Dissertations / Theses on the topic 'Biological Active Molecules'
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Strawbridge, Sharon Mary. "Redox-active sensors for molecules of biological interest." Thesis, University of Exeter, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414263.
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Lu, Biao. "Evaluation of physico-chemical properties of biorefinery-derived amphiphilic molecules and their effects on multi-scale biological models." Thesis, Compiègne, 2015. http://www.theses.fr/2015COMP2218/document.
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Aujourd'hui, un grand nombre de nouvelles molécules peuvent être synthétisées à partir de la biomasse. Les tensioactifs dérivés de sucre sont notamment considérés comme une alternative aux tensioactifs fossiles en raison de leur biodégradabilité et de leur biocompatibilité. Cependant, les études associant la caractérisation physico-chimique et les propriétés biologiques de ce type de tensio-actifs sont limitées. Il est ainsi difficile de prédire les propriétés d'un tensioactif à partir de sa structure chimique. L'établissement d'une méthodologie permettant de relier la structure des surfactants à leurs propriétés apparait pertinent. Dans ce travail, quatre surfactants dérivés de sucre ayant chacun une chaîne C8 liée à une tête glucose ou maltose par un groupe amide ont été caractérisés par leurs propriétés tensio-actives dans différentes solutions (eau et milieu biologique). Leurs interactions avec des protéines ont également été analysées. Concernant l'évaluation des propriétés biologiques, des tests de cytotoxicité/irritation ont été effectués sur trois modèles in-vitro : 1) modèle cellulaire 20 (cellules L929 cultivées en monocouche), Il) modèle cellulaire 30 (cellules L929 cultivées dans un gel de collagène), Ill) épiderme humain reconstitué. Les résultats indiquent que les quatre surfactants synthétisés présentent de bonnes propriétés tensio-actives et trois d'entre eux sont moins cytotoxiques que des tensioactifs de référence. Plusieurs hypothèses permettant de relier la structure chimique des molécules à leurs propriétés physico-chimiques et biologiques ont été proposées. Des travaux futurs permettront d'enrichir la base de données sur les relations structure-propriétés des tensioactifs issus de la biomasse, et de l'utiliser pour synthétiser des surfactants présentant des propriétés adaptées aux applications envisagéesNowadays, a wide variety of new molecules can derive from biomass. Among them, the family of sugar-based surfactants, which are considered as alternatives to fossil-based surfactants, due to their relatively high biodegradability and biocompatibility, exhibit interesting properties both in terms of their self-assembly and their ability to induce biological responses. In the study, for the purpose to analyse these properties, different methodologies have been established. In this work, physico-chemistry and cellular biology methodologies are associated to analyse the properties of pre-selected molecules characterized by gradua) structure modifications. Firstly, we have screened synthesized sugar-based surfactants according to their solubility and their ability to reduce surface tension of water. Four pre-selected molecules, with a C8 chain linked to a glucose or maltose head through an amide functional group, either under the form of carbamoyl (carbohydrate scaffold bearing the carbonyl) or alkylcarboxamide (the alkyl chain bearing the carbonyl), were then dissolved in water/ cell culture media for surface tension measurements. Their behaviors in solutions were characterized by Krafft points, Critical Micellar Concentrations or self-assembling properties through different methods. To evaluate the cytotoxic/ irritant effects of these molecules on cells and tissues, 3 in-vitro models were established: I) 2D cell culture mode! (L929 cell monolayer) II) 3D ce!! culture mode! (L929 cells embedded in collagen gel) and III) Reconstituted human epidermis (differentiated human keratinocytes). Corresponding experiments were carried out on these models with increasing complexity. Results show that the synthesized sugar-based surfactants, GlulamideC8, Glu6amideC8, Glu6amideC8' and MallamideC8 can reduce the surface tension of water solution to the came level as standard surfactants (Tween 20 and Hecameg). In the meantime, GlulamideC8, Glu6amideC8' and MallamideC8 present Iess cytotoxicity effects on L929 cells both in the monolayer model and the 3D mode! than Tween 20 and Hecameg. All synthesized and standard surfactants (GlulamideC8, Glu6amideC8, Gu6amideC8', MallamideC8, Tween 20 and Hecameg) have no significant cytotoxic/ irritant effects on reconstituted human epidermis at 1000 ig/mL after 48 h of topical application. Discussions have been made according to the results of experiments to establish possible structures/ physico-chemical properties - cytotoxicity relationships of these surfactants
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Shortt, Marie Fiona. "Synthetic approaches to biologically active molecules." Thesis, Bangor University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282267.
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Finn, P. W. "Computer studies on biologically active molecules." Thesis, University of Manchester, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374793.
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d'Ippolito, Giuliana. "Biologically active molecules from marine microalgae." Thesis, Open University, 2005. http://oro.open.ac.uk/54203/.
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Diatoms are unicellular photosynthetic microalgae responsible for approximately 40% of marine primary productivity. This algal class has traditionally been regarded as providing the bulk of the food that sustains the marine food chain to top consumers and important fisheries. However, this beneficial role has recently been questioned on the basis of laboratory and field studies showing that although dominant zooplankton grazers such as copepods feed extensively on diatoms, the hatching success of eggs thus produced is seriously impaired. Short chain polyunsaturated aldehydes, such as 2,4,7-decatrienal and 2,4-decadienal, were correlated to the antiproliferative effect of diatoms on copepod reproduction. After establishing a method of analysis, the aldehyde profile of some ecologically relevant species of marine diatoms was assessed. The results showed that the production of aldehydes is species-specific. Detailed chemical analysis revealed the presence of fatty acid derivatives other than aldehydes such as hydroxyacids, ketoacids, oxoacids and epoxyalcohols, increasing the complexity of a chemical defence of diatoms mediated only by aldehydes. All these compounds belong to a class of compounds called oxylipins, that are oxygenated compounds biosynthesized from fatty acids by oxygenasecatalyzed oxygenation. Marine diatoms are able to produce the major antiproliferative oxylipins by a novel oxygenase-dependent oxidation of C16 fatty acids hexadecatrienoic acid (16:3 (w-4)) and hexadecatetrenoic acid (16:4 (w-1)), and C2o eicosapentaenoic acid (20:5 (w-3)). This process is triggered by lypolitic acyl hydrolase activity, that feeds the downstream lipoxygenase pathway. The ecological meaning of the oxylipin pathway in the diatom-copepod interactions is discussed, showing that attention should move from single compounds to complex biochemical process. The deleterious effect on copepod reproduction could be due to a biochemical process such as the generation of an high oxidative potential, rather than only by aldehydes or other secondary oxygenated products, that when present can co-occur to produce the final effect.
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Tunbridge, Gemma Ann. "Efficient synthesis of biologically active small molecules." Thesis, University of Bath, 2012. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.571862.
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Pancratistatin and narciclasine are natural products isolated from Pancratium litorale1 and Narcissus poeticus2 respectively. Pancratistatin and Narciclasine have been shown to possess potent antitumour activity3 however they have never been widely exploited due to their limited availability from natural sources.4 Pancratistatin and narciclasine both contain a dihydroisoquinolinone framework. The work described in this thesis explores synthetic routes relating to this dihydroisoquinolinone framework, as well as comparable tetrahydroisoquinolines. An initial proposed synthetic route involved the synthesis of the dihydroisoquinolinone framework via the corresponding indanone. Indanones have also been shown to possess potential antitumour activity.5 A range of lactam and indanone analogues were synthesised and a selection were tested for biological activity against cancer cell lines. The most biologically active lactam analogue synthesised was lactam 170. Lactam 170 was synthesised via two steps from commercially available starting materials in an overall 51 % yield and was tested in the HT29 colon cancer cell line to give an IC50 value of 9 μM. Indanone 177 is an analogue of natural product indanocine and was synthesised via two steps in an overall 49 % yield. Analogue 177 was tested in the 60 cell line screen by the National Cancer Institute (NCI) to give a mean GI50 value of 1.29 μM and is currently under consideration for further testing. This thesis describes the synthesis and biological testing of the aforementioned compounds as well as an array of analogues.
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Gutierrez, Mauricio R. (Mauricio Roberto). "Size adjustable separation of biologically active molecules." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/34150.
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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2004.Includes bibliographical references (p. 92-96).
Separation of biologically active molecules (BAM's) is a problem for the pharmaceutical and biotechnology industries. Current technologies addressing this problem require too many techniques, toxic additives, and time to filter desired materials. As a result, a new technology is needed. The objective of this thesis is to contribute towards the development of a new method for separating biologically active molecules in the size range of 0.5 nanometers to 500 nanometers. A normally open diaphragm valve is proposed that can control a gap formed by two flat surfaces. For accurate control of gap height, the valve was designed to ensure that the flat surfaces remain parallel during operation . Modularity was also part of design considerations to address issues of eventual biocompatibility breakdown specifically protein adsorption. Control of the gap has been achieved to increments of 1.8 nanometers.
by Mauricio R. Gutierrez.
S.M.
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Perez-Powell, Isabel Rose. "From fragments of prostanoids to biologically active molecules." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707737.
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Jiang, Xiaohui. "Computational and NMR studies of biologically active molecules /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1998. http://wwwlib.umi.com/cr/ucsd/fullcit?p9906482.
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Muller, Christophe. "The synthesis of biologically active molecules using organocobalt complexes." Thesis, Kingston University, 1997. http://eprints.kingston.ac.uk/20608/.
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Giacomini, Elisa <1983>. "Innovative Strategies for the Synthesis of Biologically Active Small Molecules." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5537/.
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The post genomic era, set the challenge to develop drugs that target an ever-growing list of proteins associated with diseases. However, an increase in the number of drugs approved every year is nowadays still not observed. To overcome this gap, innovative approaches should be applied in drug discovery for target validation, and at the same time organic synthetic chemistry has to find new fruitful strategies to obtain biologically active small molecules not only as therapeutic agents, but also as diagnostic tools to identify possible cellular targets.
In this context, in view of the multifactorial mechanistic nature of cancer, new chimeric molecules, which can be either antitumor lead candidates, or valuable chemical tools to study molecular pathways in cancer cells, were developed using a multitarget-directed drug design strategy. According to this approach, the desired hybrid compounds were obtained by combining in a single chemical entity SAHA analogues, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives able to block cell cycle, to induce apoptosis and cell differentiation and with Sorafenib derivative, a multikinase inhibitor. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on leukemia Bcr-Abl-expressing K562 cell lines, as well as their HDACs inhibition. Preliminary results confirmed that one of the hybrid compounds has the desired chimeric profile.
A distinct project was developed in the laboratory of Dr Spring, regarding the synthesis of a diversity-oriented synthesis (DOS) library of macrocyclic peptidomimetics. From a biological point of view, this class of molecules is extremely interesting but underrepresented in drug discovery due to the poor synthetic accessibility. Therefore it represents a valid challenge for DOS to take on. A build/couple/pair (B/C/P) approach provided, in an efficient manner and in few steps, the structural diversity and complexity required for such compounds.
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Ianni, Cristina <1980>. "Synthesis of Biologically Active Small Molecules: Different Approaches to Drug Design." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6403/.
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In the past years, genome biology had disclosed an ever-growing kind of biological targets that emerged as ideal points for therapeutic intervention. Nevertheless, the number of new chemical entities (NCEs) translated into effective therapies employed in the clinic, still not observed. Innovative strategies in drug discovery combined with different approaches to drug design should be searched for bridge this gap. In this context organic synthetic chemistry had to provide for effective strategies to achieve biologically active small molecules to consider not only as potentially drug candidates, but also as chemical tools to dissect biological systems.
