid-base state changes resulting from substrate contact and corrosion. Due to industrial concerns over the current cost associated with polyaniline inhibitor pigments, the inhibitory properties of novel organic acid etch primers were explored on both iron and zinc substrates. The findings of this study led to the proposition that the presence of polyaniline may not be required within the model organic coating system in order to provide a similar level of inhibition. Alongside the investigations of inhibitory organic coating systems, attention was directed towards novel Mg-Al-Zn metallic coatings. These are shown to provide inhibition of cathodic disbondment of organic coatings where no form of in-coating inhibition is present. These alloy-coated steels were found to suffer from a novel form of corrosion and full mechanistic proposition is provided, as well as important initiation factors. Finally, the photovoltaic possibilities of polyaniline were explored in order to find novel, high value coating systems for the pre-painted steel industry. Accordingly the photovoltaic properties of polyaniline are compared to established photovoltaic polymers.
7
Mizuhara, Tsukasa. "Development of Novel Anti-HIV Pyrimidobenzothiazine Derivatives." 京都大学 (Kyoto University), 2013. http://hdl.handle.net/2433/174545.
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8
Errey, James C. "Mechanistic studies of novel anti-tuberculosis targets." Thesis, University of East Anglia, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398794.
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9
Seaton, Angela. "Anti-tumour activity of novel phenolic compounds." Thesis, University of Nottingham, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324524.
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10
Gorsuch, Stephen. "Synthetic approaches towards novel anti-HIV agents." Thesis, University of Reading, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265108.
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11
McNaughton, Emily Francis. "Novel anti-inflammatory peptides based on chemokines." Thesis, University of Bristol, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730839.
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12
Gong, Miranda Christina, and Miranda Christina Gong. "Strategies for a Novel Anti-Influenza Therapy." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/624996.
Повний текст джерелаАнотація:
This experiment compares the implications of two methods of measuring viral particles, specifically Influenza particles in human cell lines in vitro. These strategies include plaque assays and xCELLigence screening. Plaque assays, also known as reduction assays, are plates that are overlaid with semi-solid medium that limits the spread of the virus and shows where each particle is located based on the "plaque" or empty space on the plates where cells have died and been removed. xCELLigence screening is a newer program that checks for "impedance", an artificial number that will measure the cells killed by virus as well as cell to cell interaction on a 96 well plate that utilizes gold microelectrodes. Both methods have variables that can make them useful in certain situations, however, the focus is on how reliable the xCELLigence program is in comparison to more traditional methods of quantifying viral particles.
13
Laughridge, Carrie Butler. "Anti-Catholicism in the eighteenth century novel." Winston-Salem, NC : Wake Forest University, 2009. http://dspace.zsr.wfu.edu/jspui/handle/10339/42524.
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14
Tench, Allen James. "The synthesis of novel anti viral nucleosides and novel glutamic acid analogues." Thesis, University of Reading, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394416.
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15
Lyu, Jun Fang. "Discovery of cholesterol trafficking inhibitors as novel anti-angiogenic and anti-cancer agents." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3953967.
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16
Hagan, Damien James. "The synthesis of novel anti-cancer acridine derivatives." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284428.
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17
Cook, Andrew James. "Metal catalysed approaches to novel anti-cancer agents." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411359.
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18
Conner, Elaine Margaret. "Novel metal conjugates as potential anti colitic agents." Thesis, University of Strathclyde, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249764.
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19
Mullan, Patrick Joseph. "A microbiological study of novel anti-plaque agents." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299397.
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20
Rowling, Emily. "Pre-clinical evaluation of novel anti-metastatic targets." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/preclinical-evaluation-of-novel-antimetastatic-targets(caa9ab41-c054-4559-b575-3fd8974005a7).html.
Повний текст джерелаАнотація:
Background: Radiotherapy is used in the treatment of over 50% of cancer patients and bar surgery, is the most effective cancer intervention. However, in the clinic secondary malignancies have been observed following radiotherapy and in vitro increased cell migration and invasion have been seen following radiation. The Src/FAK signalling pathway is known to play an important role in the metastatic phenotype through its involvement in cell adhesion, migration and invasion and we have previously demonstrated that radiotherapy can activate this pathway along with the phosphoinositide 3-kinase (PI3K) pathway, also associated with tumour metastases and an aggressive phenotype. Using pharmacological inhibitors, we have investigated combination approaches to evaluate whether Src and PI3K targeting is beneficial in a radiotherapy context, especially focusing on metastatic phenotype. We wished to relate pathway activation to cellular phenotype and increase understanding of the metastatic cascade, the processes involved and the signalling pathways taking the lead. Method: Using thyroid carcinoma cell lines FTC133 and 8505c the effects of Src inhibition using AZD0530, FAK inhibition using FAKi and PI3K inhibition using GDC-0941 were studied. The effects of radiotherapy alone, and in combination with the above inhibitors, were also studied. In vitro MTT, apoptosis and clonogenic assays were used to assess cell proliferation and cell survival and scratch assays, cell adhesion and cell spreading assays were used to assess the effects of the drugs on metastatic characteristics. In vivo tumour growth, survival and ex vivo clonogenics were used to measure the effects of AZD0530 and GDC-0941. Western blotting, immunofluorescence and immunohistochemistry was used to observe the effects on pathway activation and protein localisation. Results: Src and FAK inhibition reduced metastatic characteristics of thyroid carcinoma cell lines in vitro such as cell spreading and migration. FAK inhibition showed a greater effect on cell survival by MTT, clonogenic and apoptosis. In the thyroid carcinoma cell lines radiotherapy enhanced the metastatic phenotype. This was seen by enhanced activation of the Src and PI3K pathways, increased migration and invasion in vitro and enhanced tumour metastasis in vivo. By combining Src inhibition with radiation a reduction in metastatic characteristics was observed and by combining PI3K inhibition with radiotherapy radiosensitivity could be improved. With the triple combination of Src and PI3K inhibition with radiotherapy a significant reduction in cell survival was demonstrated in vitro compared to radiation alone and either inhibitor combined with radiation, with a corresponding significant reduction in tumour growth being observed in vivo. With the combination of Src and PI3K inhibition significant reductions in metastatic characteristics were also observed both in vitro and in vivo seen by a reduction in cell migration and tumour metastasis. Finally combined inhibition of the Src and PI3K pathway reduced the radiation enhanced activation of several pathways in vivo including Src and PI3K.Conclusions: Together these results suggest that the Src and PI3K pathways play a role in radiation enhanced metastatic characteristics in thyroid carcinoma and through combined inhibition of the pathway the negative effects of radiation, enhanced migration and invasion, can be inhibited and the cells can be made more radiosensitive. Full characterisation of the pathways involved in radiation induced motility and radioresistance will provide further rationale for combination therapies and provide potential for application of these therapies in the clinic.
21
Duffy, Judith Clare. "Design of novel non-steroidal anti-inflammatory drugs." Thesis, Liverpool John Moores University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521744.
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22
Carson, L. "Novel anti-virulence and anti-infective strategies targeting the opportunistic bacterial pathogen, Proteus mirabilis." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546022.
