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Synthesis of new types of succinimides as a potential adjuvant
Božiková, Slavomíra ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Slavomíra Božiková Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Consultant: RNDr. Dávid Maliňák, PhD Title of Diploma Thesis: Synthesis of new types of succinimides as a potential adjuvant Adjuvants represent a big group of the compounds used for the increased immune response to vaccines. This whole concept of these helper substances is more than 80 years old. The first finding that started the research of more substances was the alternative system of the aluminium salt. Important group of adjuvants are substances, which activate the immunity system to increased reaction after stimulation of toll-like receptors (TLRs) that are present in the human body. These receptors are considered as one of the most important immunity molecules. The best examined receptors of this group is the TLR4 receptor that binds various ligands. The most important ligands are the lipopolysaccharide of Gram-negative bacteria. Mechanisms of the interaction of these ligands with TLR4 are being examined recently. In my thesis I focused on the TLR4 receptors and on the synthesis of new molecules of the succinimide type, which eventually can stimulate these receptors and be potential adjuvants.
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Synthesis and biological evaluation of novel uncharged cholinesterase reactivator against nerve agent intoxication
Vaněk, Mojmír ; Roh, Jaroslav (advisor) ; Krátký, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mojmír Vaněk Supervisor: doc. PharmDr. Jaroslav Roh Ph.D. Advisors: PharmDr. Jan Korábečný Ph.D.; PharmDr. Vendula Hepnarová Ph.D. Title of diploma thesis: Synthesis and biological evaluation of novel uncharged cholinesterase reactivator against nerve agent intoxication Nerve agents (NPL) and pesticids are strongly toxic organophosphorus compounds with high affinity to acetylcholinesterase (AChE) enzyme. This enzyme is present in CNS and neuromuscular synapses. The intoxication leads into an acute cholinergic crisis, which can ultimately results into death. The therapy must be quick and includes application of atropine, reactivators of AChE and diazepam. Among the commonly used AChE reactivators, mono- or bis- quarternary aldoximes cen be found. These compounds are permanently charged, so their penetration through the blood-brain barrier (HEB) is very limited (up to 10 %, often only 1-3 %). Within the diploma thesis, a non quarternary AChE reactivator has been developed by multiple-steps synthesis approach. This compound, denoted as K1396, would exert high ability to penetrate through HEB. In vitro assessments of his capability to reactivate AChE has been carried out by method of Ellman....
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Synthesis of substituted nitrogen heterocycles as potential antitubercular agents
Němeček, Jan ; Roh, Jaroslav (advisor) ; Vinšová, Jarmila (referee) ; Hampl, František (referee)
Charles University Faculty of Pharmacy in Hradec Králové Candidate: Mgr. Jan Němeček Supervisor: Assoc. Prof. PharmDr. Jaroslav Roh, PhD Title of doctoral thesis: Synthesis of substituted nitrogen heterocycles as potential antitubercular agents Tuberculosis (TB) is one of the most common causes of death in the world. It is an infectious disease caused by Mycobactetrium tuberculosis (M.tb.). Worldwide, it is estimated that only in 2017 TB caused 1.6 million deaths and 10 million new cases of TB have appeared. TB is treatable and curable disease, but multidrug-resistant (MDR-TB) and extensively drug- resistant (XDR-TB) strains of TB have appeared and the treatment of these resistant strains of TB is very complicated. During the last several decades, only two new antitubercular drugs bedaquilin and delamanid have been introduced into the clinical practice. Thus the development of new antitubercular drug is still very important. In our group, we developed new antitubercular compounds based on 3,5- dinitrobenzylsulphanyl tetrazole and oxa(thia)diazole, whose efficient concentrations reached tens of nM against drug susceptible and drug-resistant strains of M. tb. In my work, I dealt with both structural types. At first, we prepared series of substituted 5-(3-...
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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 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...
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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...
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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...
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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...
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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.
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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...
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