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Synthesis of purine derivatives with potential antimycobacterial activity
Finger, Vladimír ; Roh, Jaroslav (advisor) ; Doležal, Martin (referee) ; Brulíková, Lucie (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Doctoral Degree Program Bioorganic Chemistry Candidate: Ing. Vladimír Finger Supervisor: Assoc. Prof. PharmDr. Jaroslav Roh, Ph.D. Title of Doctoral Thesis: Synthesis of purine derivatives with potential antimycobacterial activity The theoretical part of this dissertation briefly summarizes basic data on tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb.). The epidemiological data published in the annual report of the World Health Organization (WHO) and the structure of drugs used in current TB therapy are presented. The theoretical section also gives a brief overview of the treatment of TB and mentions four compounds that are currently in phase II clinical trials. The mechanism of action of these compounds is inhibition of the enzyme decaprenylphosphoryl-β-D-ribose-2'-epimerase, specifically the DprE1 subunit. This enzyme plays an important role in the synthesis of mycobacterial call wall. The next part of the dissertation summarizes the results of research on potential purine and pyrrolo[3,2- d]pyrimidine antituberculosis agents derived from purine-6-one 10. Compound 10 was identified as derivative with moderate anti-TB activity (MIC99(Mtb) = 4 μM) in a high-...
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Isolation and semi-synthesis of germacranolide derivatives: onopordopicrin
Cejnarová, Eliška ; Karabanovich, Galina (advisor) ; Roh, Jaroslav (referee)
University of Salamanca Faculty of Pharmacy Department of Pharmaceutical Science: Pharmaceutical Chemistry Student: Eliška Cejnarová Supervisor: prof. Esther del Olmo Title of thesis: Isolation and semi-synthesis of germacranolide derivatives: onopordopicrin This work is focused on onopordopicrin (ONO) as a potent molecule with antiprotozoal activity. ONO is a sesquiterpene lactone of germacranolide structure. Sesquiterpene lactones are typical secondary metabolites of family Asteraceae. As a source of ONO Centaurea ornata Willd. (Asteraceae) was used. It is a thistle-like endemic plant of the Iberian Peninsula. The plant was collected in July 2022, in Zamora region. First, an ether extract from the aerial flowering part of the plant was obtained (0.26 % of the dried plant weight). The crude plant extract was dissolved in methanolic solution and fractionated by liquid/liquid separation with hexane. Then the methanolic part was concentrated, dissolved in water and fractionated with solvents of increasing polarity (chloroform, ethyl acetate and n-butanol). The chloroform fraction containing ONO was purified by column chromatography to obtain the major compound ONO, which represented 54.8 % of crude extract. Figure 1. Modifications of onopordopicrin The aim of this work was the synthesis of novel...
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Synthesis of protein-kinase inhibitors as a potential treatment of cancer
Merdita, Sara ; Roh, Jaroslav (advisor) ; Karabanovich, Galina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry in collaboration with Biomedical Research Center UH HK Author: Sara Merdita Supervisor: Assoc. Prof. PharmD. Jaroslav Roh, PhD. Advisors: PharmD. Lukáš Górecki, PhD.; Assoc. Prof. PharmD. Jan Korábečný, PhD. Title of diploma thesis: Synthesis of protein-kinase inhibitors as a potential treatment for cancer Cancer is one of the leading causes of fatalities worldwide, which is attracting attention of many researchers with desire to develop treatments that selectively target cancerous cells while simultaneously sparing healthy cells. The main overall strategy is to exploit features specific to cancer - the cancer hallmarks. Those are represented, for instance, by genomic instability and aberrant DNA damage response (DDR) pathways. The DDR consists of cascades of kinases and other proteins and messengers, where we highlighted the synthetic lethal interaction between the kinases ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related). The two are major driving forces in the DDR, where in cancer ATM tends to be mutated and therefore dysfunctional, making the cells' viability reliant on ATR. Thus, ATR inhibition makes a particularly attractive strategy for abrogating cancer survival without...
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Synthesis and study of hyaluronic acid derivatives modified on carboxyl
Volfová, Gabriela ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Gabriela Volfová Supervisors: Mgr. Radovan Bu a, Ph.D. doc. PharmDr. Jaroslav Roh, Ph.D. Title: Synthesis and study of hyaluronic acid derivatives modified on carboxyl Abstract: Hyaluronic acid (HA) is a naturally occurring linear polysaccharide. Due to its biocompatibility and non-immunogenicity, HA and its derivatives are widely used in various biological and medical applications. The e cacy of each formulation is strongly related to the molecular weight (MW) of the HA used. Unfortunately, various factors can a ect the MW during the manufacturing process. Elevated tem- perature required during the sterilization process is one significant example, which can lead to a reduction in molecular weight and result in a loss of some desired properties of the final product. This work focuses on the synthesis of HA amides formed on its free carboxyl group and subsequently studying the e ect of this modifi- cation on the degradation rate at elevated temperature. Three final compounds were prepared by reacting HA with various amines using 4-(4,6-dimethoxy-1,3,5-triazin-2- yl)-4-methylmorpholinium chloride (DMTMM), all of which underwent degradation noticeably faster than native HA.