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23
Menhofer, Magdalena H. "Characterization of the myxobacterial compound Chondramide as novel anti-angiogenic and anti-metastatic agent." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-167962.
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24
Hogg, Chris. "Apelin and novel stable peptide analogues : assessing their anti-diabetic and anti-obesity potential." Thesis, Ulster University, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.734608.
Повний текст джерелаАнотація:
Apelin is a circulating peptide produced and secreted by the adipocyte and thus is considered an adipokine. It was first discovered from bovine stomach extracts as an endogenous ligand for the orphan receptor APJ (apelin receptor) and is a product of APLN (apelin) gene, translated as a 77 amino-acid prepropeptide. This precursor is subsequently cleaved to form several bioactive C-terminal peptides, including apelin-12, -13,-16, -17, - 19 and -36. Apelin and its receptor have been detected in a wide range of tissues including the pancreas and brain and thus probably possess multiple physiological actions. Apelin undergoes rapid enzymatic degradation in the circulation and has a half-life of approximately 8 min in humans. This thesis examined if novel stable analogues of apelin might be exploitable for obesity and type 2 diabetes mellitus (T2DM) therapy. Novel apelin analogues were more stable than native apelin-13 in mouse plasma and fatty acid modified synthetic analogues including, (LyssGluPAL)apelin-13-amide (P<0.001) and pGlu(Lys8GluPAL)apelin-l3-amide (P<0.001), which had an in vitro half-life of >24 h. Additionally, these analogues enhanced insulin secretion from BRIN-BD11 cells (P<0.001) compared to glucose alone through mechanisms involving elevated intracellular Ca2+ (P<0.001) and cAMP concentrations (P<0.05). Furthermore, selected peptides exhibited acute in vivo insulin-releasing and glucose-lowering properties in both normal and high-fat fed (FIFF) mice. Fatty acid modified apelin analogues displayed persistent glucose lowering actions (P<0.01), 16 h post administration compared to saline injected mice. Chronic once-daily administration (28 days) of HFF mice with (LyssGluPAL)apelin-13- amide or pGlu(Lys8GluPAL)apelin-13-amide improved long-term glycaemic control and supressed appetite, leading to weight-loss. This was accompanied by both improved insulin sensitivity and plasma lipid profiles. In conclusion, this thesis shows for the first time that chemical modification of apelin-13 can offset enzymatic degradation, as well as improve glycaemic control in a mouse model of obesity-diabetes. The efficacy of apelin analogues to decrease food intake, promote weight loss and improve glucose homeostasis makes them novel candidate molecules for combatting metabolic dysfunction in obesity related diabetes.
25
Verghese, Jenson. "Investigations of Novel Mechanisms of Action for Anti-Bacterial and Anti-Cancer Agent Development." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/611.
Повний текст джерелаАнотація:
The development of drugs and therapeutic agents for combating infections and human malignancies continues to be a forefront area in both academic and industrial research. This is driven by the rapid emergence of multi-drug resistant bacterial strains and accumulating mutations in cancer targets that is quickly rendering our current arsenal of drugs ineffective for these therapies. Unless new drugs with novel mechanisms of action are identified and developed at a faster pace, we face a losing battle in managing these diseases. The first part of this work concerns with the natural product Simocyclinone D8 (SD8). Simocyclinone D8 is an angucyclinone antibiotic that inhibits DNA gyrase with a novel mechanism of action that has been termed competitive inhibition. Simocyclinone D8 was found to inhibit the growth of both Gram-(+ve) and Gram-(–ve) organisms and also inhibit a fluoroquinolone resistant mutant of DNA gyrase. Inspired by the structure and novel mechanism of action that SD8 displays, we synthesized analogues based on the co-crystal structure of SD8 with DNA gyrase. These compounds were found to inhibit DNA gyrase, albeit by a different mechanism of action than that of SD8. We also conducted studies towards the total chemical synthesis of SD8 and made three out of the four fragments in SD8 in decent yields. The second part of this work is focused on the development of a substrate-competitive covalent inhibitor for protein kinase B (AKT). AKT is a valid target for cancer research with two compounds currently in late stage clinical trials. Developing substrate- competitive inhibitors for kinases is a novel approach in targeting them, with very few examples in the literature. This mechanism has been postulated to overcome common resistance mutations that cancer targets harbor. A major drawback in this approach is the low binding affinity for peptide substrates by kinases. We circumvented this problem of affinity by utilizing a covalent mode of binding and synthesized a potent non-peptide active-site directed irreversible compound that inhibits AKT. Further studies on this compound are underway and are expected to yield a compound that can be used as a therapeutic agent or as a probe for AKT.
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Sola, Lao Irene. "Novel approaches toward anti-Alzheimer and antiprotozoal drug candidates." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/399594.
Повний текст джерелаАнотація:
This PhD Thesis pursues the development of novel anti-Alzheimer and antiprotozoal drug candidates upon exploitation of three different novel approaches: Multitarget therapies, Drug repurposing, and Validation of a novel anti-malarial target.
The work carried out in the frame of this PhD Thesis has followed three research lines, thus dividing the next report on three main objectives, namely the development of novel diseasemodifying anti‐Alzheimer agents, novel potential 4-aminoquinoline-based anti tripanosomatid compounds, and so far unexplored substrate analog PfG6PD inhibitors for the treatment of malaria.
In the context of the anti‐Alzheimer therapeutic strategies, the innovative so‐called Multi‐ Target Directed Ligands (MTDLs) approach has inspired the structure‐based design and synthesis of two novel classes of hybrid compounds endowed with additional key target interactions beyond cholinesterases, whose modulation has shown to only confer a relief of the very late symptoms of the disease. On the one hand, rhein-huprine hybrids combine the activity of the potent catalytic anionic site (CAS) AChE inhibitor, huprine Y, with that of an anthraquinone fragment derived from rhein to afford a tau antiaggregating effect, apart from the conventional effects derived from dual site AChE interaction. Levetiracetam-based hybrids, on the other hand, comprise, apart from a CAS AChE inhibitor unit, a moiety related to the antiepileptic drug levetiracetam which tackles the Aβ-induced aberrant epileptiform activity across the neuronal network.
