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Prodrug structures to improve the drug delivery of anti-cancer agents
Králová, Vendula ; Doležal, Martin (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Vendula Králová Supervisor: Prof. PharmDr. Martin Doležal, Ph.D Specialized supervisor: Kristiina Huttunen, Ph.D Title of diploma thesis: Prodrug structures to improve the drug delivery of anti- cancer agents Cancer belongs to the most widespread diseases in the world, and we can expect that it will remain among the deadliest illnesses in the future. For this reason, scientists have put enormous efforts into researching new drugs, which would stop this growing trend. Nowadays, pharmaceutical research is focused mainly on the development of targeted treatment of oncological diseases, which aims at specific structures on the surface or in the core of the tumorous cells. This treatment is limited only to a precisely targeted group of tumors, and it usually leaves healthy cells unharmed. Through clinical studies, many new medications have been developed, and they show high efficiency in the treatment of various types of cancer. However, their success is constrained by drug resistance, which has become a significant obstacle to their use. The topic of this thesis is the synthesis of new anticancer drugs and their prodrugs. These prodrugs were prepared in such a way that they would...
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Pyrazine derivatives as potential drugs IV.
Valášek, Ondřej ; Doležal, Martin (advisor) ; Opletalová, Veronika (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Tutor - specialist: PharmDr. Jan Zitko, Ph.D. Candidate: Ondřej Valášek Title of diploma thesis: Pyrazine Derivatives as Potential drugs IV. Even in the year 2016, tuberculosis is still worldwide problem which is addressed by many national and supra-national organizations trying to eliminate it. It burdens the most developing countries which don't usually have the opportunity to access the potential of modern medicine to its full extent. In relation to ineffective treatment, there grows prevalence of tuberculosis, which can't be managed by standard treatment. There is an urgent need to find new compounds and change structures of current antituberculars, which will help us defeat multi-drug resistant M. tuberculosis. The objective of my work was to find out the influence of inversion of the amidic group in derivatives of pyrazin-2-carboxylic acid (-CO-NH- to -NH-CO-) and their efficacy and toxicity. In the theoretical part I focused on resuming all the basic facts about tuberculosis and its causing agent, about possibilities in prevention and diagnostics as well as the antituberculars, both used and currently tested, which can help us in the future. In the experimental part I wrote down the reactions and procedures, which were used...
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Tacrine-benzothiazole derivatives in Alzheimer's disease
Svobodová, Lucie ; Kučerová, Marta (advisor) ; Doležal, Martin (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Lucie Svobodová Supervisor: PharmDr. Marta Kučerová, Ph.D. Consultant: Mgr. Eugenie Nepovimová Title of Diploma Thesis: Tacrine-Benzothiazole Derivatives in Alzheimer's Disease Therapy Alzheimer's disease (AD) is a progressive fatal neurodegenerative disorder and the most common type of dementia. It is manifested by a variety of neuropsychiatric symptoms such as memory loss, visuospatial deficits etc. Ethiology of the disease has a multifactorial character and is not well known. Among the major pathological features belong: presence of extracellular amyloid plaques, intracellular aggregates of hyperphosphorylated tau protein and neuronal loss, especially loss of cholinergic neurons. Also the oxidative stress of the neuronal cells contributes to the pathophysiology of the disease. As AD is influenced by multiple factors, the main strategy in treatment is hitting multiple targets in the brain as well. Such drugs are denoted as multi-target-directed ligands (MTDLs) and they affect different molecular abnormalities of AD. Within this work, we would like to bring out new tacrine - benzothiazole hybrids combining tacrine with the amino benzothiazole moiety. Linkers of...
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Pyrazine derivatives as potential drugs V.
