|
|
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...
|
|
|
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...
|
|
|
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...
|
|
|
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...
|
|
|
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 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...
|
|
|
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...
|
|
|
Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid
Šůs, Jan ; Roh, Jaroslav (advisor) ; Špulák, Marcel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mgr. Jan Šůs Supervisors: Assoc. Prof. PharmDr. Jaroslav Roh, Ph. D. Title of rigorosum thesis: Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid Anthracyclines (ANTs) such as doxorubicin or daunorubicin are widely used anticancer drugs. However, their administration is associated with high risk of cardiotoxicity. Chronic ANT cardiotoxicity is characterized by dilated cardiomyopathy, with subsequent development of left ventricular contractile dysfunction and congestive heart failure. It is supposed that the complexation of ANTs with intracellular iron ions leads to the formation of reactive oxygen species, which causes serious tissue damage especially in myocardium. However, recent studies showed that the mechanism of action is more complex and the inhibition of topoisomerase IIβ (TOP2β) may play a crucial role. The only drug preventing cardiotoxicity of ANTs with established clinical efficacy is dexrazoxane (DEX). The mechanism of action of DEX is not fully elucidated, it probably involves either chelation of intracellular ions by its metabolite ADR-925 (Fig. 1) or the inhibition of TOP2β by the parent compound. Fig. 1. Dexrazoxane and its...
|
|
|
Development of novel cholinesterase modulators
Górecki, Lukáš ; Korábečný, Jan (advisor) ; Mičuda, Stanislav (referee) ; Roh, Jaroslav (referee)
Tittle: Development of novel cholinesterase modulators Author: Mgr. Lukáš Górecki Abstract The enzyme acetylcholinesterase (AChE) is a key component in cholinergic synapses and at the neuromuscular junctions. Its physiological function is essential in humans, as well as in animal species, including insects. In pathological conditions, AChE is also involved in various disorders such as Alzheimer's disease (AD) or myasthenia gravis. The significance of the enzyme has also been demonstrated by its successful use as a target in insecticides. In addition, it is the key mediator in the manifestation of symptoms of intoxication after exposure to Chemical warfare agents (CWA) (Nerve agents; NA). Herein, I report my study of three different aspects of this enzyme: as an anti-AD target; as an insecticidal target; and as an enzyme to be reactivated after intoxication by organophosphorus compounds (OPCs). Since the introduction of tacrine in 1993 as an anti-AD drug, much attention has been paid to the development of novel AChE inhibitors; some, such as donepezil, have been successfully marketed. At present, there is still a need for efficient drugs against AD. As AD is a multifactorial disorder, it believed that it cannot be treated by simply targeting one pathological condition. Therefore, the so-called multi-target...
|
|
|
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-...
|
guest ::