Regarding HAT and malaria treatment, current registered drugs are problematic, most of them display a range of toxic side effects, require strict and complicated parenteral administration regimens and produce resistances that undermine clinical effectiveness. For this reason, there is an acute need to find novel drugs that can circumvent the limitations of existing therapies. In the context of this PhD Thesis, drug repurposing and further optimization of 4 aminoquinoline based compounds has been considered as a useful approach to potentially speed up the drug development in the HAT field. We have demonstrated that homodimerization, heterodimerization, and side chain modification of the anti-Alzheimer investigational 4- aminoquinoline derivative huprine Y can result in potent brain permeable antitrypanosomal agents, with decreased but still significant anticholinesterasic activity. On the other hand, the bifunctional Plasmodium falciparum glucose-6-phosphate dehydrogenase-6- phosphogluconolactonase enzyme (PfGluPho) has recently emerged as attractive druggable alternative for the development of innovative antimalarial therapeutic strategies. Starting from a homology model of PfG6PD (G6PD domain of PfGluPho), a new family of selective substrate analog-based inhibitors against the parasite PfG6PD active site has been designed and synthesized, on the basis of the structural differences found at the catalytic site of the parasite and human enzymes.La present tesis doctoral pretén el desenvolupament de nous candidats de fàrmacs anti-Alzheimer i antiprotozoaris, gràcies a l’ús de tres diferents i innovadores aproximacions: “Teràpies Multidiana”, “Reposicionament de fàrmacs” i “Validació d’una nova diana terapèutica pel tractament de Malària”. En referència a la malaltia d’Alzheimer, l’estratègia terapèutica basada en fàrmacs multidiana ha representat la base del disseny molecular i posterior síntesis de dos noves famílies estructurals proveïdes d’interaccions addicionals a aquelles establertes amb els enzims de tipus colinesteràsics, les quals s’ha demostrat que tan sols confereixen un alleujament simptomàtic de l’Alzheimer. En primer lloc, la família de compostos rhein-huprina conté una estructura híbrida constituïda per un potent inhibidor d’AChE, com és l’huprina Y, a més de per un fragment de tipus antraquinona derivat del compost rhein, que resulta en un efecte antiagregant del pèptid β-amiloide (Aβ) a part dels efectes convencionals derivats de la inhibició dual de l’enzim AChE. D’altra banda, la família d’híbrids basats en levetiracetam es composen a més d’un inhibidor d’AChE, d’una unitat relacionada amb el fàrmac antiepilèptic levetiracetam (registrat com a Keppra®), el qual reverteix l’activitat epileptiforme causada per l’agregació d’Aβ. Respecte les malalties de la Tripanosomiasis Africana i de la Malària, els fàrmacs que actualment existeixen al mercat són problemàtics, requereixen d’administració parenteral i la majoria donen lloc a molts efectes adversos, a més de produir resistències que comprometen la seva efectivitat clínica. Per aquesta raó, en el context de la present Tesis Doctoral, l’estratègia terapèutica de reposicionament de fàrmacs amb estructura d’aminoquinolina i la seva posterior optimització farmacològica ha estat usada per la ràpida recerca de noves teràpies eficaces contra la Tripanosomiasis Africana. Pel que fa a la Malària, l’enzim bifuncional de Plasmodium falciparum glucosa-6-fosfat deshidrogenasa-6-fosfogluconolactonasa (PfGluPho) ha estat validat com a diana terapèutica, gràcies a la síntesis i avaluació farmacològica d’una sèrie de compostos glucosídics amb una estructura anàloga al substrat de l’enzim, la glucosa-6-fosfat.
27
Yepuri, Nageshwar Rao. "The design and synthesis of novel anti-malarial agents." Access electronically, 2004. http://www.library.uow.edu.au/adt-NWU/public/adt-NWU20050330.085201/index.html.
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28
Shah, Manish Bipin. "The development of novel quinols as anti-tubercular agents." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431861.
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29
Crapper, John Lindley. "Novel imaging and anti-tumour agents for adrenal medulla." Thesis, University of Sheffield, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389751.
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30
Malik, Navid. "Dendrimers : evaluation as novel carriers of anti-cancer agents." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313786.
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31
Yousaf, Tanzeel Ahmed. "Adiponectin : a novel circulating anti-thrombotic factor in humans?" Thesis, University of Hull, 2011. http://hydra.hull.ac.uk/resources/hull:5447.
Повний текст джерелаАнотація:
Adiponectin is an adipocyte-derived pro-inflammatory adipokine that regulates metabolic homeostasis, although it has been reported to modulate platelet function and thrombosis. In this study the effects of globular adiponectin (gAd), a novel platelet agonist that stimulates platelet aggregation was characterised. While it had been previously noted that gAd stimulated platelet aggregation through a tyrosine kinase-dependent mechanism, in this thesis we further elaborated the mechanisms underlying gAd-induced platelet aggregation by investigating the role of platelet secondary mediators, granule secretion and intracellular signalling events using a series of receptor antagonists and inhibitors. The experimental data demonstrated that gAd-stimulated aggregation required adenosine diphosphate (ADP) and thromboxane A2 (TxA2) to achieve the maximal response. Consistent with this, threshold concentrations of gAd could synergise with ADP. However, using receptor antagonists this synergy was found to occur via the Gi-coupled P2Y12 receptor and not Gq-coupled P2Y1. Since the secretion of ADP from platelet dense-granules is driven by protein kinase C (PKC), we examined the role of PKC in gAd-mediated platelet aggregation. Ablation of PKC using a general inhibitor reduced platelet aggregation and abolished dense-granule secretion stimulated by gAd. Importantly, the aggregation response and dense-granule secretion under conditions of PKC inhibition could be partially restored by ADP acting through the P2Y12 coupled Gi receptor and by adrenaline acting through the Gz-linked α2A adrenoceptor. Further examination of this pathway revealed that the activation of phosphatidyl-inositol-3-kinase (PI3K) was required to restore secretion. To clarify the role of PI3K in this process we measured Akt phosphorylation as a marker of PI3K activity. We found that ADP and adrenaline potentiated gAd-induced Akt phosphorylation which could be inhibited with a selective PI3Kβ isoform inhibitor and to a lesser degree α isoform inhibitor. These data demonstrate that gAd requires the release of platelet secondary mediators to induce full platelet aggregation and the potentiation of initialaggregation occurs through G-protein coupled receptors linked to Gi-coupled G-proteins. Furthermore, the stimulation of Gi/Gz coupled G-proteins can potentiate platelet aggregation by stimulating secretion through a PKC-independent manner. Since adiponectin accumulates at sites of vascular lesions, the ability of immobilised gAd to support platelet adhesion was examined. GAd supported the adhesion of platelets under static and flow conditions. Adhesion under static conditions was inhibited by the glycoprotein VI (GPVI) blocking antibody, 10B12, but not ethylene glycol-bis (β-aminoethyl ether)-N,N,N’,N’,-tetraacetic acid (EGTA), suggesting a GPVI-dependent and integrin-independent mechanism. Together these data significantly improve our understanding of the mechanisms by which gAd may promote unwanted platelet aggregation and adhesion at sites of vascular injury.
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Gracheva, Svetlana. "Development of novel techniques for monitoring anti-oxidant thiols." Thesis, Nottingham Trent University, 2009. http://irep.ntu.ac.uk/id/eprint/182/.