In this scenario, during my PhD, inspired by the Biology-oriented Synthesis approach, a small library of hybrid molecules endowed with privileged scaffolds, able to block cell cycle and to induce apoptosis and cell differentiation, merged with natural-like cores were synthesized. A synthetic platform which joined a Domino Knoevenagel-Diels Alder reaction with a Suzuki coupling was performed in order to reach the hybrid compounds. These molecules can represent either antitumor lead candidates, or valuable chemical tools to study molecular pathways in cancer cells. The biological profile expressed by some of these derivatives showed a well defined antiproliferative activity on leukemia Bcr-Abl expressing K562 cell lines.
A parallel project regarded the rational design and synthesis of minimally structurally hERG blockers with the purpose of enhancing the SAR studies of a previously synthesized collection. A Target-Oriented Synthesis approach was applied. Combining conventional and microwave heating, the desired final compounds were achieved in good yields and reaction rates. The preliminary biological results of the compounds, showed a potent blocking activity. The obtained small set of hERG blockers, was able to gain more insight the minimal structural requirements for hERG liability, which is mandatory to investigate in order to reduce the risk of potential side effects of new drug candidates.
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Paula, Da Cunha Denise. "Application of MOFs in adsorption and release of biologically active molecules." Versailles-St Quentin en Yvelines, 2012. http://www.theses.fr/2012VERS0050.
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La dernière classe de matériaux poreux, les solides hybrides inorganiques-organiques cristallisés aussi communément appelés Metal-Organic Frameworks (MOFs) présente de nombreux avantages pour des applications biomedicales, tels que grandes tailles de pores, biodégradabilité et propriétés d’imagerie médicale. Cependant, on a proposé d’évaluer la citotoxicité des MOFs avec différent composition et structure chez deux différent lignes cellulaire. Nous avons observé que les MOFs présent nul ou très faible citotoxicité et que cela dépend de la ligne cellulaire, du métal et de la taille de particule. Concernant MOFs comment systèmes de libération contrôle de médicaments, nous avons entrepris une étude systématique de l'encapsulation et la libération de molécules modèles telles que la caféine (cosmetique), à partir d’une série de MOFs peu toxiques, possédant des compositions et topologies différentes. Les résultats montrent que l’encapsulation et la cinétique de libération de caféine peuvent être modulées en jouant avec la composition et la structure des MOFs. La dernière approche de ce travail a consisté en la mise en forme de patchs constitués de mélanges hybrides organiques-inorganiques avec le MIL-100 chargé avec la caféine et les polymères biocompatibles pour administration transdermique de médicament. Les études de libération in vitro ont montré que les patchs hybrides sont plus efficaces pour ralentir la libération de la caféine. Les études ex vitro réalisées en chambre d’Ussing ont démontré une plus grande absorption de la caféine sur la peau dans le patch Gel-CAF et légèrement similaire dans le cas de MIL-100-CAF-Gel en comparaison avec la crème commerciale caféineThe last class of porous materials, organic-inorganic hybrid solids crystalline also commonly called Metal-Organic Frameworks (MOFs) has many advantages for biomedical applications, such as large pore sizes, biodegradability and properties of medical imaging. However, it was proposed to evaluate the cytotoxicity of MOFs with different composition and structure in two different cell lines. We found that MOFs present no or very low cytotoxicity and that depends on the cell line, metal and particle size. Regarding MOFs as controlled drugs release systems, we perfomed a systematic study of the encapsulation and release of model compounds such as caffeine (cosmetics), from a series of MOFs with low toxicity, compositions and topologies different. Results showed that encapsulation and kinetics release of caffeine can be modulated by changing the composition and structure of MOFs. The last approach of this work consisted in forming patches consisting of organic-inorganic hybrid mixtures with the MIL-100 loaded with caffeine and biocompatible polymers for transdermal drug delivery. In vitro release studies showed that the hybrid patches are more effective for slow release caffeine. Studies ex vitro carried out in Ussing chamber showed a greater absorption of caffeine on the skin patch and Gel-CAF somewhat similar in the case of MIL-100-CAF-Gel compared with commercial cream caffeine
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Gutowski, Mariusz. "Molecular detection and characterisation of biologically relevant free radicals during surgical ischaemia-reperfusion." Thesis, University of South Wales, 2011. https://pure.southwales.ac.uk/en/studentthesis/molecular-detection-and-charcaterisation-of-biologically-relevant-free-radicals-during-surgical-ischaemiareperfusion(016f6447-5d02-45f7-a543-8b880148dc23).html.
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Oxygen is one of the most important molecules in human beings. Our research is focused on how the human body can respond and adapt to the physiological challenge posed by a lack of oxygen. Ascorbic acid (Vitamin C) is one of the most important and considered the most effective water-soluble, chain-breaking antioxidant in human plasma, with the capacity to prevents damage by free radicals. This thesis presents four studies investigating the phenomenon of Reactive Oxygen Species (ROS) generation in the many different surgical conditions in the animal and in the human. Study one investigated the geometry and thermodynamic properties of vitamin C. Calculations were carried out at the restricted and unrestricted B3LYP/6-31+G(d,p), B3LYP/6-311++G(d,p) and B3LYP/EPR-II levels for two conformers (1 and 2) of L-ascorbic acid and their respective oxidation products to monodehydroascorbates of ab-initio methods by Gaussian O3W package. Conformer 1, free radical properties are compared with previously published calculations in the gaseous and aqueous solution states and with experimental EPR values. Calculated molecular structures, EPR (electron paramagnetic resonance spectroscopy), the vibration spectral and energetic properties and all are reported including some proposed changes to previous EPR assignments. Conformer 2 of L-ascorbic acid is predicted to have lower energy than Conformer 1, under the method and basis sets used, by between 11 and 26 kJ mol-1 and is stabilised by internal hydrogen bonding. Relaxed potential energy surface (PES) scans were carried out for two proton transfer processes and relative energies of stable minima and barriers between them determined. Hydrogen transfer is predicted in two systems with favourable spatial arrangements of O–H and O groups for which relaxed potential energy surface scans are reported. Calculated vibrational wavenumber values are provided for selected C=C, C=O, C–H and O–H modes assigned to particular groups and significant calculated EPR hyperfine coupling constants (HCC) values for splitting by H(1) and C(13) for radical species are also reported. These calculations contribute to a better understanding of the complex role of L-ascorbic acid and its various oxidised, neutral, ionic and radical forms in biochemistry and medicine. Study two examined if vitamin C could ameliorate the damaging effects of I-R on myocardium and we postulated that the mechanism of vitamin C protection against iii I-R-induced cell death involved quenching of ROS. In the vitamin C group after 5 min of reperfusion a significant, sudden increase of diastolic pressure in the heart was noted and reached a maximum of 77 mmHg after 12 min of reperfusion and then gradually decreased to 51 mmHg after 60 min of reperfusion period but was quicker than in Control group reaching 37 mmHg by the end of the reperfusion period. The level of A·− (ascorbate free radicals) sudden and massive increased at the time of reperfusion in the Vitamin C group. This increase was associated with poor mechanical function in hearts as indicated by the significantly depressed recovery process. After 30 min of global, now-flow ischaemia and 60min of reperfusion infarct size averaged 33% ± 1 in Control group and 30 % ± 1 in Vitamin C group, respectively, (P<0.05). There is strong evidence that oxygen centered radicals contribute to postischaemic dysfunction after global ischaemia. Our data unquestionably suggest that the large production of A·− was associated with a greater depression in myocardial contractile function, therefore could represent a marker of oxidative stress during I-R and could be related to the functional impairment during reperfusion. In summary, we have used the animal models of isolated heart perfusion to provide evidence that vitamin C did not reduce the infarct size, however “tendency” towards a decrease (↓) in infarct size with ascorbate and it protects from oxidative damage during global I-R as manifested by decreased concentrations of A·− and enhance recovery of mechanical function such as diastolic pressure and LVDP in postischaemic working rat hearts. Study three was designed to test the hypothesis that the physiological trauma associated with venous cannulation may artefactually stimulate systemic free radical formation in the acute phase that if not accounted for may under-estimate the oxidative stress response to exercise. The relationship between the time of venepuncture and the level of free radical generation during normoxic conditions was further investigated. The venous cannulation in Phase I, increased plasma A·− by 347 ± 173 AU/√G, P <0.05 after 2min of venepuncture with further increases observed after 5min and 10min of venous cannulation, respectively (403 ± 178 AU/√G; 462 ± 93 AU/√G, P < 0.05) vs baseline point time. After this time the level of A·− slightly blunted as to achieve a similar level to baseline point control after 30 minutes. In phase II the exerciseinduced increase in A·− was subsequently shown to be 48% greater (30min as opposed to the 2min post-cannulation resting baseline)(1754 ± 361 vs. 1979 ± 375 AU, P <0.05). Our findings demonstrate and confirm that venous cannulation per se stimulates iv the systemic formation of free radicals as an acute phase response which peaks at 10min and require approximately 15min to normalise. This has important interpretive implications for future studies that employ catheterisation. The final Study examined if the combination of exercise and inspiratory hypoxia would further compound regional tissue de-oxygenation that is frequently encountered during the ischaemic phase of surgery and thus, by consequence increase oxidative stress. The aim of the study was to further understand a potential relationship between oxidative stress and alterations in muscle oxygenation. Clear significant increases in the plasma concentration of A·− were detected in the peripheral blood of patients (normoxia(baseline) vs 6 data points of reperfusion after 5min of global ischaemic condition, P<0.05),(baseline vs immediate after ischaemia; 2337±525 vs 2633±508, AU, respectively). During global ischaemia the regional muscle oxygenation significantly decreased (↓∆O2Hb-oxyhaemoglobin), ↑∆HHb- deoxyhaemoglobin ), although increased regional blood volume (↑∆tHb- total haemoglobin). From the end of global ischaemia to 10 min after the regional muscle oxygenation progressively back to the start data point (↓∆HHb, ↑∆O2Hb). This study demonstrates for the first time that the I-R has got a big influence on the muscle oxygenation to increased ROS and the return of values towards baseline period in reperfusion stage appears to coincide with increased oxidative stress. Moreover, the present study has also demonstrated increased A·− level as early as the ischaemic phase of experiment independent of perioperative changes in the partial pressure of oxygen (pO2), elucidate a potentially important role for oxidative stress in provoking an appropriate vasodilation (NO-bioavailability) during the I-R period. This work demonstrates that; - Ascorbate is an antioxidant that can scavenge tissue and blood borne free radical, is essential in controlled amounts and is capable of initiating protective adaptation in the face of oxidative stress for the maintenance of physiological homeostasis. - Reperfusion is always associated with a sudden and massive release of ascorbate free radicals, with a maximal liberation within the first minutes of reperfusion. Vitamin C tended to reduce infarct size and protects from oxidative damage during global ischaemia and reperfusion. - The venous cannulation alone is enough per se stimulates the systemic formation of free radicals as a acute phase response. If this baseline artefact is not taken into account, the true magnitude of the exercise-induced oxidative stress response will be under-estimated.The I-R has got a major influence on the muscle oxygenation to increased ROS and the return of values towards baseline period in reperfusion stage appears to coincide with increased oxidative stress. Using the state-of-the-art molecular techniques that include Electron Paramagnetic Spectroscopy (EPR) for the direct detection of free radicals and Near Infrared Spectroscopy (NIRS) for the direct detection of muscle oxygenation these studies have attempted to translate the basic mechanisms associated with free radical formation during I-R and have provided unique insight into the basic mechanisms responsible for the oxidative stress with the ultimate objective of developing novel antioxidant interventions that can provide effective prophylaxis.
