National Repository of Grey Literature 43 records found  1 - 10nextend  jump to record: Search took 0.00 seconds. 
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...
Synthesis of phosphoramidate prodrugs "ProTides" as novel potential therapeutic agents for the treatment of congenital disorders of glycosylation and mitochondrial DNA depletion syndrome
Sedláková, Jana ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic And Bioorganic Chemistry Candidate: Jana Sedláková Supervisors: Dr. Fabrizio Pertusati doc. PharmDr. Jaroslav Roh, Ph.D. Title of diploma thesis: Synthesis of phosphoramidate prodrugs "ProTides" as novel potential therapeutic agents for the treatment of congenital disorders of glycosylation and mitochondrial DNA depletion syndrome At the present time, no effective treatment is available neither for the most of the congenital disorders of glycosylation (CDGs) nor the mitochondrial DNA depletion syndrome (MDS). Regarding the CDG therapy, D-mannose-1-phosphate (Man-1-P) offers considerable pharmacological potential to improve the pathological patterns in patients affected by phosphomannomutase 2 deficiency (PMM2-CDG), similarly as N-acetyl-D-mannosamine-6-phosphate (ManNAc-6-P) in case of GNE myopathy (GNEM). Administration of selected deoxyribonucleotides was proposed as a potential pharmacological strategy for the treatment of MDS. Unfortunately, the problematic membrane penetration of such polar molecules reduces their effect and limits their clinical application. Hydrophobic, membrane permeable derivatives of the sugar monophosphates and nucleotides, might represent more efficient potential therapeutics for CDGs and...
Synthesis of novel cardioprotectants and metabolites of potent anticancer drug - Bp4eT
Eisner, Tomáš ; Roh, Jaroslav (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mgr. Tomáš Eisner Supervisor: Assoc. Prof. PharmDr. Jaroslav Roh, Ph. D. Title of rigorosum thesis: Synthesis of novel cardioprotectants and metabolites of potent anticancer drug Bp4eT Anthracyclines (ANT) such as doxorubicin, daunorubicin, or epirubicin rank among the most effective anticancer drugs. However, their major side effect is chronic cardiotoxicity leading to irreversible cardiac damage and congestive heart failure. It is assumed that this side effect is caused by reactive oxygen species, whose formation is catalyzed by the complexes of anthracyclines with iron ions. The only clinically used drug preventing ANT cardiotoxicity is dexrazoxane (DXZ, Figure 1). In this work we dealt with the synthesis of novel DXZ analogues, because the structure-activity relationship studies have not been performed yet. The main analogue named ES-5 (Figure 1) was synthesized and its cardioprotective effect was evaluated both in vitro and in vivo. Fig. 1. Structures of DXZ and ES-5 Furthermore, thiosemicarbazone Bp4eT (2-benzoylpyridine 4-ethyl-3- thiosemicarbazone, Figure 2), a potent anticancer iron chelator and its metabolites were synthesized. These compounds were used as standards in metabolic...
Synthesis and in vitro evaluation of novel iron chelators based on salicylaldehyde isonicotinoyl hydrazone
Kubeš, Jan ; Roh, Jaroslav (advisor) ; Krátký, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Jan Kubeš Supervisors: doc. PharmDr. Jaroslav Roh, PhD. PharmDr. Hana Jansová, PhD. Title of Diploma Thesis: Synthesis and in vitro evaluation of novel iron chelators based on salicylaldehyde isonicotinoyl hydrazone Iron ions (Fe) are required in many vital processes. However, this transition metal may also catalyze reactions which results in the formation of toxic reactive oxygen species (ROS), e.g. Haber- Weiss reaction producing highly toxic hydroxyl radicals. Salicylaldehyde isonicotinoyl hydrazone (SIH) is a tridental chelator selectively forming complexes with Fe ions. As a result of its low molecular weight and good lipophilicity, SIH can be administered orally. It readily enters the cells, effectively chelates the intracellular Fe ions, and is therefore able to very efficiently inhibit the Fe dependent processes, such as production of ROS, but also the synthesis of some proteins and enzymes and the processes they regulate (e.g., cellular growth and proliferation). In this work we focused on the design, synthesis and in vitro evaluation of novel SIH analogues, in particular the thio analogue of SIH (thioSIH, A), analogues derived from (di)hydroxybenzophenone (B) and...