Повний текст джерелаАнотація:
The clinical exploitation of physiological biomarkers could yield considerableimprovements in diagnosis and treatment providing their measurement can be conducted peedily and preferably at the point of care. The project has sought to investigate the development of new methods that could allow such measurements to be made. The various biomarkers that could be exploited as the basis of a general “index” of physiological wellbeing have been identified and their potential clinical merit critically appraised. Anti-oxidant sulphur compounds (cysteine, glutathione, sulphite) were selected as potential targets on the basis of their physiological role in protecting the body from damage by free radicals. The variation in their concentration within biofluids is widely acknowledged as a useful diagnostic gauge as to the degree of oxidative stress that an individual may be experiencing. The main problem, from a clinical perspective, is the lack of a suitable procedure for monitoring their concentration speedily at, or by, the patient. A brief assessment of the various electroanalytical options (encompassing voltammetric, amperometric and potentiometric methodologies) available for the detection of the sulphur anti-oxidants has been conducted. A potentiometric detection strategy was found to offer numerous advantages and a novel indicator family based on quinone interaction adopted and forms the foundation of the work presented herein. The reaction mechanism has been elucidated and the analytical applicability of the system investigated using a variety of techniques – covering both chromatographic, spectroscopic and electrochemical methodologies. The system has been characterised in terms of selectivity, sensitivity and its efficacy for the quantification of thiol containing pharmaceuticals and various biofluids (urine and plasma) has been demonstrated. The simplicity of the detection methodology is shown to markedly contrast alternative thiol detection strategies. The transfer of the technology to a mass production format through the adoption of screen print electrode formats has been achieved. A series of clinical trials were performed and the efficacy of the approach and the underlying technology format demonstrated. The results have been corroborated using standard techniques and the routes through which the system can be adopted within mainstream biomedical environments highlighted. An alternative sensor system based on a composite polymer laminate approach was also investigated as a route through which prototype sensors could be speedily prepared and which would be more accessible to general chemistry laboratories. A new approach to the detection of sulphite – based on the quinone system – was used as the principal detection system to allow the system to be evaluated and proof of principle demonstrated. The fabrication methodology adopted has been found to provide a highly versatile option for the construction of polymer film electrodes.
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Celiker, Ibrahim. "The design and synthesis of novel anti-viral agents." Thesis, University of Reading, 2017. http://centaur.reading.ac.uk/72588/.
Повний текст джерелаАнотація:
Viral infections account for 25.4% of all human illnesses. Current anti-viral nucleosides are able to prevent viral replication; however, viruses evolve resistance to available treatments. Ribose nucleosides are ubiquitous; however due to the discriminatory nature of kinases, low intracellular concentrations of the active triphosphate is a significant factor in inactivity. In contrast, oxetane nucleosides have been shown to be phosphorylated by these kinases with high levels of the required active nucleotide triphosphate (NTP) resulting. Oxetane nucleosides, however, have been found to be inactivated by pyrimidine nucleoside phosphorylases (PNPs). Previous studies have illustrated that sulfur containing nucleosides are not hydrolysed by PNPs. Therefore in this programme a library of 9 novel 3,3-bis(hydroxymethyl)-thietan-2-yl nucleosides was synthesised using Vorbrüggen conditions starting from a fluorothietane precursor, over 8 steps. Cell viability studies using an XTT assay on the thymine (103% ± 4.9%), uracil (95% ± 2.3%), 5- fluorouracil (98% ± 7.5%) and 5,6-dimethyl uracil (82% ± 4.1%) derivatives showed no significant loss in cell viability at up to 100 μM concentration, suggesting they were suitable for further study in anti-viral screens. Steps towards the synthesis of a complementary library of 4,4-bis(hydroxymethyl)-thietan-2-yl nucleosides have been optimised with successful synthesis of a novel key intermediate, thietane-2-one, in a yield of 37% over 6 steps. 4’-Thiohamamelose nucleosides show promise as potential anti-viral compounds as previous studies have shown that 4’-thioribose nucleosides are stable to PNPs and have longer half-lives than ribose nucleosides. Increasing the stability of the 4’-thiohamamelose nucleosides could improve the potential for development of the anti-viral profiles of this class of compounds. Therefore the chemistry of 4’-thiohamamelose nucleosides has been explored, with an intermediate hamamelolactone being prepared in a yield of 44% over 5 steps. Small molecule nucleosides offer the greatest benefits as anti-viral compounds versus other small molecule anti-viral agents as nucleosides are able to directly halt viral replication. The sulfur containing nucleosides are potentially more stable than their ribose counterparts, leading to better pharmacological and pharmacodynamics outcomes.
34
Repasky, Paul J. "Novel Trisubstituted Arylidene Oxindoles with Potent Anti-Apoptotic Properties." Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1310326721.
Повний текст джерела
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Figueiredo, Joana Rita Monteiro. "Toxicity of novel anti-fouling nanomaterials in Marine organismsv." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22019.
Повний текст джерелаАнотація:
Mestrado em Ecologia AplicadaBiofouling is an ecological succession of fouling communities in submerged surfaces that has extensive ecological, environmental and economic impacts worldwide when developed over man-made structures. In order to minimize this problem, biocides with anti-fouling properties are commonly used in protective coatings of submerged structures. Some decades ago, organotin compounds were used as effective anti-fouling agents, however they were completely banned in 2008 due to the toxic and biomagnification effects. As a consequence, a new generation of biocides were developed with lower toxicity and persistence in the environment when compared to organotin compounds. Recently, one of these biocides (DCOIT) was encapsulated in an engineered nanomaterial (silica mesoporous nanocapsules, SiNC-DCOIT) in order to prevent the interaction of biocides with coatings’ ingredients and control their leaching rate during the early lifetime of conventional paints, with environmental and economic benefits. The present study aimed to assess the toxicity of SiNC-DCOIT and a modified version of the engineered nanomaterial including two biocides, the SiNC-DCOIT coated with silver, to marine species and compare its toxicity with the free counterparts (empty SiNC, DCOIT and Ag). Ecotoxicity tests were carried out with eleven marine species, including bacteria (Vibrio fischeri), microalgae (Isochrysis galbana, Nannochloropsis gaditana, Phaeodactylum tricornutum), rotifers (Brachionus plicatilis), bivalves (Cerastoderma edule, Mytilus galloprovincialis), polychaetes (Hediste diversicolor), crustaceans (Artemia salina, Palaemon varians) and echinoderms (Paracentrotus lividus), following standard tests (with some adaptions in some cases). Acute or short-term chronic endpoints were used upon each species and adopted test. Globally, values of L/E/IC50 for SiNC-DCOIT, SiNC-Ag and SiNC-DCOIT-Ag were higher than the estimated values for DCOIT and silver (dissolved in solution), except for some target groups involved in the early fouling stages, proving that these alternative agents are more environmentally-friendly comparatively to free biocides. The obtained L/E/IC50 and NOEC values from the tested compounds were then used to create species sensitivity distributions together with data from literature. The HC5 and PNEC values derivated from these curves showed that the hazard of DCOIT and silver is reduced when encapsulated, highlighting these novel nanomaterials as a promising anti-fouling solution.