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Fitzsimmons, C. M. "Biologically active domains in collagen important in its haemostatic function." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.377902.
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Dickinson, Niall. "The application of iminium ions to the synthesis of biologically active molecules." Thesis, University of Southampton, 2013. https://eprints.soton.ac.uk/354554/.
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Zaki, Afroditi Maria. "Molecular dynamics study of biomembrane interactions with biologically active polymers." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/molecular-dynamics-study-of-biomembrane-interactions-with-biologically-active-polymers(0e61623d-d73c-4f84-a1ef-6698026c4aa2).html.
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Among the great breakthroughs in nanoscience and nanotechnology is the emergence of synthetic polymers that demonstrate biological activity and thus can be exploited for biomedical applications, extending from agents in therapeutics to drug delivery and tissue engineering. A key factor in the fabrication of such polymeric materials is the ability to tune and control their properties. To this end, an insight into the mode of interactions with biological systems is imperative. Computer simulations have proved to be a valuable tool that can compliment experiments and provide -otherwise inaccessible- information. In the context of this thesis, different aspects of the polymeric biological activity were investigated by studying two polymeric materials suitable for different types of applications, aiming to clarify yet undisclosed mechanisms that govern the polymers' behaviour either in solution or in conjunction with model lipid membranes. The first part of the thesis is dedicated to a nonionic amphiphilic copolymer known as Pluronic L64 that is considered as a candidate for the design of novel hybrid polymer-lipid vesicles that will act as carriers for drugs or genes. The hybrid bilayers are subjected to mechanical stress and their properties are compared to those of pure lipid bilayers. The simulations showed that the hybrid membranes can sustain increased surface tension prior to rupture, are stiffer, thicker and the polymers can induce higher lipid tail packing and also reduce the lipid mobility, rendering the membranes more ordered and less fluid. At high values of lateral pressure, which leads to pore formation, the copolymer chains decelerate the pore growth. The examination of the defect formation mechanism reveals that the hydrophilic PEO segment plays the most vital role. The same systems were also observed in varying temperatures and the impact of the inserted polymers on the phase behaviour was investigated. The data suggested that the polymers change the nature of the phase transition from a discontinuous to a continuous one. The hybrid membranes transform between the ordered and the disordered phase in a continuous manner and not at a critical melting temperature. Interestingly, the effect of polymers is different at the low and high temperature regions, as proved by the analysis of the mechanical, structural and dynamic membrane properties. The second part is focused on the study of polyhexamethylene biguanide (PHMB), a biguanide-based polyelectrolyte, that possesses remarkable biocidal properties. Even though PHMB's activity is known, the specific mode of action against bacterial membranes is still puzzling. Our work revealed that the polyelectrolyte assumes a counterintuitive behaviour in aqueous solution tending to self-organise into ordered compact structures, despite the repulsive electrostatic interactions of its positively charged segments. The formed nano-objects are thermodynamically stable, as was confirmed by free energy calculations and could be linked to PHMB's antibacterial mechanism. These findings pave the way for further computational and experimental exploration of these fascinating and promising materials that could lead to the design of novel smart biologically active nanoparticles.
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Davidson, Louise. "Synthesis and evaluation of solid supported receptors for biologically active steroids." Thesis, University of Reading, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250678.
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Aleksandra, Cvetanović. "Оптимизација савремених екстракционих поступака за изоловање апигенина из цвета камилице (Chamomilla recutita L.) и карактеризација биолошке активности добијених екстраката." Phd thesis, Univerzitet u Novom Sadu, Tehnološki fakultet Novi Sad, 2016. http://www.cris.uns.ac.rs/record.jsf?recordId=101724&source=NDLTD&language=en.
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У оквиру ове докторске дисертације изведено јеиспитивање различитих екстракционих поступака заизоловање апигенина из цвета камилице, као и евалуацијабиолошке активности добијених екстраката. Полазнибиљни материјал сачињавале су две групе латицакамилице: ферментисане и неферментисане (нативне).Екстракција ферментисаних цветова је извођена применомултразвучне екстракције користећи етанол као екстрагенс,а добијени екстракти су се одликовали изузетно високимсадржајем апигенина. Оптимизација екстракције је билаизведена применом методе одзивне површине. Применомелектрон-спин резонанце испитана је антирадикалскаактивност екстраката. Додатно, фармаколошка вредностдобијених екстраката је потврђена и одређивањем њиховогантимикробног и антипролиферативног потенцијала.Нативни цветови камилице су екстраховани применомразличитих екстаркционих техника: микроталасне,ултразвучне, Soxhlet екстракције као и екстракцијесубкритичном водом. Eкстрaкција водом у субкритичномстању се показала супериорнијом у односу на све осталетехнике у погледу садржаја укупних фенола и флавоноида.У циљу добијања екстраката са максималним садржајемапигенина изведена је оптимизација овог екстракционогпроцеса. Изоловање чистог апигенина је изведено изекстракта добијеног под оптималним екстракцијомусловима (однос дрога:растварач 1:30, брзина мешања 3 Hz,притисак 45 bar, температура 115ºC, време 30 мин,концентрација модификатора 0,001 М) применом поступкаколонске хроматографије на стубу полиамида. Хемијскипрофил као и садржај појединачних полифенолнихкомпонената у екстрактима добијеним на различитимпритисцима, температурама и уз присуство модификатораразличитих концентрација одређен је применом UHPLCDAD-HESI-MS/MS. У свим анализираним екстрактимадетектован је велики број полифенолних компонената, докје апигенин у свима био доминантно једињење. Садржајапигенина у екстракту добијеном под оптималнимекстракционим условима је износио 1.700,34 mg/kg.Применом седам различитих тестова извршена јеевалуација антиоксидативног и антирадикалскогпотенцијала екстраката. Антимикробни потенцијалекстраката је одређен за осам различитих микробнихлинија. in vitro тестовима испитана је способностинхибиције α-амилазе, α-глукозидазе и тирозиназе.Деловањем на раст три хистолошки различите ћелијскелиније, испитана је антипролиферативна активностекстраката добијених субкритичном водом.Антимотилитетна активност обе групе екстраката(ферментисаних и неферментисаних цветова) одређена је уin vitro условима.U okviru ove doktorske disertacije izvedeno jeispitivanje različitih ekstrakcionih postupaka zaizolovanje apigenina iz cveta kamilice, kao i evaluacijabiološke aktivnosti dobijenih ekstrakata. Polaznibiljni materijal sačinjavale su dve grupe laticakamilice: fermentisane i nefermentisane (nativne).Ekstrakcija fermentisanih cvetova je izvođena primenomultrazvučne ekstrakcije koristeći etanol kao ekstragens,a dobijeni ekstrakti su se odlikovali izuzetno visokimsadržajem apigenina. Optimizacija ekstrakcije je bilaizvedena primenom metode odzivne površine. Primenomelektron-spin rezonance ispitana je antiradikalskaaktivnost ekstrakata. Dodatno, farmakološka vrednostdobijenih ekstrakata je potvrđena i određivanjem njihovogantimikrobnog i antiproliferativnog potencijala.Nativni cvetovi kamilice su ekstrahovani primenomrazličitih ekstarkcionih tehnika: mikrotalasne,ultrazvučne, Soxhlet ekstrakcije kao i ekstrakcijesubkritičnom vodom. Ekstrakcija vodom u subkritičnomstanju se pokazala superiornijom u odnosu na sve ostaletehnike u pogledu sadržaja ukupnih fenola i flavonoida.U cilju dobijanja ekstrakata sa maksimalnim sadržajemapigenina izvedena je optimizacija ovog ekstrakcionogprocesa. Izolovanje čistog apigenina je izvedeno izekstrakta dobijenog pod optimalnim ekstrakcijomuslovima (odnos droga:rastvarač 1:30, brzina mešanja 3 Hz,pritisak 45 bar, temperatura 115ºC, vreme 30 min,koncentracija modifikatora 0,001 M) primenom postupkakolonske hromatografije na stubu poliamida. Hemijskiprofil kao i sadržaj pojedinačnih polifenolnihkomponenata u ekstraktima dobijenim na različitimpritiscima, temperaturama i uz prisustvo modifikatorarazličitih koncentracija određen je primenom UHPLCDAD-HESI-MS/MS. U svim analiziranim ekstraktimadetektovan je veliki broj polifenolnih komponenata, dokje apigenin u svima bio dominantno jedinjenje. Sadržajapigenina u ekstraktu dobijenom pod optimalnimekstrakcionim uslovima je iznosio 1.700,34 mg/kg.Primenom sedam različitih testova izvršena jeevaluacija antioksidativnog i antiradikalskogpotencijala ekstrakata. Antimikrobni potencijalekstrakata je određen za osam različitih mikrobnihlinija. in vitro testovima ispitana je sposobnostinhibicije α-amilaze, α-glukozidaze i tirozinaze.Delovanjem na rast tri histološki različite ćelijskelinije, ispitana je antiproliferativna aktivnostekstrakata dobijenih subkritičnom vodom.Antimotilitetna aktivnost obe grupe ekstrakata(fermentisanih i nefermentisanih cvetova) određena je uin vitro uslovima.
In the frame of this thesis different extraction approaches forapigenin isolation from chamomile ligulate flowers wereexamined and biological activity of obtained extracts wasevaluated. Starting plant samples included fermented andnonfermented (native) flowers.Extraction of fermented flowers was performed by usingultrasound-assisted extraction with ethanol. The concentrationof apigenin was high in obtained extracts. Optimization of theextraction procedures was performed by response surfacemethodology. Antiradical activity of observed extracts wasexamined by electron-spin resonance spectroscopy.Furthermore, pharmacological potential of obtained extractswas confirmed by determining their antimicrobial andantiproliferative activity.Native chamomile flowers were extracted by differentextraction techniques: microwave, ultrasound, Soxhlet andsubcritical water extraction. Subcritical water extractionshowed to be superior in comparison to other applied techniquesin respect to total phenols and flavonoids content. Optimizationof the subcritical water extraction was directed to maximizationof apigenin content. Isolation of pure apigenin from extractsobtained under optimal extraction conditions (sample-tosolventratio 1:30, agitation rate 3 Hz, temperature 115ºC,pressure 45 bar, extraction time 30 min) was performed bypreparative chromatography. Chemical profiles and content ofindividual polyphenolic components in extracts obtained atdifferent pressures, temperatures, and with differentconcentrations of a modifier was determined by UHPLC-DADHESI-MS/MS. In all analyzed extracts the great number ofpolyphenolic components was detected while apigenin was thedominant compound in all extracts. Content of apigenin in theextract obtained under optimal extraction condition was1,700.34 mg/kg. Antioxidant and antiradical potential ofextracts was evaluated according to different mechanisms.Antimicrobial potential of extracts was determined against eightdifferent microbial strains. Ability of extracts to inhibit α-amylase, α-glucosidase and tyrosinase was determined by invitro assays. Antiproliferative activity of subcritical waterextracts was defined by testing their influence on the growth ofthree histologically different cell lines.Anti-intestinal motility activity of both group of extracts (nativeand fermented) was determined by in vivo experiments.
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Donaldson, Lauren Rona. "New methods for the synthesis of biologically active phenanthridine-based libraries." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/5736.
