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Synthesis of Ortho-fused Heterocycles as the Precursors of Azaphthalocyanine Dyes
Gela, Petr ; Roh, Jaroslav (advisor) ; Kopecký, Kamil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of inorganic and organic chemistry Candidate Mgr. Petr Gela Consultant PharmDr. Jaroslav Roh, Ph.D. Title of Thesis Synthesis of ortho-fused heterocycles as the precursors of azaphthalocyanine dyes Chemical compounds containing tetrazole in recent years display an unprecedented boom. They exhibit a wide area of implementation in many areas especially in the pharmaceutical industry. The tetrazole group in these compounds acts as a bioisosteric surrogate for the functional group of carboxylic acid mainly because of close physical and chemical properties. The most important drugs containing tetrazole are used in the treatment of hypertension. In presented work we focused on the conversion of the tetrazole cycle into a different heterocyclic compound. The tetrazole can be used to the formation of other heterocycles with different number of cycles and hetero atoms. Moreover, the newly formed cycle can be also part of ortho-condensed system. In this work, we delt with the reactions of 5-substituted tetrazole with 6-substituted 5-chloropyrazine-2,3-dicarbonitrile, resulting in corresponding [1,2,4]triazolo[4,3-a]pyrazin-5,6-dicarbonitrile. Eight new and previously undescribed compounds were prepared. Synthetised compounds were used as a...
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Synthesis of ceramide and dihydroceramide analogues and evaluation of their effects on the skin barrier properties
Jandovská, Kateřina ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Jandovská, Kateřina: Synthesis of ceramide and dihydroceramide analogues and evaluation of their effects on the skin barrier properties. Ceramides belong to sphingolipids, their molecule is formed by a sphingoid base and long fatty acid. They are known not just as important second messengers playing a significant role in cell differentiation, proliferation and apoptosis, but also as essential part of functional skin barrier. Although these molecules are studied intensively, the exact effect of their structure on barrier function of the skin is poorly understood. The aim of my work was to study the effect of acyl chain length and stereochemistry on C3 of dihydroceramides (ceramides with single bond on C4) on the permeability of model membranes simulating the skin barrier. I have synthetized 3 ceramides with short acyl chain of 4 carbons (derived from dihydrosphingosine (dS), L-threo-dihydrosphingosine (L-dS) and L-threo-sphingosine (L-S)), and prepared model membranes of stratum corneum (SC) containing dihydroceramides with C2, C4, C6, C8 and C24 acyl chain length and stereoisomeres of C4-ceramides and C4-dihydroceramides as well. I have evaluated their electrical impedance and permeability for two model drugs. The effects of the prepared ceramides on the model membrane permeability were evaluated...
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Synthesis and Functionalization of 5-Substituted Tetrazoles
Roh, Jaroslav ; Hrabálek, Alexandr (advisor) ; Potáček, Milan (referee) ; Csöllei, Jozef (referee)
In the last decades, the chemistry of tetrazoles underwent a great expansion, which was closely connected with their usage as an isosteric replacement of carboxylic acid moiety in the molecules of potential or clinically used drugs. In this work, existing methods of the preparation of 5-substituted tetrazoles were modified by utilising microwave irradiation and by changing the reaction conditions and the reaction medium. First, Sharpless synthesis, consisting in the conversion of nitriles into 5-substituted tetrazoles via the reaction of sodium azide and zinc halide in boiling water, was modified. The application of the microwave irradiation decreased reaction time while maintaining high yields of products. Furthermore, a new method for the preparation of 5-substituted tetrazoles was developed, based on the reaction of nitrile with sodium azide and triethylammonium chloride in the polar aromatic solvents under microwave irradiation. By this method, 5-substituted tetrazoles were prepared in high yields in short reaction times from nitriles, including those that react poorly using common methods. Based on the results of several selected methods of the preparation of 5-substituted tetrazoles, carried out under either conventional or microwave heating at the same reaction temperatures, the non-thermal...
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Synthesis of precursors of fluorescent polyene ceramide
Říha, Michal ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Michal Říha Supervisor: Doc. PharmDr. Kateřina Vávrová, Ph.D. Title of diploma thesis: Synthesis of precursors of fluorescent polyene ceramide Ceramides, a complex group of lipids belonging to sphingolipids, have significant func- tions in many processes in living systems. Their crucial importance consists in the cell signa- lization and co-creation of functional skin barrier. Fluorescently labelled lipid analogues are often used in the lipid research. Polyene-lipids, in which the fluorophore is formed by five conjugated double bonds, represent an advanced way of fluorescent labelling of lipid molecules. Thanks to their structure, the polyene-lipids uniquely mimic their natural counterparts. This thesis studies the possibilities of the synthesis of fluorescent polyene ceramide and describes the precursors, i.e. the key substances, suitable for the preparation of the target labelled ceramide. The fluorophore was planned to be situated in the sphingosine part of the molecule, so as the properties of analogues with variable acyl chain length could be studied in the future. Three synthetic ways have been designed and investigated. The first way (Synthesis A) consists in the...
