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Derivatives of Pyrazinecarboxylic Acid as Potential Antituberculotics (Synthesis and Biological Evaluation)
Zitko, Jan ; Doležal, Martin (advisor) ; Vinšová, Jarmila (referee) ; Csöllei, Jozef (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Dpt. of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Jan Zitko Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Title of Doctoral Thesis: Derivatives of pyrazinecarboxylic acid as potential antituberculotics (synthesis and biological evaluation) This thesis deals with derivatives of pyrazine-2-carboxylic (POA) acid with potential antimycobacterial activity. In the theoretical part of the thesis there is a short description of tuberculosis (TB) disease, discussion of its epidemiology an associated risk factors of increasing resistance to fist-line antituberculars and the co-infection with HIV. Antituberculars used in clinical practice are described as well as the summary of new antituberculars under clinical trials is presented. Pyrazinamide (PZA) as one of the most important first-line antituberculars is in the focus of this thesis. Multiple up-to-date theories of PZA (POA) mechanism of action are described and discussed. Importantly, a summary of structural changes of PZA/POA attempted in the past to prepare new antituberculars is presented and the importance and relevance of individual structural changes is discussed. In the practical part of this thesis, 76 derivatives of PZA/POA were prepared, 68 of...
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Synthesis of NK1 antagonists.
Puchnerová, Lucie ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Synthesis of NK-1 antagonists Lucie Puchnerová Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy University of Seville NK-1 receptor antagonists are represented so far by only one drug, Aprepitant, which is available on the market for prevention of chemotherapy-induced nausea and vomiting. Nevertheless, it is assumed that NK-1 antagonists will be able to participate in treatment of migraine, rheumatoid arthritis, asthma, pain, inflammatory bowel disease, Parkinson's disease, anxiety and depression in future. This thesis is concerned with asymmetric synthesis of derivatives of 2-amino-4H-pyran, which thanks their substitutions are in accordance with structure of pharmacophore of NK-1 antagonists. As a starting material for their preparation has been used commercial methyl p-tolyl sulfone and (R)-methyl p-tolyl sulfoxide, which was synthesized from menthyl-(S)-p- toluenesulfinate by nucleophilic substitution. These compounds were subjected to reaction with ethyl 2-picolinate. From prepared β- ketosulfoxide and β-ketosulfone were obtained 2-amino-4H-pyrans by Michael addition. The derivatives proceeding from β-ketosulfoxide were subjected to reduction of the sulfoxide and trifluoroacetylation of the amine group on the carbon 2 of the pyran ring. Prepared derivatives had agonistic activity...
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Approximate Polynomial Greatest Common Divisor
Eliaš, Ján ; Zítko, Jan (advisor) ; Hnětynková, Iveta (referee)
Title: Approximate Polynomial Greatest Common Divisor Author: Ján Eliaš Department: Department of Numerical Mathematics, MFF UK Supervisor: Doc. RNDr. Jan Zítko, CSc., Department of Numerical Mathematics, MFF UK Abstract: The computation of polynomial greatest common divisor (GCD) ranks among basic algebraic problems with many applications. The Euclidean algorithm is the oldest and usual technique for computing GCD. However, the GCD computation problem is ill-posed, particularly when some unknown noise is applied to the polyno- mial coefficients. Since the Euclidean algorithm is unstable, new methods have been extensively studied in recent years. Methods based on the numerical rank estimation represent one group of current meth- ods. Their disadvantage is that the numerical rank cannot be computed reliably due to the sensitivity of singular values on noise. The aim of the work is to overcome the ill-posed sensitivity of GCD computation in the presence of noise. Keywords: AGCD, Sylvester matrix, numerical rank, TLS
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Analýza výpočtu největšího společného dělitele polynomů
Kuřátko, Jan ; Zítko, Jan (advisor) ; Janovský, Vladimír (referee)
In this work, the analysis of the computation of the greatest common divisor of univariate and bivariate polynomials is presented. The whole process is split into three stages. In the first stage, data preprocessing is explained and the resulting better numerical behavior is demonstrated. Next stage is concerned with the problem of the computation of the numerical rank of the Sylvester matrix, from which the degree of the greatest common divisor is obtained. The last stage is the actual algorithm for calculating the greatest common divisor of two polynomials. Furthermore, the underlying theory behind the computation of the greatest common divisor is explained and illustrated on many examples. 1
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Numerické metody zpracování obrazu
Tóthová, Katarína ; Hnětynková, Iveta (advisor) ; Zítko, Jan (referee)
The aim of this thesis is to provide a concise overview of the numerical techniques in digital image processing, specifically to discuss the construction, properties and methods of solving of the image deblurring problems modelled by a linear system Ax = b. Often, these problems fall within a group of the ill-posed problems with severely ill-conditioned matrix A and hence require special numerical treatment. We provide a brief overview of selected regularization methods that can be used in this situation, including direct (TSVD, Tikhonov regularization) and iterative ones (CGLS, LSQR), together with the pertinent parameter-choice methods - L-curve, GCV and the discrepancy principle. The theoretical discussion is supplemented by the numerical experiments with real-life image data.