Synthesis of novel huprine derivatives as potential cholinesterase inhibitors
Pokrievková, Lucia ; Roh, Jaroslav (advisor) ; Kováčik, Andrej (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic And Bioorganic Chemistry Student: Lucia Pokrievková Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Supervisor specialist: RNDr. Eva Mezeiová, Ph.D., PharmDr. Jan Korábečný, Ph.D. Title of Diploma thesis: Synthesis of novel huprine derivatives as potential cholinesterase inhibitors Alzheimer's disease (AD) is a complex neurodegenerative disease that is manifested by the gradual loss of short-term and, at more advanced stages, also of long-term memory. The characteristic histopathological features of AD is the presence of neuritic plaques and neurofibrillary tangles in affected brain regions. Cholinergic neurotransmission is also one of the key pathological findings in AD. Only two drug groups are used in AD therapy. The first group consists of acetylcholinesterase inhibitors (AChEIs). Memantine, which is a glutamate receptors antagonist, belongs to the second one. The aim of the diploma thesis was the synthesis of a new group of drugs acting as multipotent ligands (multi-target directed ligands, MTDLs) derived from huprines. The new compounds were designed to be able to interact with both anionic sites of acetylcholinesterase (AChE), thereby exaggerating the enzyme-inhibiting effect. In the experimental part of the diploma...
Synthetic studies leading to CAR receptors ligands
Palša, Norbert ; Špulák, Marcel (advisor) ; Roh, Jaroslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Norbert Palša Supervisor: PharmDr. Marcel Špulák, PhD. Title of the Diploma Thesis: Synthetic studies leading to CAR receptor agonists CAR, which belongs to the family of xenobiotic nuclear receptors, affects xenobiotic and endogenic metabolic processes via metabolic enzyme genes expression. Since up to this day there is no available agonist which would activate CAR strictly without having an effect on similar nuclear receptors, thus, the effort to find such a compound is still ongoing. The aim of this diploma thesis was the synthesis of quinazoline derivatives, which, after previous preparation of 2-(3-methoxyphenyl)quinazoline-4-ol, a CAR agonist model compound, proved to be a promising group of chemical species with potential CAR activation effect - target compounds included amides of carboxylic acids via reaction with 2-aminobenzonitrile, derivatives of quinazoline-4-ol, quinazoline-4-thiol, 4-methoxyquinazoline and 3-methyl-3,4-dihydroquinazoline-4-one.
Synthesis of phosphoramidate prodrugs "ProTides" as novel potential therapeutic agents for the treatment of congenital disorders of glycosylation and mitochondrial DNA depletion syndrome
Sedláková, Jana ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic And Bioorganic Chemistry Candidate: Jana Sedláková Supervisors: Dr. Fabrizio Pertusati doc. PharmDr. Jaroslav Roh, Ph.D. Title of diploma thesis: Synthesis of phosphoramidate prodrugs "ProTides" as novel potential therapeutic agents for the treatment of congenital disorders of glycosylation and mitochondrial DNA depletion syndrome At the present time, no effective treatment is available neither for the most of the congenital disorders of glycosylation (CDGs) nor the mitochondrial DNA depletion syndrome (MDS). Regarding the CDG therapy, D-mannose-1-phosphate (Man-1-P) offers considerable pharmacological potential to improve the pathological patterns in patients affected by phosphomannomutase 2 deficiency (PMM2-CDG), similarly as N-acetyl-D-mannosamine-6-phosphate (ManNAc-6-P) in case of GNE myopathy (GNEM). Administration of selected deoxyribonucleotides was proposed as a potential pharmacological strategy for the treatment of MDS. Unfortunately, the problematic membrane penetration of such polar molecules reduces their effect and limits their clinical application. Hydrophobic, membrane permeable derivatives of the sugar monophosphates and nucleotides, might represent more efficient potential therapeutics for CDGs and...
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...
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...
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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