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Synthesis of tetrazole derivatives as potential antituberculotics
Němeček, Jan ; Roh, Jaroslav (advisor) ; Vávrová, Kateřina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Jan Němeček Supervisor: PharmDr. Jaroslav Roh, PhD. Title of diploma thesis: Synthesis of tetrazole derivatives as potential antituberculotics Tuberculosis is a widespread infectious disease; however, no substances were introduced to the clinical practise during the last decade. In this diploma thesis, a series of potential antitubercular substances based on 1-substitued-5-alkyl/arylsulphanyl-1H-tetrazole were prepared. First, we prepared two compounds, 5-[(1-phenyl-1H-tetrazole-5-yl)sulphanylmethyl]-1H- tetrazole and 5-[(1-phenyl-1H-tetrazole-5-yl)sulphanyl]-1H-tetrazole, as the main building blocks, which were further functionalized. 5-[(1-phenyl-1H-tetrazole-5-yl)sulphanyl]-1H-tetrazole was substituted by methyl, propyl and benzyl groups on the terminal tetrazole ring. The same substitutions were performed with 5-[(1- phenyl-1H-tetrazole-5-yl)oxymethyl]-1H-tetrazole, which had already been prepared in our laboratory. Furthermore, we prepared 5-[(2-methyl-1,3,4-oxadiazole-5-yl)methylsulphanyl]-1-phenyl-1H- tetrazole, 5-[(2-methyl-1,3,4-oxadiazole-5-yl)sulphanyl]-1-phenyl-1H-tetrazole and 5-[(2-methyl- 1,3,4-oxadiazole-5-yl)methoxy]-1-phenyl-1H-tetrazole from the...
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Enantioselective synthesis of homoallylic alcohols using chiral N-oxide organocatalysts
Mikušek, Jiří ; Pour, Milan (advisor) ; Roh, Jaroslav (referee)
In order to extend the earlier work in the group,1 we endeavored to explore the ability of the terpene-derived pyridine N-oxide organocatalyst (+)-METHOX to catalyze allylations of non-aromatic, α,β-conjugated aldehydes with allyltrichlorosilane in CH3CN. This thesis describes the synthesis of 5 novel homoallylic alcohols of high enantioselectivities (≤ 96% ee). O HR + SiCl3 METHOX 10 mol% CH3CN -30 řC R OH * (S) 96% ee N+ O- OMe OMe OMe (+)-METHOX 1 Malkov, A. V.; Bell, M.; Castelluzzo, F.; Kočovský, P. Org. Lett. 2005, 7, 3219
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Synthesis of novel cardioprotective iron chelators
Hrušková, Kateřina ; Roh, Jaroslav (referee) ; Vávrová, Kateřina (advisor)
Oxidative stress participates in patophysiology of many serious cardiovascular diseases. Free intracellular iron occurs as a catalyst of Haber-Weiss and Fenton reaction between superoxides and peroxides increasing the formation of highly toxic hydroxyl radicals, which cause cell damage. Iron chelators diminish the pool of free iron and thus become perspective agents in therapy of various diseases, e.g. anthracycline-induced cardiotoxicity. Aroylhydrazones group, such as salicylaldehyde-isonicotinoylhydrazone (SIH), appear to be highly efficient chelators. Unfortunately, pharmacokinetic studies focused on these compounds revealed their low stability in plasma. Therefore, I synthesised a series of SIH analogs in order to increase their stability together with preserving the ability to chelate free intracellular iron and to define their structure-activity relationships. A basic hypothesis in design of the novel chelators was using substituted ketone instead of aldehyde, leading potentially to an enhanced stability of hydrazone bond. SIH Two different methods were used during the reactions, a conventional heating in an oil bath and heating in a microwave reactor. The latter caused a significant shortening of the reaction time. In vitro studies of novel compounds showed their higher stability in plasma,...
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Synthesis of 5-substituted tetrazoles - a comparison of classical synthetic aproach with synthesis under microvawe activation
Gela, Petr ; Hrabálek, Alexandr (referee) ; Roh, Jaroslav (advisor)
1. Abstract Chemistry of 5-substituted tetrazoles has been the subject of intense investigation during last ten years. 5-substituted tetrazoles have found widespread use in many branches of industry, especially in pharmacy. In many cases, 5-substituted tetrazole present an optimal isosteric analogue of carboxylic group due to similar physico-chemical properties. The advantage of 5-substituted tetrazoles is their low metabolic degradability. One of the most important uses of 5-substituted tetrazoles are antihypertensives, antagonists of angiotensin II receptors, so called "sartans". Advance in synthesis of 5-substituted tetrazoles has occurred since the publication of W. G. Finnegan in 1958. In the following years numerous new methods have been published, originating from this work. The latest trend in chemistry of tetrazoles is microwave activation instead of conventional heating. In our work we focused on efficiency of microwave activation compared to conventional heating in several methods of the preparation of 5-substituted tetrazoles. We selected a preparation of 5-phenyl-1H-tetrazole from an easily available benzonitrile as the model reaction. Surprisingly, microwave irradiation did not result in a significant decrease in the reaction time or a higher yield. Furthermore, we aimed at preparation of...
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Synthesis of precursors and studies of "click" azide-alkyne cycloaddition
Ivincová, Jana ; Zimčík, Petr (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate: Jana Ivincová Supervisor: PharmDr. Petr Zimčík, Ph.D. Title of diploma thesis: Synthesis of precursors and studies of "click"azide-alkyne cycloaddition . Photosensitizers are used in photodynamic therapy that is based on a destruction of tumor cells by singlet oxygen. Singlet oxygen is generated during irradiation of photosensitizers. The third generation of the photosensitizers is characterized by high efficiency, optimal spectral properties and particularly by targeted distribution into the tumor cells. This can be achieved by conjugation of phthalocyanine photosensitizer with biomolecules. My thesis concerned with conjugation of suitable phthalocyanine with mestranol using 1,3 azide-alkyne cycloaddition (also called "click chemistry"). Selected photosensitizer with optimal photophysical and photochemical properties was prepared in our department earlier. 1,3 azide-alkyne cycloaddition is CuI catalyzed reaction of azide and terminal alkyne. This reaction is high yielding, selective and easy to perform, without any considerable effects of substituents in proximity of azide or alkyne. Pre-prepared 3-azidopropylamine was linked to the selected phthalocyanine...
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