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Small molecule libraries have become essential for the development of drug discovery campaigns and chemical genetics. The studies towards the synthesis of a small molecule library, based upon the cis-ring fused phenanthridine core I, will be described. The first section of this thesis examines the development and application of a novel intramolecular Heck cyclisation to the synthesis of core phenanthridine structure II, via precursor III (Chapter 2).The second section (Chapter 3) describes the extension of this methodology towards the development of a library of phenanthridines IV. This includes methodology designed to incorporate the key principles of diversity-oriented synthesis, namely appendage, stereochemical and skeletal diversity. The final part of this thesis (Chapter 4) describes the merging of these various methodologies to generate a small library of novel phenanthridine analogues. Preliminary biological evaluation of the phenanthridine library using whole organism zebrafish phenotyping, will also be discussed.
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Spáčil, Zdeněk. "Mass Spectrometry of Biologically Active Small Molecules : Focusing on polyphenols, alkaloids and amino acids." Doctoral thesis, Stockholms universitet, Institutionen för analytisk kemi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-33233.
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The foci of this dissertation are on advanced liquid chromatography (LC) separation and mass spectrometry (MS) techniques for the analysis of small bioactive molecules. In addition to discussing general aspects of such techniques the results from analyses of polyphenols (PPs), alkaloids and amino acids published in five appended studies are presented and discussed. High efficiency and well understood principles make LC the method of choice for separating analytes in many kinds of scientific investigations. Moreover, when LC is coupled to an MS instrument, analytes are separated in two stages: firstly they are separated and pre-concentrated in narrow bands using LC and then separated according to their mass-to-charge (m/z) ratios in the MS instrument. Some MS instruments can provide highly accurate molecular weight measurements and mass resolution allowing identification of unknown compounds based purely on MS data, thus making prior separation unnecessary. However, prior separation is essential for analyzing substances in most complex matrices – especially useful is the ultra-high performance LC (UHPLC). The advantages of using UHPLC rather than HPLC for the analysis of PPs in tea and wine were evaluated in one of the studies this thesis is based upon. The phenolic composition of red wine was also examined, using a novel LDI technique, following solid phase extraction (SPE). A class of small aromatic molecules (medicinally important alkaloids) also proved to be amenable to straightforward analysis, by thin layer chromatography (TLC) work-up followed by LDI-MS. Finally, a LC-MS method for monitoring neurotoxins (β-N-methyl-amino-L-alanine and 2,3-diaminobutyric acid) in complex biological matrices was developed and applied. Overall, the studies show that careful attention to the physicochemical properties of analytes can provide insights that can greatly facilitate the development of alternative methods to analyze them, e.g. by LDI.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: In press. Paper 5: Manuscript.
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Patel, Pratiq A. "Functionalization of Nitrogen-Containing Heterocycles in the Synthesis of Biologically Active Molecules." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1382064973.
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Spáčil, Zdeněk. "Mass spectrometry of biologically active small molecules focusing on polyphenols, alkaloids and amino acids /." Stockholm : Department of analytical chemistry, Stockholm University, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-33233.
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Diss. (sammanfattning) Stockholm : Stockholms universitet, 2010.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: In press. Paper 5: Manuscript. Härtill 5 uppsatser.
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Orlando, Michele. "Modification of proteins and low molecular weight substances with hydroxyethyl starch (HES) HESylation - a new technology for polymer conjugation to biologically active molecules /." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=96981545X.
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Hill, David Brooks. "Changes in the number of molecular motors driving vesicle transport in PC12 /." Electronic thesis, 2003. http://dspace.zsr.wfu.edu/jspui/handle/10339/206.
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Alli, Zaman. "Expression of biologically active human granulocyte macrophage colony stimulating factor in the seeds of transgenic tobacco." Thesis, University of Ottawa (Canada), 2001. http://hdl.handle.net/10393/9046.
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The feasibility of producing recombinant (rt) and biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) in the seeds of transgenic tobacco plants was investigated. The rice seed-specific glutelin promoter (Gt1) was used to direct the expression of the human (h) GM-CSF coding sequence in tobacco seeds. Transgenic tobacco plants producing rthGM-CSF were compared in biological assays with tobacco plants expressing a glutelin/rthGM-CSF fusion protein, driven by the Gt3 promoter. The T7 Sequencing kit from Pharmacia was used to sequence and confirm the authenticity of the Gt1 expression construct. The glutelin-1 signal sequence was fused in the correct orientation to the hGM-CSF cDNA. The rthGM-CSF expression cassette (2.5 kb) was subcloned in a plant binary vector pRD400, which contained a kanamycin resistance gene. The pRD400 vector containing the 2.5 kb construct was used to transform Agrobacterium tumefaciens cells. Tobacco (Nicotiana tabacum cv. Xanthi) leaf sections were transformed by A. tumefaciens carrying the complete 2.5 kb construct. (Abstract shortened by UMI.)
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Randhawa, Sukanya. "Active control of surface plasmons in hybrid nanostructures." Doctoral thesis, Universitat Politècnica de Catalunya, 2012. http://hdl.handle.net/10803/124095.
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Plasmonics nanostructures are becoming remarkably important as tools towards manipulating photons at the nanoscale. They are poised to revolutionize a wide range of applications ranging from integrated optical circuits, photovoltaics, and biosensing. They enable miniaturization of optical components beyond the "diffraction limit'' as they convert optical radiation into highly confined electromagnetic near-fields in the vicinity of subwavelength metallic structures due to excitation of surface plasmons (SPs). These strong electromagnetic fields generated at the plasmonic "hot spots'' raise exciting prospects in terms of driving nonlinear effects in active media.
The area of active plasmonics aims at the modulation of SPs supported at the interface of a metal and a nonlinear material by an external control signal. The nonlinear material changes its refractive index under an applied control signal, thereby resulting in an overall altered plasmonic response. Such hybrid nanostructures also allow for the creation of new kinds of hybrid states. This not only provides tools for designing active plasmonic devices, but is also a means of re-examining existing conventional rules of light-matter interactions. Therefore, the need for studying such hybrid plasmonic nanostructures both theoretically and experimentally cannot be understated.
The present work seeks to advance and study the control of SPs excited in hybrid systems combining active materials and nanometallics, by an external optical signal or an applied voltage. Different types of plasmonic geometries have been explored via modeling tools such as frequency domain methods, and further investigated experimentally using both near-field and far field techniques such as scanning near field optical microscopy and leakage radiation microscopy respectively. First, passive SP elements were studied, such as the dielectric plasmonic mirrors that demonstrate the ability of gratings made of dielectric ridges placed on top of flat metal layers to open gaps in the dispersion relation of surface plasmon polaritons (SPPs). The results show very good reflecting properties of these mirrors for a propagating SPP whose wavelength is inside the gap. Another passive configuration employed was a plasmonic resonator consisting of dielectric-loaded surface plasmon polariton waveguide ring resonator (WRR). Also, a more robust variant has been proposed by replacing the ring in the WRR with a disk (WDR). The performance in terms of wavelength selectivity and efficiency of the WDRs was evaluated and was shown to be in good agreement with numerical results.
Control of SPP signal was demonstrated in the WRR configuration both electro-optically and all-optically. In the case of electro-optical control, the dielectric host matrix was doped with an electro-optical material and combined with an appropriate set of planar electrodes. A 16% relative change of transmission upon application of a controlled electric field was measured. For all-optical control, nonlinearity based on trans-cis isomerization in a polymer material is utilized. More than a 3-fold change between high and low transmission states of the device at milliwatt control powers ( ~100 W/cm^2 intensity) was observed.
Beyond the active control of propagating surface plasmons, further advancement can be achieved by means of nanoscale plasmonic structures supporting localized surface plasmons (LSP). Interactions of molecular excitations in a pi-conjugated polymer with plasmonic polarizations are investigated in hybrid plasmonic cavities. Insights into the fundamentals of enhanced light-matter interactions in hybrid subwavelength structures with extreme light concentration are drawn, using ultrafast pump-probe spectroscopy.
This thesis also gives an overview of the challenges and opportunities that hybrid plasmonic functionalities provide in the field of plasmon nano optics.Las nanoestructuras plasmónicas han adquirido una importante relevancia como herramientas capaces de manipular los fotones en la nanoescala, y pueden llegar a revolucionar un amplio abanico de aplicaciones tales como los circuitos ópticos integrados, la fotovoltaica o los dispositivos biosensores. Dichas estructuras hacen posible la miniaturización de los componentes ópticos más allá del “límite de difracción” de la luz, ya que convierten la radiación óptica en campos electromagnéticos fuertemente confinados en la proximidad de estructuras metálicas de tamaño inferior a la longitud de onda mediante la excitación de plasmones de superficie (SPs). Estos campos electromagnéticos tan intensos generados en los llamados “puntos calientes” plasmónicos brindan perspectivas muy interesantes para la generación de efectos no lineales en medios activos. El área de investigación denominado plasmónica activa busca la modulación de los SPs sostenidos por la intercara entre un metal y un material no lineal mediante una señal de control externa. El índice de refracción del material no lineal cambia bajo la aplicación de la señal de control, lo cual da lugar a la modificación de la respuesta plasmónica. Estas nanoestructuras híbridas también hacen posible la aparición de nuevos tipos de estados híbridos, lo cual proporciona tanto herramientas para diseñar dispositivos plasmónicos activos como mecanismos que permiten re-examinar las reglas convencionales de la interacción luz materia. Por lo tanto, es necesario el estudio de dichas nanoestructuras plasmónicas híbridas de manera teórica y experimental. En este trabajo de tesis se analiza el control de los SPs excitados en sistemas híbridos que combinan materiales activos y nanoestructuras metálicas mediante una señal óptica externa o un voltaje aplicado. Se han investigado distintos tipos de geometrías plasmónicas utilizando herramientas de simulación basadas en métodos en el dominio de la frecuencia, y posteriormente se han caracterizado experimentalmente dichas geometrías mediante técnicas de campo cercano y de campo lejano tales como la microscopía óptica de campo cercano y la microscopía basada en pérdidas radiativas, respectivamente. En primer lugar se estudiaron elementos plasmónicos pasivos, en particular espejos plasmónicos dieléctricos que demuestran la capacidad que tienen las redes periódicas de caballones de material dieléctrico colocados sobre una superficie metálica plana para abrir intervalos prohibidos en la relación de dispersión de los plasmones de superficie propagantes o plasmones-polaritones de superficie (SPPs). Los resultados muestran que dichos espejos poseen muy buenas propiedades reflectantes para SPPs cuya energía está en el intervalo prohibido. Otra configuración pasiva analizada fueron los resonadores plasmónicos basados en anillos de guía de onda plasmónica fabricada a partir de estructuras dieléctricas sobre metal (WRR, del inglés waveguide ring resonator ). Asimismo, se propone una versión más robusta de resonador plasmónico, basada en la sustitución del anillo del WRR por un disco (WDR, del inglés waveguide disk resonator). Se ha evaluado el funcionamiento de los WDRs en términos de selectividad en longitud de onda y de eficiencia, y los resultados obtenidos presentan un buen acuerdo con las predicciones numéricas. Pasando a las configuraciones activas, se demuestra el control de la señal plasmónica en configuración WRR por medios tanto electro-ópticos como completamente ópticos. En el caso del control electro-óptico, el material dieléctrico que compone el WRR estaba dopado con un componente electro-óptico y a la estructura pasiva se le añadió un conjunto de electrodos planos. Bajo la aplicación de un campo eléctrico externo, se midió un cambio relativo en la transmisión a través de la guía plasmónica del 16%. En cuanto al control puramente óptico, se utilizó la no linealidad de un material polimérico con origen en una isomerización trans-cis. En este caso se detectó un factor 3 entre los estados de alta y baja transmisión del dispositivo con potencias de control del orden de milivatios (intensidad del haz óptico de control de unos 100W/cm2 aproximadamente). Además del control activo de los plasmones de superficie propagantes, la utilización de nanoestructuras plasmónicas que poseen resonancias plasmónicas localizadas puede dar lugar a nuevos fenómenos. En esta tesis también se han estudiado las interacciones entre las excitaciones moleculares en un polímero pi-congujado con las polarizaciones plasmónicas en nanocavidades plasmónicas híbridas. Utilizando espectroscopia de tipo bombeo-sonda con pulsos ultrarrápidos, se han analizado diversos aspectos del aumento en la interacción luz-materia para estructuras híbridas de dimensiones inferiores a la longitud de onda sometidas a concentraciones de luz muy altas. Por último, esta tesis también proporciona una visión general de los desafíos y posibilidades que las funcionalidades plasmónicas híbridas ofrecen en el campo de la nano-óptica basada en plasmones de superfície.