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Od problému momentů k moderním iteračním metodám - historické souvislosti a inspirace
Tůma, Martin ; Strakoš, Zdeněk (advisor) ; Zítko, Jan (referee)
In the present work we study the connections between the moment problem and the modern iterative methods. A short historical review of the study of the moment problem is given. Some different definitions of the moment problem are shown. Motivation and results of some mathematicians, who used the moment problem in their work are discussed. Connections between different definitions of the moment problem, Gauss-Christoffel quadrature, orthogonal polynomials, continued fractions, Sturm-Liouville problem, reduction of the model in linear dynamical systems and some of the iterative methods like Lanczos and Conjugate gradients method are explained.
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Teoretické otázky popisu chování krylovovských metod
Strnad, Otto ; Strakoš, Zdeněk (advisor) ; Zítko, Jan (referee)
The presented thesis is focused on the GMRES convergence analysis. The basic principles of CG, MINRES and GMRES are briefly explained. The thesis summarizes some known convergence results of these methods. The known characterizations of the matrices and the right hand sides gen- erating the same Krylov residual spaces are summarized. Connections and the differences between the different points of view on GMRES convergence analysis are shown. We expect that if the convergence curve of GMRES applied to the nonnormal matrix and the right hand side seems to be de- termined by the eigenvalues of the matrix then exists a matrix that is close to normal and has the same spectrum as the matrix and for the right hand side has the same GMRES convergence curve (We assume that the initial approximation 0 = 0). Several numerical experiments are done to examine this assumption. This thesis describes an unpublished result of Gérard Meu- rant which is the formula for the norm of the -th error of GMRES applied to the matrix and right hand side and its derivation. The upper estimate of the -th GMRES error is derived. This estimate is minimized via spectrum.
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Intracellular trafficking of an anti - Amyloid Protein Precursor antibody.
Zitko, Jan ; Doležal, Martin (advisor) ; Trejtnar, František (referee)
Intracellular trafficking of an anti-Amyloid Protein Precursor antibody Alzheimer's disease is characterized by over-accumulation of beta-amyloid peptide (Aβ) in the brain. Aβ is produced by proteolytic cleavage of beta-amyloid precursor protein (APP) by β- and γ-secretases. Novel monoclonal antibody, 2B12, has been shown to bind to β-secretase cleavage site of APP, reducing the production of APP, presumably by preventing the cleavage by steric hindrance. 2B12 is hypothesized to bind to APP molecules exposed on the cell surface and to be internalized in the form of complex with APP via natural endocytic pathway. This hypothesis was confirmed by San Pei Ho's (2007), who followed the internalization of 2B12 in living astrocytoma MOG-G-UVW, cells in time-course experiment. This project is focused on intracellular trafficking of 2B12 and its localization within specific cellular compartments. Experiments were performed with fixed astrocytoma MOG- G-UVW cells (constitutively expressing APP). Originally planned experiments with live cells could not be performed due to decreased stability of 2B12 (causes remain unknown). 2B12 was tested for colocalization with polyclonal affinity purified antibodies labelling subcellular markers (proteins) associated with compartments known to participate in APP...
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