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Synthesis of precursors of 4-quinolones against Trypanosoma brucei for 18F-radiolabelling
Šůs, Jan ; Roh, Jaroslav (advisor) ; Špulák, Marcel (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Jan Šůs Supervisors: Prof. Dr. Ulrike Holzgrabe PharmDr. Jaroslav Roh, PhD Title of diploma thesis: Synthesis of precursors of 4-quinolones against Trypanosoma brucei for 18F-radiolabelling Human African trypanosomiasis (HAT), also known as sleeping sickness, is a parasitic disease caused by two subspecies of Trypanosoma brucei (T.b.gambiense and T.b.rhodesiense). This parasite is transmitted by the bite of infected tsetse flies. The sleeping sickness occurs in two clinical stages. The first one is characterized by the multiplication of parasites in the blood and lymphatic system. Very nonspecific symptoms, like fever, swollen lymph nodes, joint pain and headache are present. After a few weeks, a parasite crosses the blood-brain barrier and neurological symptoms like behavior changes, confusion, aggression and disruptions of sleep cycle appear. A coma and death results, if left untreated. Nowadays, there are only five drugs available for the medical treatment of HAT. Suramin and pentamidine are used for the first stage, melarsoprol and eflornithine in combination with nifurtimox for the second one. Life threatening side-effects and a developing of resistances are the reasons,...
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Synthesis of dexrazoxane analogues as potential cardioprotectants II
Kratochvíl, Marek ; Roh, Jaroslav (advisor) ; Nováková, Veronika (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Kralove Department of Inorganic and Organic Chemistry Candidate: Marek Kratochvíl Supervisor: PharmDr. Jaroslav Roh, PhD. Title of diploma thesis: Syntesis of dexrazoxane analogues as potential cardioprotectants II ! Doxorubicin, daunorubicin and other anthracycline antineoplastic antibiotics are very important anticancer agents. Due to their high toxicity in the heart muscle, these highly effective drugs are often associated with acute cardiotoxicity and dose-dependent cardiomyopathy. This cardiomyopathy is characterized by enlargement of the left ventricle and complete systolic dysfunction. It is assumed that this side effect is mainly caused by reactive oxygen species, whose formation is catalysed by complex of anthracyclines and iron ions. The only clinically used drug that significantly reduce anthracycline cardiotoxicity is dexrazoxane (DEX). DEX is in vivo metabolised to a substance ADR-925, which chelates the iron ions. DEX is also a catalytic inhibitor of topoisomerase II (TOP2). Interestingly, the cardioprotective effects of DEX were discovered accidentally and only few structure-cardioprotective activity relationships studies were published. The aim of this work was to develop a method for the preparation of DEX analogue 4,4'-...
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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 study of O- and N-modified ceramides
Pavlíková, Ludmila ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Ludmila Pavlíková Supervisor: doc. PharmDr. Kateřina Vávrová, Ph.D. Title of diploma thesis: Synthesis and study of O- and N-modified ceramides Ceramides which are composed of fatty acid and basic alcohol, naturally occur in the human body and play a role in many physiological processes. They are known like molecules participating in the cell signaling, they take part in differentiation, proliferation and apoptosis of the cell but they are also structural elements of cell membrane. Last but not least, they are included in extracellular matrix of stratum corneum where they participate in the barrier function of the skin. In addition to research of naturally occurring ceramides, of course it is necessary to study various modifications of these substances and to find connections between structure of ceramides and their ability to keep the barrier function. 1-deoxy, 3-deoxy a N-methyl analogues of ceramides, that I investigate in my diploma thesis, have not been examined yet in terms of their barrier function. Before the measuring of the properties of model membranes consisting of these analogues, it was necessary to synthesize these analogues. Synthesis was performed in two ways....
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Synthesis and biological evaluation of dimefluron and benfluron derivatives
Kolenič, Marek ; Špulák, Marcel (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Marek Kolenič Consultant: PharmDr. Marcel Špulák, Ph.D. Title of Thesis: Synthesis and biological evaluation of dimefluron and benfluron derivatives Benflurone is an original Czechoslovak cytostatic drug developed at Research Institute of Pharmacy and Biochemistry (VÚFB). Due to its unfavorable pharmacokinetic properties it has not been used for human therapy of cancer. Dimeflurone, developed with aim to improve pharmacokinetics of benflurone, was discontinued either at the phase of preclinical trials. Disadvantageous properties of both drugs is caused by rapid deactivation leading to formation of nearly inactive 7-hydroxyderivatives. In my diploma thesis, I concern about synthesis, in vivo and in vitro biological evaluation of C7-derivatives of both compounds. We assume lower deactivation rate and also longer and more potent effect. Firstly, sufficient amount of dimeflurone had to be synthesized, this process was improved and scaled-up. Although all the derivatives are more cytotoxic on cell lines MCF-7, BT-549 and MDA-MB-231 and they are also less toxic in mice after p.o. administration, they do not reduce weight of solid Ehrlich tumor neither prolong time of survival.