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Yam, Noymi. "Molecular interactions of biologically active derivatives of sulfamide with pharmaceutical polymers in solid state." Scholarly Commons, 2009. https://scholarlycommons.pacific.edu/uop_etds/2398.
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Molecular interactions of small molecules with polymers in solid state have numerous applications in pharmaceutical research. This dissertation examines the mechanism of the solid state interactions of the biologically active sulfamide derivatives with polyethylene glycol (PEG) and structurally related polymers. It is shown that in addition to the formation of the eutectic systems, PEG and related polymers cause polymorphic transitions of sulfamide derivatives. A new polymorphic form of a model sulfamate, topiramate, has been discovered and characterized using multiple analytical techniques. The phase diagrams describing the interactions of Topiramate with PEG and poloxamer block copolymer in solid state were constructed and the mechanism of the polymorphic transformations has been proposed. It was concluded that formation and stabilization of the new polymorphs occurred due to rearrangement of the hydrogen bonding networks of the sulfamide derivatives caused by the conformational changes of the polymer chains.
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Yamamura, Ei-tora. "Biochemical and molecular biological studies on enzymatic synthesis of vitamin B6 derivatives and optically active carboxylic acids." Kyoto University, 2020. http://hdl.handle.net/2433/245820.
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Kyoto University (京都大学)0048
新制・論文博士
博士(農学)
乙第13305号
論農博第2880号
新制||農||1074(附属図書館)
学位論文||R2||N5242(農学部図書室)
富山大学大学院理工学研究科生命環境科学専攻
(主査)教授 小川 順, 教授 阪井 康能, 教授 栗原 達夫
学位規則第4条第2項該当
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Ng, Sean. "Regioselective copper(I)-NHC-catalysed allylic oxidation reactions : application towards the total syntheses of biologically active molecules." Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.577144.
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The metal-catalysed allylic oxidation of alkenes has emerged as a powerful method for the functionalisation of Sp3 C-H bonds. This transformation has allowed for the expedient preparation of synthetically useful materials from hydrocarbon building blocks. With the development of air stable and environmentally benign copper(I)-NHC catalysts from readily available materials, it has been shown that these catalysts can participate in the allylic oxidation of alkenes in an effective manner. We have developed a powerful protocol for the functionalisation of alkenes into allylic alcohols and enones, by the use of different terminal oxidants in a divergent fashion. The highly regio- and chemoselective copper(I)-NHC-catalysed allylic oxidation has been examined in the syntheses of functionalised cyclopentenones and cyclohexenones, which has provided mechanistic insights into the oxidation. The system displays excellent tolerance of a plethora of sensitive functional groups and provides a general approach with high efficiency. It has been shown that high regioselectivity is not necessary straightforward and can depend on many factors, including stereoelectronic interactions. The studies towards the enantioselective variant via the desyrnrnetrisation of the proposed prochiral intermediate utilising a range of chiral copper(I)-NHC catalysts was unsuccessful. The synthetic utility of this transformation has been validated by the total synthesis of (±)-untenone A in the shortest and most efficient approach to date. Studies towards the total synthesis of cephalimysin A are currently ongoing, which would employ the late stage copper(I)-NHC-catalysed allylic oxidation on a densely functionalised intermediate.
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Merrifield, Jonathan David. "Development of novel sensors for biologically active molecules based on the selective modification of supported phospholipid monolayers." Thesis, University of Leeds, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446053.
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Tiao, Jim Yu-Hsiang. "The neuregulin-3 intracellular domain is biologically active : molecular and functional characterisation of protein interactions." University of Western Australia. School of Medicine and Pharmacology, 2006. http://theses.library.uwa.edu.au/adt-WU2006.0083.
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[Truncated abstract] Neuregulins (NRG’s) are pleiotropic growth factors that participate in a wide range of biological processes. The family of membrane-bound growth factors bind to and activate ErbB receptors on adjacent target cells, mediating multiple biological processes. NRG-1, NRG-2 and NRG-3 are all highly expressed in the nervous system, where it has been shown that NRG-1 is important for neuronal development, migration, synapse formation and glial cell proliferation. Little is known, however, on the specific roles of NRG-2 and NRG-3, although it is apparent that despite similar expression patterns and overlapping receptor specificity, NRG-2 and NRG-3 do not compensate for the loss of NRG-1 and mediate their own distinct activities. … Subcellular localisation experiments showed that this domain is important for trafficking of the fulllength protein to various intracellular compartments in an activity dependent manner. In addition, the ICD is required to elicit a cell death response in cultured cells and provoke an elevated α-amino-3-hydroxyl-5-methylisoxazole-4-propionate (AMPA) response in organotypic neuronal cultures following transient expression of NRG-3. A yeast two-hybrid screen identified 14-3-3ζ and PICK1 as two proteins that interacte with the human NRG-3 ICD. These interactions were confirmed both in vitro and in vivo, and were further characterised at a molecular level. This study demonstrates the ability of NRG-3 to mediate signal transduction through a biologically active ICD; a conclusion supported by identifying cytoplasmic proteins that interact with the ICD. These observations point to an additional layer of complexity where bi-directional signalling contributes to the full repertoire of NRG-3 functions.
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Friesen, Sergej [Verfasser], and Richard [Akademischer Betreuer] Buchner. "Hydration and Ion Binding of Small Biologically Active Molecules: The Case of Neurotransmitters / Sergej Friesen ; Betreuer: Richard Buchner." Regensburg : Universitätsbibliothek Regensburg, 2020. http://d-nb.info/1203875258/34.
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Sánchez, Mirna Inés Mosquera. "Interação de moléculas biologicamente ativas com filmes de Langmuir de fosfolipídios." Universidade de São Paulo, 2000. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-08112013-102613/.
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A interação de várias substancias bioativas com monocamadas de fosfolipídios foi investigada usando isotermas de pressão e potencial de superfície, incluindo as drogas farmacológicas dipiridamol (DIP), clopromazina (CPZ) e trifluoperazina (TFP), além da melatonina (MEL) e o colesterol (COL). Os fosfolipídios empregados foram o zwiteriônico dipalmitoil fosfatidil colina (DPPC) e o aniônico dipalmitoil fosfatidil glicerol (DPPG) espalhados na superfície de água ultrapura, sendo que as monocamadas servem como modelo simples de membranas. A cooperatividade na interação entre fosfolipídios e moléculas com atividade biológica foi essencial para entender os acentuados efeitos na expansão (ou condensação) das monocamadas e as mudanças no momento de dipolo (até 10% de aumento na expansão em relação à monocamada do fosfolipídio puro para as misturas DIP/DPPC) que ocorreram a concentrações molares muito baixas entre 0,2-0,4% do DIP. Tais efeitos foram observados para todas as cinco substâncias investigadas, em todos os regimes de pressão. Nas altas concentrações, o comportamento da interação depende do tipo de mólecula e também de se a monocamada é de DPPC ou DPPG. Para o DPPC, as drogas farmacológicas foram expelidas da interface em vários graus a altas pressões, e existia um máximo de concentração da droga acima do qual ocorria a saturação, provavelmente porque as moléculas em excesso foram para a subfase. Essas concentrações críticas foram de 2% em mol para o DIP e a CPZ e de 5% em mol para a TFP. Para o DIP, em particular, os resultados das isotermas foram correlacionados com experimentos de espectroscopia de FTIR e microscopia de fluorescência \"in situ\", realizados por colaboradores, os quais permitiram a determinação de uma localização precisa da droga estudada. Não existe inserção do DIP na região da cauda hidrofóbica da monocamada do DPPC, com a interação ocorrendo com o grupo fosfato no zwiteríon, cujas pequenas mudanças na orientação induzidas pelo DIP levam a grandes mudanças no momento de dipolo. Como o DPPG está carregado negativamente sobre a superfície da água pura, não existe saturação nos efeitos de expansão com o aumento da concentração das drogas. O aumento do momento de dipolo efetivo na monocamada mista é atribuído a alterações na densidade de carga superficial pela adsorção da droga catiônica, que reduz a contribuição negativa do potencial da dupla camada, quando comparado com o da monocamada de DPPG puro. Os resultados do COL e a MEL devem ser considerados separadamente devido a sua natureza distinta, embora um comportamento cooperativo também tenha observado com grandes efeitos nas baixas concentrações. Tanto o COL como o MEL induzem mudanças na expansão das monocamadas de DPPC até a máxima concentração empregada, 20% molar. Para o COL foi observado um efeito de condensação a baixas concentrações, o qual foi seguido por uma expansão a altas concentrações, confirmando assim resultados prévios da literatura. Todas as monocamadas mistas COL/DPPG apresentavam-se expandidas, também confirmando alguns resultados da literatura para lipídios (diferentes do DPPC) quando misturados com o COL. A interação da MEL com o DPPC foi essencialmente similar à do COL, apesar do fato de a MEL pura não formar monocamadas estáveis. Sua interação com o DPPG foi peculiar já que o efeito que esta induz satura a 5% em mol. Isto também difere do comportamento das drogas farmacológicas. A MEL é neutra em todos os pHs, portanto, sua intenção com as membranas modelo de DPPG e DPPC só pode ocorrer via dipolo. O mesmo se aplica ao colesterol, o que justifica as diferenças no comportameto destas duas moléculas quando comparadas com as drogas (DIP, CPZ, TFP), que são carregadas sobre a água pura, nas misturas com os dois fosfolipídios (DPPG e DPPC).The interaction of various bioactive substances with phospholipids monolayers has been investigated using surface pressure and surface potential isotherms, which include the pharmaceutical drugs dipyridamole (DIP), chlorpromazine (CPZ) and trifluoperazine (TFP), in addition to melatonin (MEL) and cholesterol (COL). The phospholipids employed were the zwitterionic dipalmitoyl phosphatidyl choline (DPPC) and the anionic dipalmitoyl phosphatidyl glycerol (DPPG) spread onto ultra pure water surfaces, where the monolayers served as simple model membrane systems. Cooperativity in the interaction between phospholipid and bioactive molecules was essential to account for the large effects of expansion (up to 10% increase in area in relation to the pure phospholipid monolayer for the DIP/DPPC mixture) of the monolayers and changes in dipole moment, which occurred at very low concentrations, e.g. 0.2 - 0.4 mol% of the substance. Such large effects were observed for all 5 substances investigated, at all surface pressure regimes. At higher concentrations, the interaction behavior depended on the type of molecule and also on whether the host monolayer was DPPC or DPPG. For DPPC, the pharmaceutical drugs were expelled at varying degrees from the interface at high surface pressures, and there was a maximum drug concentration above which the effects saturated, probably because the molecules in excess were lost to the subphase. These critical concentrations were 2mol% for DIP and CPZ and 5mol% for TFP. For DIP, in particular, the results from isotherm were correlated with in situ FTIR spectroscopy and fluorescent microscopy experiments, carried out by collaborators, which allowed the precise location of the drug to be determined. There is no insertion of DIP into the hydrophobic tail region of the DPPC monolayer, with interaction taking place with the phosphate group in the zwitterion, whose small changes in orientation induced by DIP lead to the large changes in dipole moment. Because DPPG is negatively charged on a pure water surface monolayer, there is no saturation of the expansion effects with the increase in drug concentration. The increase in the effective dipole moment of the mixed monolayers are attributed to alterations in the surface charge density by adsorption of the cationic drugs, which then reduces the negative contribution of the double-layer potential as compared to the pure DPPG monolayer. The results for COL and MEL must be considered separately owing to their distinct nature, even though a cooperative behavior was also observed with large effects at low concentrations. Both COL and MEL induce changes in the DPPC monolayers up to the highest concentration employed, viz. 20mol%. For COL, a condensation effect was observed at low concentrations, which was followed by monolayer expansion at high concentrations, thus confirming previous results in the literature. All COL/DPPG monolayers were more expanded than pure DPPG, also confirming previous results from the literature. While the interaction of MEL with DPPC was essentially similar to that of COL, in spite of the fact that MEL does not form stable monolayers on its own, its interaction with DPPG was somewhat peculiar in that the effects it induced saturate at 5mol%. This also differs from the behavior of the pharmaceutical drugs. MEL is neutral over a wide range of pHs, and therefore its interaction with DPPC and DPPG monolayers must occur via dipole interaction. The same applies to COL, and this explains why the behavior of these two substances is different from the drugs (DIP, CPZ and TFP) that are charged on the water surface, in the interaction with DPPC and DPPG.