Mindlová, Alžběta ; Doležal, Martin (advisor) ; Kučerová, Marta (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Author: Alžběta Mindlová Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Title of diploma thesis: Pyrazine Derivatives as Potential Drugs V This study deals with the issue of tuberculosis, which is a second leading cause of deaths after HIV from all infectious diseases worldwide. This is supported by an ever increasing number of mycobacteria, which is resistant to conventional antituberculotics. Because of grow of the multidrug-resistant tuberculosis, there is need for the development of new drugs in the therapy of this disease. The design of final compounds was based on the previously prepared pyrazine-2- carboxilic acid, which exerted antituberculotic activity. The object of study was to verify the effectiveness of N-(pyrazine-2-yl)benzamides created by an imaginary variation of the connecting bridge between the pyrazine and benzene ring. In the experimental part of the work the synthesis of twenty three substances derived from 2-aminopyrazin or 6-chlor-2- aminopyrazin is described. All products have been described by melting point, 1 H, 13 C NMR, IR spectroscopy and the elementary analysis. The substances were send for the biological evaluation, where were tested for...
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Separation and determination of acetylcholinesterase tacrine inhibitors by HPLC
Novák, Martin ; Doležal, Martin (advisor) ; Kučera, Radim (referee)
Charles University in Prague, Faculty od Pharmacy in Hradec Králové Department of: Pharmaceutical Chemistry and Drug Control Student: Martin Novák Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Consultant: Mgr. et Mgr. Rafael Doležal, Ph.D. Title of bachelor thesis: Separation and determination of acetylcholinesterase tacrine inhibitors by HPLC The bachelor thesis is focused on development of HPLC-UV method for determination of enantiomers of substance N-(8-((6-chlor-1,2,3,4-tetrahydroakridin-9-yl)amino)oktyl)-6-hydro- xy-2,5,7,8-tetramethylchroman-2-karboxamid (in text 1-AO-43.1), selected compound from tacrine-trolox hybrids. These hybrid structures composed of tacrin and trolox, could be consider as promising candidates of potential drugs, which in contemporary research of drugs against Alzheimer's disease occupy leading position. The aim of this bachelor thesis is to evaluate a separation of enantiomers, which are produced in organic synthesis of tacrine derivative on the chiral stationary phase (CSP). The thesis brings an explanation of basic charakteristic of HPLC, chiral separation of enantiomers, pathophysiology and treatment of Alzheimer's disease and short charakteristic of tacrine- trolox hybrids in the teoretic section. In the experimental section, development of metodology of chiral...
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Identification and characterization of G protein-coupled nucleotide and nucleotide-like receptors P2Y13 and GPR17
Klenotič, Ondřej ; Doležal, Martin (advisor) ; Mladěnka, Přemysl (referee)
Identification and characterization of G protein-coupled nucleotide and nucleotide-like receptors P2Y13 and GPR17 Purinergic receptors are divided into three subfamilies, P1 (adenosine), P2 (nucleotide) and P0 (adenine) receptors. P2 receptors comprise ligand-gated ion channels - shortly LGICs, receptors P2X1-7, and class A, δ-branch GPCRs termed P2Y1,2,3,6,12-14. The P2Y13 receptor is physiologically activated by ADP and coupled to Gi whose activation results in an inhibition of adenylate cyclase. P2Y13 receptor activation has been reported to be neuroprotective. P2Y13 receptors also play a role in lipoprotein metabolism and cholesterol transport, making the receptor an interesting target for the potential treatment of atherosclerosis. The nucleotide-like orphan receptor GPR17, whose endogenous agonist remains still unknown, is also Gi-coupled. GPR17 appears to be involved in demyelinating diseases such as multiple sclerosis, and some inflammatory diseases. The development of potent, selective ligands, agonists and antagonists, for both P2Y13 and GPR17, is required to study their physiological and pathophysiological roles and for validating the receptors as future drug targets. In the present study, we aim to find out, if the approach via β-arrestin assay employing an enzyme complementation is...