A bioincrustação é uma sucessão ecológica de comunidades incrustantes em superfícies submersas que tem extensos impactos ecológicos, ambientais e económicos em todo o mundo quando desenvolvida em estruturas artificiais. Para minimizar esse problema, os biocidas com propriedades anti-incrustantes são comummente utilizados em revestimentos protetores de estruturas submersas. Há algumas décadas atrás, os compostos organoestânicos eram amplamente utilizados como agentes anti-incrustantes eficazes, porém foram definitivamente banidos em 2008 devido a efeitos tóxicos e de biomagnificação reportados. Como consequência, foi desenvolvida uma nova geração de biocidas com menor toxicidade e persistência no meio ambiente em comparação com os compostos organoestânicos. Recentemente, um desses biocidas (DCOIT) foi encapsulado num nanomaterial manufaturado (nanocápsulas de sílica mesoporosas, SiNC-DCOIT), a fim de evitar a interação dos biocidas com os ingredientes dos revestimentos e controlar a sua taxa de libertação durante o início de vida das tintas convencionais, com benefícios ambientais e económicos. O presente estudo teve como objetivo avaliar os efeitos em diversas espécies marinhas do nanomaterial SiNC-DCOIT e de uma versão modificada deste, contendo dois biocidas (SiNC-DCOIT revestido com prata), e comparar a sua toxicidade com os componentes destes nanomateriais (SiNC vazias, DCOIT e Ag). Os testes de ecotoxicidade foram realizados com onze espécies marinhas, incluindo bactérias (Vibrio fischeri), microalgas (Isochrysis galbana, Nannochloropsis gaditana, Phaeodactylum tricornutum), rotíferos (Brachionus plicatilis), bivalves (Cerastoderma edule, Mytilus galloprovincialis), poliquetas (Hediste diversicolor), crustáceos (Artemia salina, Palaemon varians) e equinodermes (Paracentrotus lividus), seguindo testes padrão (com algumas adaptações em alguns casos) ou com protocolos bem definidos. Foram determinados parâmetros agudos ou crónicos de curta duração dependendo da espécie testada e do teste adotado. Globalmente, os valores de L/E/IC50 para SiNC-DCOIT, SiNC-Ag e SiNC-DCOIT-Ag foram superiores aos valores estimados para DCOIT e prata (dissolvidos em solução), com exceção de alguns grupos alvo envolvidos nos primeiros estádios de incrustação, provando assim que estes são agentes alternativos mais amigos do ambiente comparativamente aos biocidas livres. Os valores obtidos de L/E/IC50 e NOEC para os compostos testados foram depois utilizados para derivar curvas de distribuições de sensibilidade de espécies, juntamente com dados da literatura. Os valores HC5 e PNEC derivados dessas curvas mostraram que o perigo do DCOIT e da prata diminui quando encapsulados, destacando que estes nanomateriais inovadores parecem ser uma solução anti-incrustante promissora.
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Soroush, Fariborz. "A Novel Microfluidic System for Screening Anti-inflammatory Therapeutics." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/500666.
Повний текст джерелаАнотація:
Mechanical EngineeringPh.D.
Inflammation is a crucial physiological protective response of body to infection or injury. However, in pathological conditions such as sepsis or radiation damage, the body may exhibit a strong inflammatory response and cause organ damage. Loss of barrier function and leukocyte dysfunction plays an important role during inflammation (e.g. sepsis, radiation exposure, etc.) and induces tissue injury through release of proteases and oxygen radicals. Currently, pharmacological therapies for inflammatory conditions are supportive and there is an urgent need for specific treatments to effectively target key points in neutrophil-endothelial interaction. Our research team has developed a novel microfluidic system to study the mechanisms by which Protein Kinase C isotype delta (PKCδ) impacts neutrophil-endothelial interactions and its inhibition can protect vascular endothelial integrity and attenuate sepsis-induced tissue damage. This novel system will allow for rational design of next generation therapeutics for treating inflammation. We will utilize our novel biomimetic microfluidic assay (bMFA) to systematically delineate the mechanism by which PKCδ regulates individual steps in neutrophil recruitment to the inflamed/activated endothelium. In Specific Aim 1, we will investigate the impact of PKCδ inhibition on neutrophil interaction with endothelial cells as well as adhesion molecules expression. In Specific Aim 2, we will test the specificity of the PKCδ inhibitor in microcirculation and among different species. In Specific Aim 3, we will investigate the role of PKCδ in crosstalk between neutrophils and endothelial cells and endothelium integrity after high dose X-ray irradiation. Our findings indicate that PKCδ inhibition significantly reduces neutrophil interactions with the endothelium during acute inflammation. Our novel biomimetic microfluidic assay (bMFA) provides a rapid screening system for testing the specific response of novel therapeutics. Moreover, results indicate that in many cases the response of murine cells to inflammatory signals may be a poor predictor of response in human cells. Furthermore, our discoveries indicate a key role for PKCδ regulation of radiation-induced changes in endothelial cell barrier structure and function, expression of several key cell adhesion molecules, neutrophil-endothelial cell interaction and leukocyte migration through the endothelium. Our findings indicate that PKCδ-TAT peptide inhibitor may offer an important approach for treating inflammatory disease and we propose that PKCδ inhibition may serve as a novel medical countermeasure for treating radiation-induced vascular damage. Findings from this study will not only elucidate the mechanisms of action for this novel therapeutic but also provide a roadmap for the rational design of future therapeutics for acute inflammatory diseases. The long-term goal of this work is to establish microfluidic devices as a novel prescreening tool for screening therapeutics to allow for fast and precise prediction of response in human. This allows for efficient design of therapeutics using human cells and tissues, designing proper drug carrier, and planning possible future clinical studies.
Temple University--Theses
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Molgora, Martina. "IL-1R8 : a novel checkpoint regulating anti-tumor and anti-viral activity of NK cells." Thesis, Open University, 2018. http://oro.open.ac.uk/56253/.
Повний текст джерелаАнотація:
IL-1R8 is an Interleukin-1 receptor family member that acts as a negative regulator of IL-1 family receptor and Toll-like receptor (TLR) signaling. Both murine and human NK cells express high levels of IL-1R8 but its functional role in this cell type has not been described so far. Natural Killer (NK) cells are innate lymphoid-derived cells and are able to recognize damaged, stressed, viral infected or tumor cells, which express ligands interacting with activating NK cell receptors. The expression of IL1R8 in NK cells prompted us to analyze its potential role in controlling NK cell effector functions. Expression analysis showed that IL-1R8 was acquired during differentiation in human and murine NK cells. IL-1R8 deficiency in the mouse was associated with higher frequency and absolute number of mature NK cells in blood, spleen, bone marrow and liver. Moreover, IL-1R8 deficient NK cells display an increased Interferonγ (IFNγ), Granzyme B and Fas ligand expression and degranulation. IL-18, which is a key regulator of NK cell activities and can be targeted by IL-1R8, was responsible for this phenotype. Indeed, IL-1R8 regulated IL-18 axis during NK cell differentiation and activation and IL-18-dependent activation of mTOR and JNK pathways increased in IL-1R8-deficient NK cells. To assess the role of IL-1R8 in NK cells in pathology, we used models of 3-methylcholanthrene (MCA)-induced lung metastasis, colon cancer-derived liver metastasis and diethylnitrosamine (DEN)-induced hepatocellular carcinoma. The number and dimension of liver and lung metastasis and the liver disease severity were significantly reduced in Il1r8-/- mice. The depletion of NK cells in these models totally abrogated the protection observed in Il1r8-/- mice. Finally, we investigated the role of IL-1R8 in NK cell antiviral activity, in a model of murine cytomegalovirus (MCMV) infection. Il1r8-/- mice showed an improved virus control in the liver and the protection was associated with enhanced NK cell degranulation and IFNγ production. The adoptive transfer of Il1r8-/- NK cells conferred protection in both metastasis and viral infection models. Collectively, these results showed that IL-1R8 played a non-redundant role in the regulation of NK cell development and effector functions by tuning IL-18-dependent activities. IL-1R8 therefore emerges as a novel checkpoint molecule modulating NK cell antitumoral and antiviral potential. Preclinical models showed that the inactivation of IL-1R8 unleashed NK cell effector functions, unveiling IL-1R8 as a potential immunotherapy target in the context of cancer and viral infections.