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Tatarski, Miloš. "Molecular mechanism of dBigH1 action." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663021.
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INTRODUCTION:
For decades it was known that many species contain embryo specific linker histone H1 variants that replace the somatic H1 during early embryogenesis. This is especially important because the early embryo shows typically zero to very little activity of transcription, and the first cleavages of the embryo depend exclusively on maternally deposited factors that are important for transcription and chromatin assembly. The first species shown to contain an embryo specific histone H1 was the sea urchin. Other species like the mouse, Xenopus or the zebrafish followed. Even in humans there are embryo specific H1 variants. Drosophila seemed to be an exception to this, until in 2013 the first linker histone H1 variant was discovered that was called dBigH1. Like other embryo H1 variants, dBigH1 is expressed in the early embryo and disappears when cellularization starts and it gets replaced by the somatic H1. Likewise, to its counterparts in other species, dBigH1 is responsible for the inhibition of transcription during the early stage of fly development.
OBJECTIVES:
In this thesis, we addressed the questions about the mechanism of inhibition of dBigH1 as well as the factors that are responsible for its deposition into chromatin.
RESULTS:
To answer the first question, we used an in vitro system for chromatin reconstitution based on an extract from early Drosophila embryos (DREX) that contains dBigH1 and all other factors needed for proper chromatin assembly. We then used the reconstituted chromatin in transcription experiments using HeLa nuclear extract that contains all factors needed for transcription.
We saw that transcription for chromatin reconstituted in DREX could be reduced when the extract was previously depleted from dBigH1 using specific antibodies against it. By adding back recombinant dBigH1 to the depleted extract we were able to restore the initial lever of transcription. This showed us that dBigH1 was the repressive factor, as it was already confirmed in vivo.
We then used a truncated construct of dBigH1 where we depleted the N-terminal domain of the protein. This was of particular interest as the N-terminal region of dBigH1 is the one that differs most form the somatic H1. It is much longer and more importantly very enriched with acidic residues, something that is very unique amongst all embryo specific H1 variants. We saw that when using the truncated construct, transcription was inhibited to a much lesser extent than with the full length dBigH1, proposing that the N-terminal domain is indeed responsible for the inhibition of transcription.
To answer the second question about the factors needed for dBigH1 deposition, we used Drosophila testis to study dBigH1 in vivo. dBigH1 shows a very similar expression pattern in testis as the chromatin remodeler ACF1. This is why we decided to investigate a possible interaction between those two proteins. Additionally, we knew that ACF1 uses NAP1 as a histone chaperone for H1 in some species, so we also asked if NAP1 could play a role in dBigH1 deposition as well.
Indeed, we saw that when using flies deficient for ACF1 we see much less dBigH1 in the testis tip where the germal stem cells (GSC) reside, suggesting that ACF1 plays an important role in dBigH1 deposition. In accordance, we see more dBigH1 in the GSCs when using flies overexpressing ACF1. At the same time, we can see that when depleting NAP1 from DREX, we see more dBigH1.
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Ikeda, Yasunori. "Synthesis and molecular imprinting studies of small analogues of heparan sulfates : preparation and characterization of biologically active oligosaccharides." Paris 12, 2007. http://www.theses.fr/2007PA120052.
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White, Colin P. "Molecular Microbial Ecology and Operational Evaluation of a Full-scale and Pilot-scale Biologically Active Filter for Drinking Water Treatment." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1277154047.
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Ying, Jinfa. "Studies of biologically active peptides by NMR and molecular dynamics simulations: From structure and dynamics to design and synthesis." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280667.
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Nuclear magnetic resonance spectroscopy and molecular dynamics simulation have been used to study the structure and dynamics of biologically active peptide ligands for glucagon and melanocortin receptors, providing valuable insights into the receptor ligand interactions and useful information for the further design of more potent and selective ligands for these receptors. The NMR structure of the potent glucagon antagonist [desHis¹, desPhe⁶, Glu⁹]glucagon amide consists of an unstructured N-terminal segment (2-5), an irregular helix (7-14), a hinge region (15-18), and a well-defined α-helix (19-29). The two helices form an L-shaped structure with an angle of about 90° between the helix axes. There is an extended hydrophobic cluster, which runs along the inner surface of the L-structure and incorporates the side chains of the hydrophobic residues of each of the amphipathic helices. The outer surface contains the hydrophilic side chains. This result is the first clear indication of an overall tertiary fold for a glucagon analogue in the micelle-bound state. In addition to the structural difference, molecular dynamics simulations showed both N- and C-terminal residues in the glucagon antagonist are more highly ordered than those in glucagon. The single helix obtained for glucagon in the crystal state was found to unravel in the simulation around the region approximately corresponding to the hinge region in the antagonist. These results may have important implications for the biological activities of both peptides. The conformational study of cyclic alpha-melanocyte stimulating hormone analogues by NMR showed that their overall backbone structures are similar around the message sequence (His⁶-D-Phe⁷/D-Nal(2')⁷-Arg⁸-Trp⁹). beta-Turns spanning His⁶ and D-Phe⁷/D-Nal(2')⁷ were identified in all analogues. However, a stacking between the aromatic rings of His⁶ and D-Phe⁷/D-Nal⁷ was observed for the melanocortin agonists, but not for the antagonists. Based on the NMR structure of MTII, a library of new alpha-MSH analogues was designed and synthesized with a disulfide or lactam bridge used as a conformational constraint and the pharmacophore group in Arg⁸ mimicked by Nᵅ-alkylation via the Mitsunobu reaction. These new analogues exhibited high binding affinity and selectivity for the human melanocortin-4 receptor, thus suggesting the usefulness of the NMR structural model of α-MSH peptides.
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Ruiz, Carmona Sergio. "Virtual screening for novel mechanisms of action: applications and methodological developments." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/400297.
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The main motivation of this thesis has been to validate, improve and develop new methods with respect to the ones available nowadays in the area of drug discovery, in order to be able to study more challenging targets in the near future that currently are out of our reach.
As the productivity of the pharmaceutical industry is decreasing year after year over the last decades, the improvement of such methods would be a step forward. As we are mostly a computational lab, this thesis has focused on different computational approaches such as docking, molecular dynamics or chemoinformatics.
On the first part of the thesis (first author on the publication in PLoS Computational Biology in 2014), I worked on Docking-based Virtual Screening (VS). Particularly, in validating rDock, a little-known but very powerful program that was published and released during this thesis as open source software. In order to validate it, we performed several benchmarking experiments with DUD and ASTEX sets to compare the performance of rDock against Glide and AutoDock Vina, two commonly used docking programs. The capabilities of rDock with respect to binding mode prediction (predict how a ligand structure will be upon binding to its receptor) and virtual screening (selecting the most likely active ligands amongst thousands or millions of drug-like molecules) were compared with Glide and Vina, and we demonstrated that rDock performed as well as them.
On the second project of the thesis (first author on the publication in Nature Chemistry in 2016), we wanted to develop a novel computational tool for drug discovery not only that was complementary to the existing ones, but also that improved them by adding new ways of interpreting the data.
Taking advantage of the already known technique of Steered Molecular Dynamics (SMD), we proposed an approach consisting in reducing the size of the system, focusing around a key interaction point and running SMD to discriminate between active and inactive ligands.
This approach, or as we call it: "Dynamic Undocking", is intended to foster drug design efforts in the lead optimization stage by improving the efficiency of the in silico assessment of protein-ligand binding affinity.
After a positive retrospective assessment of the method using different systems of the DUD set, a prospective validation was required to evaluate its feasibility in a real drug discovery project. Hsp90 was selected as the test system: A fragment library was created and a subset of fragments was selected for a first stage of docking-based VS. About 300.000 ligands were docked with rDock and the top-scoring ones were subjected to Dynamic Undocking. In a collaboration with Vernalis, a pharmaceutical company in the UK, we tested tens of compounds selected with Dynamic Undocking and we were able not only to find positive and novel hits but also to improve hit-rate with respect to standard fragment screening by almost 10 fold.
Finally, we had the opportunity to participate in the D3R Grand Challenge 2015 where we could apply all the methods from this thesis (first author on the publication in Journal of Computer-Aided Molecular Design in 2016). This challenge was designed as a blind public test where different groups around the world tried to predict the binding mode and the affinity of a set of ligands for their respective protein target. Our approach consisted in a combination of docking and Dynamic Undocking and our results were placed amongst the best for the two systems of the challenge. We also discussed how the level of available data and previous knowledge on each of the systems impacted on the final results.La motivación principal de esta tesis ha sido validar, mejorar y desarrollar nuevos métodos con relación a los disponibles hoy en día en el área del desarrollo de fármacos, para en un futuro poder estudiar dianas que actualmente están fuera de nuestro alcance. Debido a que la productividad de la industria farmacéutica está disminuyendo durante los últimos años, una mejora en los métodos disponibles sería un gran paso adelante. Esta tesis se ha centrado en diferentes métodos computacionales, como el docking o la dinámica molecular. En la primera de las partes, trabajé en el cribado virtual (Virtual Screening) basado en docking. Concretamente, participé en la validación del programa de docking rDock mediante la comparación con dos programas muy usados hoy en día de su capacidad de predecir correctamente el modo de unión de un ligando con su proteína diana y de sus resultados en el cribado virtual de posibles fármacos. En la segunda parte de la tesis, participé en el desarrollo de un método computacional novedoso en el diseño de fármacos que complementase y mejorase los métodos actualmente disponibles. Éste método, bautizado en inglés como “Dynamic Undocking”, consiste en una implementación específica de dinámica molecular mediante la cual somos capaces de detectar si un ligando puede ser activo o inactivo de manera rápida y eficiente. Se validó el método de manera retrospectiva y posteriormente se aplicó en otro proyecto con el objetivo de encontrar nuevos posibles fármacos para una proteína relacionada con cáncer. Gracias a una colaboración con una empresa del Reino Unido, encontramos nuevos ligandos de manera que aumentamos la tasa de éxito con relación a un método estándar en casi 10 veces. Por último, participé en el “D3R Grand Challenge 2015”, un experimento a escala mundial donde los participantes aplicaron diferentes métodos y compararon sus resultados respecto a dos métricas distintas: la predicción del modo de unión y la capacidad de ordenar los ligandos proporcionados por la organización por su afinidad respecto a la proteína diana. En nuestro caso, aplicamos una combinación de docking y “Dynamic Undocking” con unos resultados excelentes.
