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Optimization of the synthesis of 32-hydroxydotriacontanoic acid
Sommerová, Veronika ; Opálka, Lukáš (advisor) ; Roh, Jaroslav (referee)
1 Abstract Acylceramides belong to the subgroup of ultralong chain ceramides. They are essential components of the extracellular lipid matrix of stratum corneum, where they play a crucial role in proper function of skin barrier (they help preventing the excessive water loss and penetration of exogenous substances and pathogens to the organism). The 32-hydroxydotriacontanoic acid is one of the fatty acids forming the backbone of all the acylceramides. In the molecule of acylceramide, the carboxyl group of this acid is bound to a primary amino group of the sphingoid base and the ω-hydroxy group is esterified with linoleic acid. In the stratum corneum, 32-hydroxydotriacontanoic acid may remain as a part of free acylceramides or it can be covalently linked to the surface of corneocytes and form the "first lamela", which then serves as a basis for the orientation of other lipids in the matrix. The recent literature describes the synthesis of 32-hydroxydotriacontanoic acid but only with relatively small overall yields. The most problematic part of the synthesis seems to be the connection of two shorter fragments leading to the ultralong chain. The main aim of this research project was to optimalise the reaction conditions to increase the yield of formation of the utralong acid, focusing on the most complicated...
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Synthesis of pyrrole-based inhibitors of the macrophage infectivity potentiator proteins
Škoda, Josef ; Roh, Jaroslav (advisor) ; Špulák, Marcel (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Supervisors: Prof. Dr. Ulrike Holzgrabe PharmDr. Jaroslav Roh, PhD Candidate: Josef Skoda Title of diploma thesis: Synthesis of pyrrole macrophage infectivity potentiator inhibitors Pathogens Burkholderia pseudomallei and Legionella pneumophila cause severe diseases like Legionnaire's disease and melioidosis. While Legionnaire's disease manifests as acute pneumonia, melioidosis has different clinical features and ends by multi-organ involvement and septic shock. Low sensibility of gram negative bacteria B. pseudomallei and L. pneumophila to antibiotics together with threatening resistance represent a great problem. For these pathogens their virulent factor macrophage infectivity potentiator (MIP) protein is a suitable target. MIP proteins are peptidyl/prolyl cis/trans isomerases, highly important factor of penetration and dissemination for B. pseudomallei a L. pneumophila. MIP protein belongs to FK506 binding protein (FKBPs) superfamily, which forms highly stable complex with its inhibitors tacrolimus and rapamycin. Due their immunosuppressive activity, these drugs are contraindicated for treatment of infection diseases. However inhibition of the protein proves that MIP protein is...
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Synthesis of novel acetylcholinesterase reactivators of isoquinolinic type
Hozová, Miroslava ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Miroslava Hozová Supervisor: PharmDr. Jaroslav Roh, Ph.D. Consultant: RNDr. Dávid Maliňák, Ph.D. Title of Diploma Thesis: Synthesis of novel acetylcholinesterase reactivators of isoquinolinic type Organophosphates are worldwide the most common cause of poisoning, whether in the field of agriculture, attempted suicide, accidental contact or abuse as organophosphorus nerve agents. They can be absorbed by all paths - inhaled, ingest or by transdermal penetration. For over 50 years the only causal antidotes on the market have been acetylcholinesterase reactivators. However, bioavailability is inadequate, therapy is ineffective, and there is no broad-spectrum reactivator able to efficiently restore AChE activity after intoxication by different types of organophosphates. All available reactivators are charged oximes with one or two pyridinium rings. These are pralidoxime, methoxime, trimedoxime, obidoxime, HI-6 and Hlö-7. Effective structure require functional oxime group (R-CH = NOH) which is able to bind the organophosphate agent from enzyme and restore its function. In this thesis, we focused on preparation, identifying structure and specifying physical and chemical properties of new...