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Yang, Bin Rui. "The discovery of novel ROCK inhibitors with anti-angiogenesis activity." Thesis, University of Macau, 2012. http://umaclib3.umac.mo/record=b2590323.
Повний текст джерела
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Takeshita, Shigeru. "Genetic and physiological studies to discover novel anti-diabetic agents." 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/215223.
Повний текст джерела
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Puniani, Evaloni Takavaha. "Novel natural product based anti-anxiety therapy and natural insecticides." Thesis, University of Ottawa (Canada), 2004. http://hdl.handle.net/10393/29155.
Повний текст джерелаАнотація:
The EtOH extracts of the leaves of Margraviaceae, a relatively rare Central American vine for which ethnobotanical reports suggested possible anti-anxiety properties, showed significant anti-anxiety activity in animal models for anxiety. Subsequent bioassay-guided fractionation of these extracts yielded an EtOAc active fraction (f1). Further bioassay-directed chromatography of (f1), led to the isolation of betulinic acid (3) as the bioactive constituent in 0.01% of dry weight. Six known pentacyclic triterpenoids [( 1a), (1b), (2a), (2b), ( 4), (5a)], six known flavonoids [(6), ( 7), (8a), (8b), (9), ( 10)], chondrillasterol (11), linolenic acid (12 ) and a porphyrin type compound (13) were also isolated.
When (3) was administered at 0.5 mg per kg (possibly less) in a variety of rat and mouse model assays, the activity of (3) was comparable to that of Valium, the most famous member of the benzodiazepines family.
Synthetic derivatives of (3) were prepared and evaluated for anti-anxiety activity. Several of the simple esters appear to have ideal properties as new drug Candidates. In particular, betulinic acid methyl ester or methyl betulinate (3a) exhibited anti-anxiety activity superior to (3). The activity profile of (3a) is such that (3a) can be considered a viable drug candidate.
An excellent relay synthesis of (3) from another closely related natural product betulin (14), that is abundantly available in Eastern Ontario, was developed.
Radioactive 3H-labelled betulinic acid methyl ester ( 3a″) was also prepared in order to facilitate identification of relevant anti-anxiety receptors and the mechanism of action of the compound. This is important since (3) showed no significant binding to any of the 40 anti-anxiety receptors currently implicated in anxiety. Therefore, it appears to act as an anti-anxiety agent via a new mode of action.*
In a second project, the active components of a member of the Piperaceae or Pepper family (P. tuberculatum) from Costa Rica, were isolated and their structures characterized as 5,6-dihydropiperlonguminine (25), 5,6-dihydropiperine (26), piperine ( 27) and piperlonguminine (28).
Extracts from this neotropical plant had been previously demonstrated by our biology collaborators, Professor Arnason's group, to be strongly insecticidal towards a variety of pests including mosquitoes, earwigs and white grubs. Moreover, the P. tuberculatum extracts were as effective as the well-documented Asian (P. nigrum) and African ( P. guineense) Piper species.
Piperamides (25)--(28) were synthesized in sufficient amounts to allow extensive evaluation of their insecticidal properties. Experiments with these piperamides showed that the tertiary and quaternary mixtures have greater-than-additive toxicity compared to single compounds or binary mixtures. That is, these piperamides synergize each other. Compound (25) was the most acutely toxic in mosquito larvae bioassays. The field trials to date indicate a high potential for the development of an effective, relatively inexpensive botanically based insecticide.
Radioactive 3H-labelled piperine (27″ ) was also synthesized for toxicokinetic studies.
*Please refer to dissertation for diagrams.
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Kinnear, D. J. "Development and characterisation of novel anti-infective endotracheal tube biomaterials." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.557654.
Повний текст джерелаАнотація:
Nosocomial infection, including ventilator-associated pneumonia (VAP) affects more than 1 million people each year. The first step in VAP is colonization of the endotracheal tube; prevention of which has failed using traditional approaches such as antibiotic prophylaxis. This work looks at the development of anti-infective materials capable of resisting bacterial adherence. The strategy centres around the use of biocides (QACs) which target the negatively charged bacterial cell wall, disrupting cell structure and causing death. Chapter 2 examines the incorporation of 3 QACs into PVC via the solvent cast method. The materials resisted colonization but possessed poor mechanical properties. Chapter 3 examines an alternative method of incorporation, hot melt extrusion. The QACs and PVC were stable despite the application of heat but when combined, the QACs catalyzed the degradation of PVC and resulted in materials unsuitable for use in a medical device. Chapter 4 reconsiders the solvent cast method, but with ion pairs formed from quaternary ammonium cations and docusate anion. This produced ionic liquids with improved solubility in PVC, which improved the mechanical properties of the materials. However, the antimicrobial activity of the materials was not equivalent to that of the precursor QACs. Chapter 5 examines an alternate approach to the modification of PVC, by the production of an ultrahydrophobic surface. This did not prevent adherence but the materials showed no bacterial viability in adhered biofilm after 24 hours incubation. This was attributed to transition metals used to roughen the surfaces. Chapter 6 reports a second attempt at the exchange of anion paired with the quaternary ammonium cation, for sulfonate based anions. This produced films which showed improved mechanical properties and reduced bacterial adherence. This reduces the need for additional plasticisers, and these materials are suggested as suitable candidates for anti-infective ET tube biomaterials.
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Puri, Sanyogitta. "Novel functionalized polymers for nanoparticle formulations with anti cancer drugs." Thesis, University of Nottingham, 2007. http://eprints.nottingham.ac.uk/10316/.
Повний текст джерелаАнотація:
The chemistry and structure of Poly (glycerol adipate) facilitate its substitution with various pendant functional groups leading to modifications of the physicochemical properties of the polymer. Modified backbones then can be selected based upon the properties of the compound to be incorporated. Thus, this could be explored as a drug delivery system without many of the limitations of commercially available polymers. The aim of this study was investigate whether various polymers and drugs interact in a specific manner and whether the nature of these interactions influence the physicochemical characteristics of the particles and their drug loading and release profile. By investigating drugs belonging to various classes and with different properties it has been possible to correlate properties associated with drugs and pendant functional groups of the polymer which are ultimately responsible for the drug loading and release characteristics. For some drug polymer formulations, good loading and controlled release rates have been achieved. Compared to various conventional polymer systems reported for nanoparticle formulations, poly (glycerol adipate) polymers have also demonstrated the ability to control rate of release of highly water soluble drugs, even from the most hydrophilic polymer backbone in its unsubstituted form. From the various drug loading and release profiles it has been demonstrated that, unlike reported literature, particle size is not the primary factor influencing drug release over the relatively small range of particle sizes seen in this study. Neither is the water solubility of either the drug or the polymer alone responsible for the rapid and uncontrolled release profile from nanoparticles. Thus, Drug polymer interactions are more likely to influence drug loading and release and unlike common reports in the literature, hydrophilicity, molecular weight or concentration of polymer / drug are less likely to affect these parameters in isolation.