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Enzinger, Monika [Verfasser], and Sabine [Akademischer Betreuer] Amslinger. "Reactivities of biologically active small molecules: Kinetic assessment of electrophilic enones and characterization of a photoactive phosphoantigen probe / Monika Enzinger ; Betreuer: Sabine Amslinger." Regensburg : Universitätsbibliothek Regensburg, 2020. http://d-nb.info/1218299029/34.
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Teixeira, Lúcia de Fátima Moreira. "Role and mechanism of action of human immunoregulatory iNKT cells in Leishmania infection: new approaches for vaccination?" Doctoral thesis, Faculdade de Farmácia da Universidade do Porto, 2010. http://hdl.handle.net/10216/63808.
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Teixeira, Lúcia de Fátima Moreira. "Role and mechanism of action of human immunoregulatory iNKT cells in Leishmania infection: new approaches for vaccination?" Tese, Faculdade de Farmácia da Universidade do Porto, 2010. http://hdl.handle.net/10216/63808.
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Bergamini, Fernando Rodrigues Goulart 1988. "Síntese, caracterização, modelagem molecular e ensaios antibacterianos de novos complexos de Ag(I) com ligantes biologicamente ativos." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/249125.
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Orientador: Pedro Paulo CorbiDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química
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Resumo: Neste trabalho, são descritas a síntese e a caracterização de três complexos inéditos de prata com os ligantes L-butionina sulfoximina (BSO), ácido 2-tiazolidina carboxílico (2-TC) e ácido 4-tiazolidina carboxílico (4-TC). O complexo de prata com BSO foi caracterizado por um conjunto de análises químicas e espectroscópicas, a saber: análise elementar, análise térmica, espectroscopia na região do infravermelho (IV), espectroscopia Raman, espectroscopia de ressonância magnética no estado sólido de C (C-RMN), estudos por DFT e ensaios biológicos. Os complexos de prata(I) com 2-TC e 4-TC, por sua vez, foram caracterizados por análise elementar, análise térmica, espectroscopia na região do infravermelho (IV), espectroscopia de ressonância magnética no estado sólido de C-RMN e N-RMN, estudos por DFT e ensaios biológicos. O complexo de prata com BSO, [Ag2(BSO)], apresenta uma composição 2:1 metal/ligante, sendo que a coordenação do ligante a um dos átomos de prata ocorre através dos grupamentos amino e carboxilato, enquanto que a coordenação ao segundo átomo de prata ocorre através do nitrogênio da sulfoximina. Os complexos de prata com 2-TC e 4-TC também apresentam proporção 2:1 metal/ligante, com um átomo de prata coordenado através do nitrogênio e o segundo átomo de prata coordenado através do carboxilato. As análises biológicas revelaram que os complexos [Ag2(BSO)], [Ag2(2-TC)] e [Ag2(4-TC)] são efetivos sobre cepas patogênicas Gram-positivas de Staphylococcus aureus, e cepas Gram-negativas de Escherichia coli e Pseudomonas aeruginosa
Abstract: This work deals with the synthesis and characterization of three new silver(I) complexes with the ligands Lbuthionine sulfoximine (BSO), thiazolidine-2 carboxylic acid (2-TC) and thiazolidine-4 carboxylic acid (4-TC). The silver complex with BSO was characterized by elemental and thermal analyses, infrared and Raman spectroscopies, C nuclear magnetic resonance in the solid-state (C-NMR), DFT studies and biological assays. The silver(I) complexes with 2-TC and 4-TC were characterized by elemental and thermal analyses, infrared spectroscopy, C and N nuclear magnetic resonance in the solid-state, DFT studies and biological assays. The silver-BSO complex, [Ag2(BSO)], presents a 2:1 metal/ligand ratio. One of the silver(I) ion was shown to be coordinated through the amine nitrogen atom and the oxygen of carboxylate, while the second ion was shown to be coordinated through the nitrogen atom of the sulfoximine group. The silver(I) complexes with 2-TC and 4-TC also presented a 2:1 metal/ligand ratio, and are coordinated by the nitrogen and the oxygen atom of the carboxylate group. The biological assays revealed that the [Ag2(BSO)], [Ag2(2-TC)] and [Ag2(4-TC)] complexes are active against Gram-positive pathogenic strains of Staphylococcus aureus and Gramnegative pathogenic strains of Escherichia coli and Pseudomonas aeruginosa
Mestrado
Quimica Inorganica
Mestre em Química
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Matkar, Smita S. "Mechanism of action of potential anticancer drugs." Scholarly Commons, 2008. https://scholarlycommons.pacific.edu/uop_etds/2368.
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Traditionally, inoperable or metastatic cancers have been treated by causing massive DNA damage in order to induce self-destruction (apoptosis) of the rapidly multiplying cancer cells. Initially, this strategy works for many cancers, in particular those which express normal p53 tumor suppressor protein. However, most cancers eventually aquire mutations in either p53 or other signaling molecules and fail to initiate apoptosis in response to severe DNA damage. During this study three types of compounds were investigated for their DNA damaging and anticancer effects: a pair of novel metal containing compounds, a pair of natural products, and a known synthetic drug which had been used many years ago for completely different indication. It was shown that all stop the growth of cancer cells and that the latter two classes do not require functional p53 because they work equally well in cells with normal (wildtype), mutant or no p53. The two nickel complexes investigated in this dissertation, differ in their ability to cause DNA damage and cell death. The oxidized form of the nickel complex, [Ni(CR-2H)] 2+ causes DNA damage and cell death at a much lower concentration than its reduced counterpart [Ni(CR)] 2+ . The phenanthridine alkaloids, Sanguinarine and Chelerythine cause high levels of DNA strand breaks and extremely rapid apoptosis which is not due to DNA damage because the quick onset precludes extensive signaling. The effects of the phenanthridines were linked to production of large amounts of reactive oxygen species (ROS), in particular hydrogen peroxide (H 2 O 2 ). The importance of ROS for the action of anticancer drugs as well as antibiotics is increasingly being recognized. In addition we also investigated the thioxanthone Lucanthone or Miracil D (which was used for the treatment of parasitic worms more than 50 years ago). It causes DNA strand breaks and apoptosis. Apoptosis occurs on a timescale consistent with signaling. However, p53 does not seem to be involved and alternative mechanisms are being investigated. This work provides new directions for designing novel anticancer drugs that are not subject to the limitations of DNA damaging agents.
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González, Abuín Noemí. "Modulation of active glucagon-like peptide-1 (glp-1) levels by grape-seed procyanidins." Doctoral thesis, Universitat Rovira i Virgili, 2013. http://hdl.handle.net/10803/128942.
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Modulation of active glucagon-like peptide-1 (GLP-1) levels by grape-seed procyanidins
Les procianidines del pinyol de raïm (GSPE) poden millorar estats de disrupció de la homeòstasi de la glucosa i es va hipotetitzar que la modulació de GLP-1, incretina que millora la producció d¿insulina i la seva detecció a teixits perifèrics, podria ser un mecanisme de actuació del GSPE. Per demostrar aquesta hipòtesi, s¿ha avaluat, in vivo i in vitro l¿efecte del GSPE en la secreció i producció de GLP-1, així com l¿efecte sobre la activitat de DPP4, enzim que degrada GLP-1. Els resultats obtinguts demostren que el tractament oral amb GSPE millora el nivells de GLP-1 induïts per una càrrega oral de glucosa. A més a més, s¿ha vist que GSPE modula la secreció i producció de GLP-1, així com la activitat de DPP4. En conclusió, la modulació del nivells de GLP-1 activa pot, en part, explicar els efectes antihiperglicèmics del GSPE.
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Sans, i. Duran Cristina. "Millora de soques i estudi d’estratègies de procés per a la producció de Fuculosa-1-fosfat aldolasa recombinant activa en Escherichia coli." Doctoral thesis, Universitat Autònoma de Barcelona, 2011. http://hdl.handle.net/10803/84008.
Full textAbstract:
Aquest treball de tesi doctoral s’engloba dins la coneguda Biotecnologia Blanca, concretament en el camp de la Producció de Proteïnes Recombinants. Les aplicacions d’aquesta àrea de coneixement en processos industrials es basa en el disseny de microorganismes per obtenir productes d’alt valor afegit. En aquest cas, el microorganisme productor és Escherichia coli i la proteïna d’interès es tracta de Fuculosa-1-fosfat aldolasa, enzim que catalitza estereoselectivament reaccions d’addició aldòlica.
Per una banda, s’han dut a terme diverses modificacions a nivell de plasmidi per tecnologia de DNA recombinant a fi de millorar un sistema d’expressió auxotròfic per la glicina. Aquestes millores no tan sols han anat enfocades a l’increment dels nivells de producció de la proteïna d’interès, sinó també a la obtenció d’un sistema d’expressió segur, simplificat i estable. El creixement i producció de la Fuculosa-1-fosfat aldolasa mitjançant les soques modificades han estat efectuats en matrassos d’Erlenmeyer i en fermentadors operant en discontinu alimentat quan s’ha requerit.
Per altra banda, l’expressió de la proteïna d’interès en forma de cossos d’inclusió, a banda de soluble, ha permès obtenir alts nivells de Fuculosa-1-fosfat pura i activa. L’aplicació d’aquests cossos d’inclusió prèviament immobilitzats per encapsulament mitjançant la tecnologia Lentikat® en una reacció estereoselectiva d’addició aldòlica ha donat com a resultat un biocatalitzador actiu, robust i estable a llarg termini.
Per tant, es tracta d’una petita aportació en la biotecnologia industrial que intenta conceptualitzar el bioprocés de manera hol·lística tot fusionant diverses àrees de coneixement. Tot i que no s’ha realitzat una avaluació econòmica del procés, consideracions tals com la possibilitat de reutilització del biocatalitzador han estat contemplades, per tal que el resultat fos atractiu industrialment parlant.
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Quesada, Vázquez Helena. "Dietary proanthocyanidins: their effectiveness in dyslipidemic nutritional models and the role of liver and intestine in their hypotriglyceridemic action." Doctoral thesis, Universitat Rovira i Virgili, 2010. http://hdl.handle.net/10803/8689.
Full textAbstract:
Las proantocianidinas ejercen efectos beneficiosos sobre algunos desordenes metabólicos que se consideran factores de riesgo de las enfermedades cardiovasculares. La desregulación del metabolismo lipoproteico juega un papel muy importante en los estados lipídicos alterados. Por lo tanto, los objetivos de esta Tesis fueron: estudiar la contribución del hígado y el intestino en la respuesta hipolipidémica de las proantocianidinas y evaluar los efectos de las proantocianidinas en modelos dislipidémicos nutricionales. Para realizar los experimentos se utilizaron tres modelos experimentales: ratas, ratones y células Caco2. Los resultados obtenidos fueron: que en un test de tolerancia lipídica tanto los quilomicrones como las VLDL contribuyen al efecto hipotrigliceridémico de las proantocianidinas pero su influencia depende del tiempo. Además, las proantocianidinas reprimen la secreción de TG por el hígado in vivo y por el intestino in vitro. ACSL se manifiesta como un gen diana de ellas en las células intestinales. Y finalmente, las proantocianidinas corrigen la dislipidemia pero no contrarrestan la ganancia de peso inducida por la dieta aunque estas tienen un efecto bimodal sobre la retención de energía in vivo.Proanthocyanidins have been shown to exert advantageous actions on several metabolic disorders that are risk factors of cardiovascular diseases. Lipoprotein metabolism plays an important role in altered lipid states. Therefore, the aims of this Thesis were: To assess the contribution of the liver and the intestine in the hypolipidemic response triggered by proanthocyanidins and to evaluate the short-term effect of an oral intake of proanthocyanidins in dyslipidemic nutritional models. For these purposes, three experimental models have been used: Rats, mice and human Caco2 cells. The obtained results are: In a fat tolerance test, both chylomicrons and VLDL contribute to the hypotriglyceridemic action of proanthocyanidins but their influence depends on time. Moreover, proanthocyanidins repress TG secretion by the liver in vivo and by the intestine in vitro. Furthermore, ACSL manifests as their target gene in intestinal cells. Finally, proanthocyanidins correct dyslipidemia but not the weight gain induced by diet though these have a bimodal effect on energy retention in vivo.
