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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 5-substituted tetrazoles - a comparison of classical synthetic aproach with synthesis under microvawe activation
Gela, Petr ; Roh, Jaroslav (advisor) ; Hrabálek, Alexandr (referee)
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 nitroheteroaromatic compounds with potential antimycobacterial activity
Bartoš, Lukáš ; Roh, Jaroslav (advisor) ; Vinšová, Jarmila (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Lukáš Bartoš Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Title of Diploma Thesis: Synthesis of nitroheteroaromatic compounds with potential antimycobacterial activity Tuberculosis (TB) is widespread infectious disease which is mainly caused by Mycobacterium tuberculosis. Referring to the World Health Organization, it is still among the top 10 causes of death in the world. Around 10 million people worldwide suffered from TB and 1.4 million died of TB only in 2019. TB is also a leading-killer in the group of HIV-positive people. This work is based on a previous successful discovery of new compounds with significant antitubercular activity, namely 1,5- and 2,5-disubstituted tetrazoles and 2,5-disubstituted oxadiazoles bearing 3,5-dinitrobenzylsulfanyl fragment, that showed minimal inhibitory concentration (MIC) values as low as 0.03 µM (i.e. lower MIC compared to first line anti-TB drugs isoniazid or rifampicin). In this work we studied the influence of the replacement of 3,5-dinitrophenyl fragment with 5- nitrofuryl group and of the position of this fragment in the molecule on the antimycobacterial activity. We also attempted to prepare several 5-nitropyridin-3-yl analogues. Hence, three...
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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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Preparation and Evaluation of New Ligands Targeting Organic Cation Transporters in the Central Nervous System for the Treatment of Depression
Monteiro, Andrea ; Roh, Jaroslav (advisor) ; Vávrová, Kateřina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Andrea Monteiro Supervisor: Assoc. Prof. PharmDr. Jaroslav Roh, Ph.D. Specialized supervisors: Nicolas Pietrancosta, Ph.D. Sophie Gautron, Ph.D. Title: Preparation and Evaluation of New Ligands Targeting Organic Cation Transporters in the Central Nervous System for the Treatment of Depression Brain organic cation transporters (OCT2, OCT3) are polyspecific facilitated diffusion transporters that regulate aminergic tonus and have a complementary role to high-affinity monoamine transporters (serotonine transporter SERT, noradrenaline transporter NET and dopamine transporter DAT) in monoamine clearance in the brain. Their complementary characteristics compared to the high-affinity transporters (widespread distribution, broader pharmacological profile) and their involvement in mood-related functions make brain OCT relevant and original targets for the development of novel antidepressants. H2-cyanome is a newly developed prodrug of cyanome that targets OCT. This prodrug showed promising antidepressant efficacy in a rodent model of chronic depression. Despite the positive impact of this prodrug on antidepressant efficacy, its limitation is its high affinity for 1 adrenergic receptors that may...
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Synthesis of lansoprazole analogs with potential antimycobacterial activity
Murínová, Mária ; Roh, Jaroslav (advisor) ; Krátký, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Mária Murínová Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Title of diploma thesis: Synthesis of lansoprazole analogs with potential antimycobacterial activity Mycobacterium tuberculosis is a bacterium that causes a serious infectious disease, tuberculosis. Recent studies show an increase in the number of patients suffering from this disease, pointing to the increasing resistance of this bacterium to most antibiotics. Given the current globalization of the world, as another factor contributing to the spread of tuberculosis in areas where the disease has been under control so far, it is essential to focus on the development of new antituberculosis drugs. Recent studies have reported that a promising candidate is lansoprazole, which is known primarily as gastric proton pump inhibitor. The mechanism of the antimycobacterial effect is that lansoprazole, after intracellular reduction to lansoprazole sulfide, kills M. tuberculosis by inhibiting cytochrome bc-1. This makes lansoprazole sulfide an excellent compound for further structural optimization and study of its structure-activity relationships. The aim of this work was to modify the structure of the lansoprazole and to prepare its...
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Synthesis of nitroheteroaromatic compounds with potential antimycobacterial activity
Bartoš, Lukáš ; Roh, Jaroslav (advisor) ; Vinšová, Jarmila (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Lukáš Bartoš Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Title of Diploma Thesis: Synthesis of nitroheteroaromatic compounds with potential antimycobacterial activity Tuberculosis (TB) is widespread infectious disease which is mainly caused by Mycobacterium tuberculosis. Referring to the World Health Organization, it is still among the top 10 causes of death in the world. Around 10 million people worldwide suffered from TB and 1.4 million died of TB only in 2019. TB is also a leading-killer in the group of HIV-positive people. This work is based on a previous successful discovery of new compounds with significant antitubercular activity, namely 1,5- and 2,5-disubstituted tetrazoles and 2,5-disubstituted oxadiazoles bearing 3,5-dinitrobenzylsulfanyl fragment, that showed minimal inhibitory concentration (MIC) values as low as 0.03 µM (i.e. lower MIC compared to first line anti-TB drugs isoniazid or rifampicin). In this work we studied the influence of the replacement of 3,5-dinitrophenyl fragment with 5- nitrofuryl group and of the position of this fragment in the molecule on the antimycobacterial activity. We also attempted to prepare several 5-nitropyridin-3-yl analogues. Hence, three...
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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 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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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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