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Ferguson, Jillian. "Synthesis of novel compounds for evaluation of anti-cancer activity." Thesis, University of Glasgow, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411855.
Повний текст джерела
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Broughton-Head, Victoria Jane. "Novel anti-inflammatory and mucolytic effects of heparin in vitro." Thesis, University of Portsmouth, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424219.
Повний текст джерела
45
Al-Obaidi, Ahlam Ismail Ibrahim. "Examination of IKKα inhibitors as novel anti-panceatic cancer drugs". Thesis, University of Strathclyde, 2017. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=30689.
Повний текст джерелаАнотація:
Pancreatic cancer has a very poor prognosis, it is the fourth most common cancer worldwide in terms of mortality, and it is expected to be the second most common within a decade. Most patients with pancreatic cancer are either resistante [sic] to chemotherapy or become so, thus surgery is the only choice with a considerable chance of tumour re-growth. Therefore an alternative treatment is urgently sought. The Nuclear Factor Kappa B (NFkB) cascade is comprised of two interdependent pathways, recognized as the classical pathway or canonical NFkB pathway, which is IKKB dependent, and IKKα-dependent non-canonical or alternative NFkB pathway. Studies have linked the hyper-activation of both pathways to pancreatic tumorigenesis. IKKβ inhibitors as a class of potential drugs for anti-cancer treatment have been accompanied by a number of issues regarding toxicity. IKKα has been implicated in a number of biological processes including cancer development, therefore targeting IKKα is a new approach for the development of pancreatic cancer therapies and is examined in this thesis. In chapter three, both NFkB pathways were characterised using different agonists; LTα1β2, TNFα and FCS. LTα1β2 stimulated the IKKα -dependent non-canonical pathway, inducing phosphorylation of p100 after 4h stimulation, while the maximum activation of p52 formation was between 24 and 48h. TNFα and FCS were without effect. TNFα and LTα1β2 stimulated the canonical NFkB pathway and taken together these studies indicated the presence of a functional non-canonical pathway. In chapter four, a number of novel IKKα inhibitors generated in-house, were also examined against both the non-canonical and canonical NFkB pathways. Three different effects were observed; selective inhibition of IKKα by SU1261, SU1411, SU1349, SU1433, SU1438 and 1434. Inhibition of both IKKα and IKKβ by (SU1087, SU1432, SU1499 and SU1436) and no inhibition of either pathway (SU1392). The effect of selective IKKα inhibitors on cell cycle and growth were also examined and confirmed that IKKα has a role in proliferation of pancreatic cancer cells. In chapter five, the expression of IKKα- dependent target genes was investigated using the agonist that activates the IKKα-dependent non-canonical NFkB pathway, LTα1β2. The findings confirmed that the expression of genes (BBC3, EZH2, TNFAIP3, VCAM, MAP3K14 and SERPINB6) was likely to be regulated through this pathway. This was confirmed using IKKα selective inhibitors, which resulted in the expression of all gene subsets were reduced [sic]. Taken together these data indicate that IKKα plays a key role in the regulation of the non-canonical NFkB pathway in pancreatic cancer cells and that selective inhibition IKKα may be a new strategy for developing anti-cancer drugs.
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Cox, Jonathan A. G. "Identifying the mode of action of novel anti-tubercular drugs." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6278/.
Повний текст джерелаАнотація:
The demand for novel antibiotics in the treatment of infections by \(Mycobacterium\) \(tuberculosis\) (\(M.\) \(tb\)), the causative agent of tuberculosis (TB) has reached new highs with the recent emergence of totally-drug resistant TB (TDR-TB). Efforts to develop antibiotics with revolutionary mechanisms of action, low minimal inhibitory concentrations (MICs) that will decrease the current drug burden and clear infection without compromising side effects has led to several collaborative efforts between pharmaceutical companies and academic institutions throughout the world. This interdisciplinary collaborative effort and advances in drug development technologies, such as high throughput phenotypic screening of compound libraries and whole genome sequencing (WGS) has accelerated the identification of new compounds (or hits) with potent anti-tubercular activity and delivered a variety of unique drug targets. These hits are also potent against drug-resistant strains of \(M.\) \(tb\), and have significant efficacy in vivo models of TB infection. Bedaquiline (Sirturo™) is the first new specifically designed anti-TB drug to be approved by the Food and Drug Administration (FDA) for use against multi-drug resistant (MDR-TB) in 40 years. This considerable step forward marks the beginning of a paradigm shift in antibiotic development, signaling a new age of drug discovery. In this thesis, the modern age of TB drug discovery will be examined as well as the efforts made to further this field through the identification of novel hits with activity against \(M.\) \(tb\) and identifying their respective inhibitory mechanisms.
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Ferguson, Elaine Lesley. "Bioresponsive polymer-phospholipase A2 conjugates as novel anti-cancer agents." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/55750/.
Повний текст джерелаАнотація:
Increasingly sophisticated new treatments such as trastuzumab (Herceptin ) and Bevacizumab (Avastin ) have contributed to reduced mortality from breast cancer over recent years, nevertheless 40--60 % of those affected still die from metastatic disease. Thus there remains an urgent need for novel therapies for breast cancer. As PLA2 (crotoxin) has proven anticancer activity but its use is limited by non-specific toxicity, and polymer-drug and polymer-protein conjugates are finding growing use as anticancer agents, the aim of this thesis was to explore the potential of polymer-PLA2 conjugates as a new treatment for breast cancer. Polymer conjugation has previously been shown to reduce systemic toxicity of proteins, prolong their plasma half-life and promote tumour-specific targeting by the enhanced permeability and retention (EPR) effect. First, the synthesis and characterisation methods were optimised using trypsin as a model. After these studies highlighted dextrin as the best polymer for conjugation, dextrin-PLA2 (Apis mellifera venom) conjugates were prepared. Dextrin was chosen for conjugation as it can be used to mask protein activity in the protein masked-unmasked polymer therapy (PUMPT) concept. Such conjugates retained 36 % enzyme activity compared to free PLA2, and moreover, unmasking by a-amylase degradation of dextrin regenerated full enzyme activity. However, while free PLA2 was found to be very haemolytic, dextrin-PLA2 displayed no haemolytic activity, and unmasking by a-amylase degradation of dextrin did not reinstate this activity. The conjugate displayed significant toxicity towards several tumour cell lines, including human breast cancer. Indirect evidence that epidermal growth factor receptor (EGFR) status and tyrosine kinase activity of the receptor influences PLA2-induced anti-proliferative activity were shown. Uptake studies have revealed that conjugation of dextrin to PLA2 reduces non-specific binding to breast cancer cells. In a further study, dextrin-PLA2's ability to burst DaunoXome using the polymer-enzyme liposome therapy (PELT) concept was assessed. Here, it was seen that the conjugate released liposomally encapsulated drug and the combination caused enhanced cytotoxicity in MCF-7 cells. These studies confirm the potential of dextrin-PLA2 as a novel anticancer agent and/or as trigger for liposomal drug release and highlight the feasibility of developing a candidate for further in vivo pharmacokinetic and activity studies.