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Murakami, Mario Tyago. "Estratégias de inibição, mecanismos moleculares e interações intermoleculares em complexos macromoleculares /." São José do Rio Preto : [s.n.], 2006. http://hdl.handle.net/11449/100483.
Full textAbstract:
Orientador: Raghuvir Krishnaswamy ArniBanca: Antônio Carlos Martins Camargo
Banca: Nilson Ivo Tonin Zanchin
Banca: Beatriz Gómez Guimarães
Banca: Roberto da Silva
Abstract: This work presents some features of essential biological processes such as the haemostatic system, integrity of biological membranes and thermostability of proteins. Crystallographic, spectroscopic and in silico tools have been used to obtain information at the molecular level of macromolecular complexes, action mechanisms and inhibition pathways. Worms, snakes, ticks, leeches and spiders produce a variety of proteins, which interfere in the regulation of these systems. Different toxins isolated from these organisms were characterized providing necessary information for the development of a new anti-myonecrotic molecule and reveal a new factor Xa exosite that is important for macromolecular substrates recognition and inhibition. The first crystal structure of a member of the sphingomyelinases D family was determined by the "quick cryo-soaking" technique and the catalytic mechanism was proposed, which involves a magnesium-binding site and two catalytic histidines. An alternative activation of the protein C pathway that does not require thrombomodulin was structurally characterized and revealed the dual role of the elestrotatic surface charge around the active site and the three strategically positioned carbohydrate moieties in the approach, recognition and activation of protein C.
Doutor
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Salazar, Montoya Vivian Angélica. "Exploring the mechanism of action of human antimicrobial ribonucleases." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/310611.
Full textAbstract:
Las ribonucleases humanas son un grupo heterogéneo de proteínas pertenecientes a la
superfamilia de la Ribonucleasa A. Estas proteínas se caracterizan por su capacidad de
hidrolizar ácidos ribonucleicos y por la presencia de actividad antimicrobiana frente
diversos organismos patógenos como bacterias, hongos, parásitos y virus.
El primer objetivo del presente estudio doctoral se centra en la caracterización de la
actividad antimicrobiana y en modelos de membrana de las formas nativas de la
ribonucleasa 3 purificadas a partir de eosinófilos. Las distintas formas nativas presentan
modificaciones postraduccionales dadas por diversos grados de glicosilación que se
correlacionan con la activación de los eosinófilos durante los procesos inflamatorios. El
estudio establece la capacidad antimicrobiana de las formas nativas y su actividad en
modelos de membrana. Los resultados indican que las modificaciones
postrasduccionales modulan la actividad biológica de la RNasa 3, sugiriendo una
contribución in vivo en su función fisiológica.
Como segundo objetivo de esta tesis, se evaluó por primera vez en nuestro grupo de
investigación la actividad antimicótica de las ribonucleasas 3 y 7 frente al hongo
Candida albicans, el cual fue elegido como modelo patógeno eucariota. Se determinó y
caracterizó la presencia de actividad frente a Candida por parte de ambas ribonucleasas
humanas.
Por último, el tercer objetivo de esta tesis se centra en la purificación y caracterización
de la ribonucleasa 8, la más reciente ribonucleasa humana descrita, identificada
inicialmente en placenta. La RNasa 8 presenta un patrón inusual de enlaces disulfuro
respecto a sus proteínas homólogas. Este cambio estructural modifica la estabilidad de
la proteína y expone regiones que facilitan el proceso de agregación proteica. Fue
necesaria la previa optimización de un protocolo alternativo de purificación. Se
analizaron sus propiedades antimicrobianas, sugiriendo su posible participación en la
respuesta inmunitaria innata.
Los resultados del presente estudio corroboran las propiedades antimicrobianas de
diversas ribonucleasas humanas miembros de la familia de la RNasa A, sugiriendo una
función ancestral en el sistema de defensa innato. El estudio contribuye a la
comprensión de su mecanismo de acción y plantea su potencial uso como herramientas
terapéuticas.Human ribonucleases are a heterogeneous group of proteins belonging to the superfamily of RNase A. These proteins are characterized by their ability to hydrolyse ribonucleic acids and the presence of antimicrobial activity against various pathogens including bacteria, fungi, parasites and viruses. The first objective of this doctoral study is focused on the antimicrobial characterization of native Ribonuclease 3 forms purified from eosinophils. Native forms present posttranslational modifications giving different glycosylation grades that modulate their activity during inflammatory processes. This study aims to establish the antimicrobial properties of native forms purified from eosinophils and their activity in a membrane model system. Results indicate that post-translational modifications contribute to the the protein biological activities, suggesting a related physiological role. As a second objective, we evaluated for the first time the antifungal activity of the antimicrobial RNase 3 and RNase 7 against Candida albicans, an eukaryotic pathogen selected as a simple model to test the antimicrobial mechanism of action. Both human ribonucleases displayed a high antifungal activity. Results highlighted a dual mechanism of action, where cell lysis takes place at high protein concentration, while depolarization, cell internalization and cellular RNA degradation is achieved at sublethal doses. Finally, the last objective is focused on the characterization of ribonuclease 8, also called the placental RNase, the most recent human ribonuclease described. RNase 8 has gained and lost one cysteine residue in non-conserved positions in a mechanism called "disulphide shuffling". The protein tendency to aggregate required the design of an alternative purification protocol. We analysed its antimicrobial abilities, suggesting a possible role in innate defence. The results of this study confirmed the high antimicrobial activity of several human ribonucleases from the RNase A superfamily suggesting an ancestral role in the host immune defence response. The study contributed to the understanding of their mechanism of action and set the basis for applied drug design.
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Arimany, Nardi Cristina. "Impact of membrane transporters polymorphisms on nucleoside-derived drug bioavailability and action = Impacte dels polimorfismes en transportadors de membrana en la biodisponibilitat i acció de fàrmacs anàlegs de nucleòsids." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/129630.
Full textAbstract:
Nucleoside-derived drugs are used for the treatment of haematological malignancies, viral infections and autoimmune or inflammatory diseases. These drugs require membrane transporters to be internalised and be active. Transporters implicated in nucleoside and nucleoside derivatives internalisation are concentrative nucleoside transporters (CNTs) encoded by SLC28 and equilibrative nucleoside transporters (ENTs) encoded by SLC29. Other transporters such as organic cation transporters (OCTs) encoded by SLC22 have been implicated in the transport of some antiviral nucleoside derivatives, too. Nucleoside transporters as well as hOCT1 have been detected in immune cells, as well as in polarised epithelia where they are asymmetrically distributed mediating a net flux of the natural nucleoside or the derivative.
Membrane transporters can present polymorphic variants which can alter its ability to interact with the substrate. Of all studied transporters, hOCT1 is the most polymorphic, being its polymorphic variants implicated in pharmacokinetics and pharmacodynamics of some drugs used in clinics such as metformine among others.
In this thesis we show the importance polymorphic variants of hOCT1 have not only in lamivudine uptake but also in drug-drug interactions with other drugs co-administrated with lamivudine. Infected PBMCs showed an up-regulation of hOCT1 expression which would made it a better lamivudine target. We also discard the possibility that polymorphisms located at the extracellular loop might affect oligomerization.
hOCT1 has been also identified as a bendamustine transporter and hOCT1 polymorphic variants modulated bendamustine sensitivity. Bendamustine sensitivity in CLL cells ex vivo can partially be explained by the hOCT1 polymorphic variants they are carrying.
In case of DNMT inhibitors, nucleoside transporters are responsible for zebularine internalisation but not decitabine and mediate a apical-basolateral flux in polarised epithelia.
hOCT1 can mediate zebularine efflux which is impaired by the presence of polymorphic variants.
In this case polymorphic variants would confer sensitivity to zebularine treatment. In order to better understand the transporter-substrates interaction a hCNT3 model has been generated based on the recent crystallised V.cholerae nucleoside transporter. This model has been preliminary proved experimentally showing, so far, to be a good model.
In summary, this thesis highlights the importance drug transporters and their polymorphic variants play in drug bioavailability and actionLos fármacos derivados de nucleósidos son ampliamente utilizados en el tratamiento de enfermedades hematológicas, infecciones virales y enfermedades autoinmunes o inflamatorias. Estos fármacos necesitan de transportadores para ser internalizados en la célula y así, ser activos. Los transportadores implicados en la internalización de los nucleósidos y sus derivados son: los transportadores de nucleósidos concentrativos (CNTs) codificados por SLC28 y, los transportadores de nucleósidos equilibrativos (ENTs) codificados por SLC29. Otros transportadores, como los transportadores de cationes orgánicos (OCTs) codificados por SLC22, están implicados también en el transporte de algunos análogos usados en el tratamiento del SIDA. Los transportadores de nucleósdios y hOCT1 han sido detectados en células de sistema inmune, así como también, en epitelio polarizado donde se encuentran distribuidos asimétricamente mediando un flujo neto de nucleósidos y de sus derivados. Los transportadores de membrana pueden presentar polimorfismos alterando su habilidad de interacción con el sustrato. De todos los transportadores estudiados, hOCT1 es el más polimórfico, estando relacionadas sus variantes con la farmacocinética y farmacodinámica de algunos fármacos, como la metformina. En esta tesis mostramos la importancia que tienen estas variantes polimórficas, no solamente en la internalización de lamivudina, sino también en las interacciones de ésta con otros fármacos co-administrados. La infección de PBMCs con VIH mostró un aumento en la expresión de hOCT1, convirtiéndolos en mejor diana. Se descartó también la posibilidad de que los polimorfismos localizados en el loop extracelular, pudieran afectar la oligomerización del transportador. hOCT1 se ha identificado también como transportador de bendamustina, observándose a su vez, que sus variantes polimórficas modificaban la sensibilidad al fármaco. La sensibilidad de células de CLL ex vivo puede ser debida, en parte, a las variantes polimórficas que presentan. En el caso de los inhibidores de la ADN metiltransferasa (DNMT), observamos que los transportadores de nucleósidos son los responsables de la captación de zebularina pero no de decitabina, mediando un flujo de esta apical-basolateral en un modelo de epitelio polarizado. hOCT1 es capaz de mediar la extrusión de zebularina, en cambio, no lo son las variantes polimórficas estudiadas. Estos resultados estarían indicando que los polimorfismos serían responsables de la sensibilidad al tratamiento con zebularina. Para poder entender mejor la interacción transportador-sustrato, se generó un modelo preliminar de hCNT3 basado en el cristal de CNT de V. cholerae. En resumen, esta tesis muestra la importancia que tienen los transportadores y sus variantes polimórficas, en la biodisponibilidad y acción de los fármacos.