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Synthesis of chiral ionic liquids
Antal, Rastislav ; Špulák, Marcel (advisor) ; Roh, Jaroslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Rastislav Antal Supervisor: PharmDr. Marcel Špulák, Ph.D. Title of diploma thesis: Synthesis of chiral ionic liquids The aim of my diploma thesis was to synthesize series of chiral ionic liquids, which would differ at the chiral centre, leading to possible libraries, either derived from (S)-hexadecylglycine, L-alanine, D-phenylglycine or L-serine. The ester scaffold of amino acid derived ionic liquids was modified by varying alkyl chain length. The polar edge of the final products resulted from the reaction of bromoacetyl intermediates with their nucleophilic counterparts. However, the first part of the proposed synthesis leading to (S)-hexadecylglycine derivatives wasn't successful. The further part of the thesis describes the efficient preparation of novel ionic liquids derived from L-alanine (nine compounds) and D-phenylglycine (three compounds). Unfortunately, the final ionic liquids based on L-serine structure could not be prepared due to problems with acylation of appropriate intermediate. The final products will undergo a screening for the capability as chiral selectors in micellar electrokinetic chromatography, which could possibly lead to chiral recognition ability. However,...
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Use of lactones in acylceramide synthesis
Moravčík, Štefan ; Opálka, Lukáš (advisor) ; Roh, Jaroslav (referee)
6 Abstract Acylceramides, subgroup of ceramides with ultralong chains, are essential component of extracellular lipid matrix in the uppermost skin layer, stratum corneum. They have crucial role in mammalian survival on dry land. Deeper understanding of their function in physiology of pathophysiology of the skin and their therapeutic potential are hampered by their limited availability. Analysis of the skin surface lipids of the ass (E. asinus) has shown, that these lipids contain up to 56% of unbranched ω-lactones (equolides), from which 51.2% is mono- unsaturated dotriacontanolide and 41.3% is mono-unsaturated triacontanolide. Carbon chain length of these lactones match the most common length of carbon chain in acylceramides (30 and 32 carbon atoms) therefore they could be used in their total synthesis. Aim of this thesis was to isolate mono-unsaturated ω-lactone with 32 carbon chain (dotriacontanolide) from the mixture of donkey skin surface lipids, followed by hydrogenation and transformation to the suitable precursor (succinmidyl ester) in order to find the easiest synthetic path in its conversion to acylceramides. We have tried many synthetic pathways. From direct aminolysis of lactone, through reaction with N-hydroxysuccinimide in various reaction conditions to opening of the lactone to the potassium...
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Synthesis of unsymmetrical cationic phthalocyanines for photodynamic therapy
Kostelanský, Filip ; Zimčík, Petr (advisor) ; Roh, Jaroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Drug Control Candidate Filip Kostelanský Supervisor Doc. PharmDr. Petr Zimčík, Ph.D. Title of Thesis Synthesis of Unsymmetrical Cationic Phthalocyanines for Photodynamic Therapy The photodynamic therapy is a curative method of cancerous and non-cancerous diseases. It uses light, oxygen and photosensitizer to destroy the cancer cells. Photosensitizer absorbs energy of light and produces singlet oxygen. Singlet oxygen attacks cellular structures like cellular membrane, lysosomes, mitochondria, etc. causing thus damage leading to cell death. Previous studies revealed that zinc phthalocyanine with methylated 2,6-bis[(1H-imidazol-1-yl)methyl]-4-methylphenoxy substituents had excellent photodynamic activity against HeLa cells and low toxicity. That is why we decided to synthesize a series of similar compounds bearing this substituent but with rather amphiphilic character. They bear interesting spatial features to be potentially incorporated into lipid bilayer or a double stranded DNA. The synthesis started by condensation of 2,6- bis(hydroxymethyl)-4-methylphenol and imidazole to obtain 2,6-bis[(imidazol-1- yl)methyl]-4-methylphenol. In the following reaction, this phenol was subjected to...