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Synthesis of magnesium(II) azaphthalocyanines as potential fluorophores
Švandrlíková, Eva ; Zimčík, Petr (advisor) ; Doležal, Martin (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical Chemistry and Drug Control Student: Eva Švandrlíková Supervisor: Doc. PharmDr. Petr Zimčík Ph.D. Title of the diploma thesis: Synthesis of magnesium(II) azaphthalocyanines as potential fluorophores Azaphthalocyanines are macrocyclic compounds, which can exist with or without central metal (i.e. metal-free). Central metal can be chosen from a wide range of cations leading to significant changes in photophysical and photochemical properties of the macrocycle. My work is focused on magnesium complexes because of their significant fluorescence. Magnesium azaphthalocyanines are generally synthesized by cyclotetramerization reaction with magnesium butoxide. However, some azaphthalocyanines may contain labile peripheral substituents that may be cleaved in butoxides or in the case of unsymmetrical azaphthalocyanines the separation must be performed in a metal-free form. For these reasons, my work concerns with direct magnesium insertion into already prepared azaphthalocyanine macrocycle. I investigated possibilities of direct magnesium insertion with different kinds of magnesium salts, in different solvents, under different dryness of solvent, different temperature and different peripheral substitution of the macrocycle....
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Preparation of cationactive tenzides with hydroxymethyl moiety.
Josková, Věra ; Doležal, Martin (advisor) ; Zimčík, Petr (referee)
Charles Univerzity in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Student: Věra Josková Supervisor specialist: PharmDr. Jan Marek, Ph.D. Supervisor: prof. PhamrDr. Martin Doležal, Ph.D. Title of Thesis: Preparation of cationactive tenzides with hydroxymethyl moiety This diploma thesis will refer about free homological series of cationic tenzides bearing quarter nitrogen in their molecule specifically 4-hydroxymethyl-1- alkylpyridinium-bromide, 3-hydroxymethyl-1-1alkylpyridinium-bromide a 2-hydroxy- methyl-1-alkylpyridinium-bromide derivatives. Each of this series contained five homologues with alkyl linker length between 10 and 18 with even number of carbon atoms. Above mentioned compounds were characterised by melting point, NMR spectra and elemental analysis. Next topic of my work was evaluation of these compounds. Critical micelar concentrations were measured employing conductimetric method. Compounds were further tested against several fungal and bacterial phylum. Structure- activity relationship studies of influence of substitututed position and length of alkyl linker on previously mentioned properties were carried out.
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Monitoring of basic pharmacokinetic parameters of acetylcholinesterase inhibitors used in the treatment of Alzheimer's disease
Krejčiová, Markéta ; Doležal, Martin (advisor) ; Vopršalová, Marie (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Control of Pharmaceuticals Student: Markéta Krejčiová Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Supervisor specialist: Mjr. PharmDr. Jana Žďárová Karasová, Ph.D. Title of diploma thesis: Monitoring of basic pharmacokinetic parameters of acetylcholinesterase inhibitors used in the treatment of Alzheimer's disease Alzheimer's disease is a progressive irreversible neurodegenerative disorder that is globally associated with the most frequent cause of dementia. The pathophysiology of this illness is not fully understood yet. The commonly used treatment is still symptomatic, based on IAChE and memantine. Great attention is paid particularly to IAChEs and their derivatives, which arise from the basic structure of tacrine and 7-MEOTA. These two molecules were used as a reference for comparison with newly synthetized IAChE derivatives KB-36 and KB-38. Changes in plasma and brain tissue concentration levels were studied. The in vivo study was performed on rats (male, tribe Wistar). Equimolar doses were administered intramuscularly. Samples of plasma and brain tissue were evaluated by using HPLC techniques. The main aim was to determine the real concentration levels of all IAChE in both...
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Preparation of cationic compounds as potential surfactants of gold nanorods
Částková, Jana ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Gold nanoparticles are widely studied for various applications. Their surface enables large amount of chemical variations. Those are important for modification of their characteristics depending on the intended purpose. For the surface modification as well as for the gold nanoparticle synthesis various surfactants are used. Our aim was the synthesis of novel type of surfactants based in quaternary ammonium salts. They consist of 12 carbons linker, thiol functional group and quarternary nitrogen incorporated in various moieties. Structure and purity of the compounds were confirmed by nuclear magnetic resonance and mass spectrometry. Produced compounds should be used as potential surfactants of the gold nanoparticles. Thiol group in the molecule should ensure covalent bond of the surfactant to the nanoparticle and thus lower toxicity, when the surfactants shouldn't be released from the surface of the gold nanoparticles into their solution. Quaternary ammonium moiety should ensure sufficient solubility in water.
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