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Design and synthesis of potential M1 muscarinic acetylcholine receptor dualsteric modulator
Průša, Petr ; Roh, Jaroslav (advisor) ; Karabanovich, Galina (referee)
Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Inorganic and Organic chemistry Consultant: Prof. Dr. Ulrike Holzgrabe, PharmDr. Jaroslav Roh, Ph.D. Student: Petr Průša Title of Thesis: Design and synthesis of potential M1 muscarinic acetylcholine receptor dualsteric modulator Dualsteric ligands can modulate activity of receptors connected with G-proteins, also known as G- protein coupled receptor. These ligands are interesting for their use as pharmacological tools to clarify activity-induced conformational transitions. Moreover, dualsteric ligands can serve like a concept for design of new drugs. It was already prove that dualsteric compounds containing orthosteric ligand, which can act as agonist or antagonist, and allosteric part, which act as address determining target receptor via own selectivity, have affected affinity to receptor. Further, dualsteric binding can serve to introduce receptor subtype selectivity. Muscarinic acetylcholine receptors are related to G-proteins. Until now five subtypes of these receptors (usually marked as M1 - M5) are known. Activation of single muscarinic acetylcholine receptors subtypes induce different replies. Muscarinic acetylcholine receptors are widely represent in entire organism and are important targets for some drugs....
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Synthesis of azaphthalocyanines substituted with moieties derived from trimesic acid
Kollár, Jan ; Zimčík, Petr (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Author: Jan Kollár Supervisor: Doc. PharmDr. Petr Zimčík, PhD. Title of diploma thesis: Synthesis of azaphthalocyanines substituted with moieties derived from trimesic acid Aim of this work was a synthesis of new photosensitizers from the group of water- soluble azaphthalocyanines (AzaPc) with future potential to be used in PDT. The starting compound for synthesis, trimesic acid, was esterified by ethanol and the triester was partially hydrolysed to mono carboxylic acid. Subsequently, the carboxyl group was selectively reduced to hydroxyl followed by oxidation to aldehyde. Benzoin condensation of this aldehyde gave acyloin that was oxidized to tetraethyl 5,5'-oxalyldiisophthalate. Substituted pyrazine-2,3-dicarbonitrile, a precursor for AzaPc, was obtained by condensation of diaminomaleonitirile with this vicinal diketon. Cyclotetramerization using magnesium butoxide as initiator gave magnesium(II) AzaPc substituted with sixteen butoxycarbonyl groups. Magnesium complexes were converted to metal-free AzaPc in acidic medium and then to zinc(II) AzaPc by reaction with anhydrous zinc acetate. Tetraethyl 5,5'-oxalyldiisophthalate was also hydrolyzed to diketon with four free...
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Synthesis of 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine and study of its physicochemical properties
Valášková, Lenka ; Roh, Jaroslav (advisor) ; Vávrová, Kateřina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of inorganic and organic chemistry Candidate: Lenka Valášková Supervisor: PharmDr. Jaroslav Roh, PhD, Carine Deleuze-Masquefa Title of diploma thesis: Synthesis of 1-(3-methoxyphenyl)-N-methylimidazo[1,2- a]quinoxalin-4-amine and study of its physicochemical properties Melanoma is malign tumor usually located in the skin, mucous membranes or rarely in other parts of the organism. Every year the prevalence of this tumor is growing. Tumors which are detected in early stages can be successfully removed, but when metastasis appear treatment of this type of cancer is difficult. Some tumors (e.g. on problematic places such as on face) cannot be removed by surgery, even if they are soon detected. In these cases, topically administered anticancer drugs can be used. One of those substances is imiquimod (ALDARA® ; Figure 1), possesses antiviral, immunostimulating and cytotoxic activity. Limiting factor of this substance is its toxicity- it can be used only topically. The research group of prof. Pierre-Antoine Bonnet deals with the synthesis of imiquimod analogues. Synthesized molecules belong to three chemical groups, which differ in the orientation of imidazole moiety. Their lead structures, providing higher in vitro cytotoxic...
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Synthesis and study of 6-hydroxysphingosine-based ceramides
Kováčik, Andrej ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Ceramides, belonging to large family of sphingolipids, play a significant role in many processes in living systems. They participate in both physiological and pathophysiological processes (cell signalization). In addition, they are essential in the human epidermis (stratum corneum), where they act as a barrier - they participate in the maintenance of stable internal environment (preventing the penetration of unwanted substances, pathogens and the loss of body water). Ceramide molecules constist of two basic components. Each molecule contains one of the four sphingo-like bases, and a fatty acid acyl, which is either non-substituted or substituted at the position α- or ω-. All these possible combinations give different types of ceramides that occur in the skin. This work focuses on ceramides based on 6-hydroxysfingosin - sphingosine base with a hydroxyl group in the 6-position. Ceramides (acylated bases) of this type were found only in the human epidermis, they do not play roles in cell signalization. Therefore, the preparation of this type of ceramides was studied in this work. Another reason to deal with 6- hydroxysfingosine was its unavailability on the market of chemical substances. Thus, the substance for further study was prepared. Synthesis of 6-hydroxysphingosine: first, commercially...
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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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