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Preparation and photophysical evaluation of tetra-3,4-pyridoporphyrazines suitable for the photodynamic therapy
Čermák, Pavel ; Nováková, Veronika (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Biophysics and Physical Chemistry Candidate: Pavel Cermak Supervisor: Assoc. Prof. Veronika Novakova, PhD. Title of Thesis: Preparation and photophysical evaluation of tetra-3,4- pyridoporphyrazines suitable for the photodynamic therapy Tetra-3,4-pyridoporphyrazines (TPyPz) are aza-analogues of phthalocyanines. Their large system of conjugated bonds enables them to absorb light in the red part of the absorption spectrum. Due to their ability to produce singlet oxygen, they can be potentially used as photosensitizers in photodynamic therapy (PDT). Its mechanism is based on co-functioning of three elements - photosensitizer, light and oxygen. Photosensitizer excited by light absorption transfers its energy into tissue oxygen, thus, creating cytotoxic singlet oxygen. This method is beneficial for its high selectivity, low toxicity, minimal invasion and fast effect. The aim of this work was to synthetize and study water-soluble TPyPz suitable for PDT. Water solubility was achieved by quarternized amines, forming of salts or using suitable delivery systems (hydrophilic emulsion). Hydrophilicity was also increased by introduction of hydrophilic non-charged substituents (OH). At first, appropriate precursors for...
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Synthesis of roscovitine analogues derived from [1,2,4]triazolo[4,3-a]pyrazines
Makovec, Jakub ; Roh, Jaroslav (advisor) ; Vávrová, Kateřina (referee)
Charles University in Prague Faculty of Pharmacy Hradec Králové Department of Inorganic and Organic Chemistry Student: Jakub Makovec Supervisor: PharmDr. Jaroslav Roh, Ph.D. Title of diploma thesis: Synthesis of roscovitine analogues derived from [1,2,4]triazolo[4,3-a]pyrazines Cancer affects all ages across the world. This is a very serious disease with high mortality and without universal therapeutic strategy. There are many drugs that inhibit cancer growth, but on the other hand these drugs have very frequent and serious side effects. Therefore there are the attempts to find such substances which have a specific activity only against changed cancerous tissue and minimal effects on healthy tissues. Roscovitine is an experimental drug with potential for the treatment of cancer. The main mechanism of action of roscovitine is inhibition of cyclin-dependent kinases participating in the regulation of cell cycle. Roscovitine is currently undergoing the clinical trials. In my thesis, we focused on the preparation of new analogs of roscovitine based on the structure of 1,2,4-triazolo[4,3-a]pyrazine. In first step, we prepared 5- (benzyl/phenylamino)-6-chloropyrazin-2,3-dicarbonitrile from commercially available 5,6-dichloropyrazin-2,3-dicarbonitrile and aniline or benzylamine. In the next step...
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Synthesis and study of deuterated and polyene analogs of selected transdermal permeation enhancers
Psík, Martin ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Martin Psík Charles University in Prague, Faculty of Pharmacy in Hradec Králové 2015 Synthesis and study of deuterated and polyene analogs of selected transdermal permeation enhancers Transdermal drug delivery offers many advantages over traditional routes of administration. Main factor limiting permeation of the drug is barrier property of the skin especially its uppermost layer stratum corneum. One of the approaches to promote drug flux through SC uses permeation enhancers. Most permeation enhancers are not suitable for clinical use due to their toxicity or irritation potential. Interesting family of permeation enhancers are amino acid derivatives, in particular for their low toxicity. Very promising amino acid derivatives seem to be dodecyl 6-dimethylaminohexanoate (DDAK) and dodecyl (S)-N-acetylprolinate (L-Pro2). Their mechanism of action is not fully understood. The main goal of this diploma thesis was to contribute to the understanding of the behavior of these two transdermal permeation enhancers in the skin. In the first part of this thesis deuterated analogues of DDAK and Pro2 with deuterated dodecyl chains (previous studies show no difference between L- and D-Pro2, thus, we only used Pro2) were prepared and then their influence on the SC lipids and proteins were studied by infrared...
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