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Omoruyi, Sylvester Ifeanyi. "Investigating the anti-cancer activity of novel phenothiazines in glioblastoma." University of the Western Cape, 2018. http://hdl.handle.net/11394/6329.
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Philosophiae Doctor - PhDGlioblastoma multiforme (GBM) remains the most malignant of all primary adult brain tumours. It is a highly invasive and vascularized neoplasm with limited treatment options and very low survival rate. GBM tumours are heterogeneous in nature with cellular hierarchy and at the apex of this hierarchy are the glioblastoma stem cells, known to promote tumourigenesis and resistance to chemotherapeutic agents and tumour recurrence. Currently, the standard care for GBM involves surgical resection, radiation, and chemotherapy treatment with temozolomide. Unfortunately, median survival after treatment is still daunting and tumour relapse is very frequent. Indeed, patients with recurrent glioblastoma have less than a year survival. To address this, novel therapies need to be developed with the early introduction of promising agents into clinical trials and subsequent approval for use. Importantly, for these novel therapies to be approved for GBM, they need to be safe, effective as well as being able to penetrate the blood-brain barrier (BBB). Due to the high cost and process time for the development of new drugs, existing approved drugs are currently being repurposed for new indications and this is gaining significance in clinical pharmacology as it allows rapid delivery of useful drugs from bench to bedside. Drugs of the antipsychotic class are well known to cross the BBB due to their neuroleptic action. To this end, the aim of this study was to identify and characterize the anti-cancer activities of novel phenothiazine-derivatives belonging to the antipsychotic class of drugs in glioblastoma. To achieve this, several novel phenothiazine-derivatives were initially screened for possible anti-cancer activity in the U87 and U251 malignant GBM cells. Two lead compounds, DS00326 and DS00329, were identified and their anti-cancer activities were determined in U87 and U251 cells as well as in primary patient-derived xenograft (PDX) glioblastoma cultures. DS00326 and DS00329 significantly inhibited glioblastoma cell viability, with minimal effects observed in the non-cancerous FG0 fibroblasts. The IC50 values of DS00326 and DS00329 for U251, U87 and PDX cells ranged from 1.61 to 12.53μM. Flow cytometry analyses showed that DS00326 and DS00329 treatment led to an increase in the G1 population of cells. Additionally, DS00326 and DS00329 induced double-strand DNA breaks, which lead to activation of the canonical DNA damage response pathway. Furthermore, DS00326 and DS00329 induced apoptosis as shown by morphological markers, flow cytometry with annexin V-FITC/propidium iodide staining, as well as western blotting with an antibody to detect levels of cleaved PARP. Interestingly, treatment with DS00326 and DS00329 also induced autophagy as evident by the increase of acidic vesicular organelles in cells following staining with acridine orange as well as an increase in levels of the autophagy marker LC3-II. Autophagy was seen as a pro-death pathway in the U87 and U251 cells as inhibition of autophagy led to a reversal of cytotoxicity and consequently increased cell survival. Moreover, it was demonstrated that DS00326 and DS00329 inhibited the PI3/Akt pathway while modulating the mitogen-activated protein kinases p38, ERK1/2 and JNK signalling pathways. Importantly DS00326 and DS00329 displayed anti-cancer stem cell activities by the inhibition of neurosphere formation and regulation of stem cell markers SOX2 and GFAP in PDX cells. Together, the findings from this study suggest that DS00326 and DS00329 may be effective in the treatment of glioblastoma and provide a strong rationale for further clinical studies exploiting phenothiazines and their derivatives as treatments for glioblastoma.
2021-09-01
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Rajalekshmi, Devi Sarika. "Development of Novel anti-estrogens for endocrine resistant Breast Cancer." Thesis, Virginia Tech, 2016. http://hdl.handle.net/10919/81275.
Повний текст джерелаАнотація:
ER+ breast cancer raises a significant diagnostic challenge since resistance invariably develops to the current endocrine therapies. 70% of breast cancers are ER+, which results from the overexpression of estrogen receptor. ER mediates strong anti-inflammatory signaling in ER+ tissues. Once activated with estradiol (E2), ER inhibits inflammatory gene expression via protein-protein interactions that block NF-kappa B transcriptional activity. Importantly, NF-kappa B is a primary mediator of resistance in many cancers, including breast cancer. All current endocrine suppressive treatments block this palliative signaling pathway, along with the desired proliferative pathway. Thus, there is a significant unmet clinical need for novel endocrine treatments for breast cancer that can ameliorate patient outcome in resistant populations, be less prone to resistance development, retain anti-inflammatory action, and cause fewer side effects.
Following the hypothesis driven approach, the work described here introduces structural analogs of an innovative ligand scaffold, 5,6-bis-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonic acid phenyl ester, termed OBHS, which reduces gene activation through ligand-induced shifts in helices 8 and 11, thereby indirectly modulating helix 12 of ER (hence, indirect antagonists). This new class of ligands with a bicyclic hydrophobic core retains strong anti-inflammatory effects while dialing out the proliferative effects of E2 (similar to Selective Estrogen Receptor Modulators, SERMS), and could potentially replace the current endocrine therapies of breast cancer. In this work, we carried out rational design and syntheses of two series of OBHS analogs, namely OBHS-A (for acetamido derivatives), and OBHS-P (for propargyl derivatives), while we explored a synthetic methodology for a third series of OBHS compounds.
Many analogs from the OBHS-A series exhibited high binding affinity. For example, the exo diastereomer of 2.11a, 2.11b, 2.11c, 2.11d, and 2.11e exhibited Relative Binding Affinities (RBAs) of 22.6%, 10.5%, 19.5%, 12.1%, and 14.4%, respectively. As observed before, endo OBHS compounds exhibited lower binding affinities than exo compounds. The RBA values with acetamide, and isobutyramide (i.e. short hydrophobic chains) were very comparable to each other. However, unexpectedly the propionamide compound showed lower binding affinity than butyramide. Nevertheless, we consider OBHS analogs with RBA values greater than 1% (Kd = 20 nM) to be very potent. This data is only the first step in a battery of assays that will be conducted eventually on these compounds. In particular, our emphasis is in ascertaining and improving the NF-kappa B mediated anti-inflammatory property, where these compounds have shown promising activity in conjunction with their anti-proliferative activity.Master of Science
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Ngwane, Andile H. "Development of novel anti-tuberculosis drugs from African medicinal plants." Master's thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/2716.
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