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Cholinesterases inhibited by novichok agents - in silico study of reactivation possibilities
Večeřa, Zbyněk ; Roh, Jaroslav (advisor) ; Holas, Ondřej (referee)
Title: Cholinesterases inhibited by novichok agents - in silico study of reacti- vation possibilities Author: Zbyněk Večeřa Department: Department of Organic and Bioorganic Chemistry Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Advisor: PharmDr. Mgr. Tomáš Kučera, Ph.D. Abstract: Substances known as Novichok agents are banned chemical warfare agents, which were developed in Soviet Union between the 1970s and the 1980s. They were brought to the public attention very recently - they were used to po- ison a double agent named Skripal in 2018 and again in 2020 to poison Russian politician Navalny. It is the 4th generation of nerve agents which cause cholinergic syndrome by irreversible inhibition of acetylcholinesterase (AChE), manifesting symptoms such as depression of bronchial tubes, cramps or even paralysis of re- spiratory muscles and depression of the respiratory control centre in the brain. Victim then dies of asphyxiation unless antidotes are administered as soon as possible. Treatment of nerve agents induced poisoning is based on reactivating AChE by oxime compounds which bind themselves with the toxic substance by nucle- ophilic attack on electropositive point of the nerve agent, releasing acetylcholi- nesterase that can continue with function of acetylcholine hydrolysis. The task was to...
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Cholinesterases inhibited by novichok agents - in silico study of reactivation possibilities
Večeřa, Zbyněk ; Roh, Jaroslav (advisor) ; Holas, Ondřej (referee)
Title: Cholinesterases inhibited by novichok agents - in silico study of reacti- vation possibilities Author: Zbyněk Večeřa Department: Department of Organic and Bioorganic Chemistry Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Advisor: PharmDr. Mgr. Tomáš Kučera, Ph.D. Abstract: Substances known as Novichok agents are banned chemical warfare agents, which were developed in Soviet Union between the 1970s and the 1980s. They were brought to the public attention very recently - they were used to po- ison a double agent named Skripal in 2018 and again in 2020 to poison Russian politician Navalny. It is the 4th generation of nerve agents which cause cholinergic syndrome by irreversible inhibition of acetylcholinesterase (AChE), manifesting symptoms such as depression of bronchial tubes, cramps or even paralysis of re- spiratory muscles and depression of the respiratory control centre in the brain. Victim then dies of asphyxiation unless antidotes are administered as soon as possible. Treatment of nerve agents induced poisoning is based on reactivating AChE by oxime compounds which bind themselves with the toxic substance by nucle- ophilic attack on electropositive point of the nerve agent, releasing acetylcholi- nesterase that can continue with function of acetylcholine hydrolysis. The task was to...
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Structure-antimycobacterial activity relationships in the series of dinitrophenyl-substituted heterocycles
Mašek, Zdeněk ; Roh, Jaroslav (advisor) ; Krátký, Martin (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Zdeněk Mašek Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Title of diploma thesis: Structure-antimycobacterial activity relationships in the series of dinitrophenyl-substituted heterocycles Tuberculosis is an infectious disease with an increasing number of cases each year. Resistance of the pathogen, namely Mycobacterium tuberculosis, to the treatment, even against combined therapy keeps increasing. In 2020, tuberculosis was the second most common cause of death by infectious disease after COVID-19 (it claimed 1.5 million lives) and it is also estimated that with COVID-19 weakening the population, these numbers will only grow. The aim of this work was to develop derivatives of previously studied 1H-tetrazoles and 1,3,4-oxadiazoles, with a sterically hindered sulfur atom (Fig. I), which may protect them from metabolic oxidation and therefore possibly increase their activity against resistant strains of M. tuberculosis as well as other mycobacterial strains and to increase biological halftime of these potential antituberculosis drugs. We prepared two test series, namely 1H-tetrazole series and 1,3,4-oxadiazole series both containing 4 compounds, whose antimycobacterial activities were...
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Synthesis of lansoprazole analogs with potential antimycobacterial activity
Kubásková, 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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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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Quantification of skin ceramides in patients after oncological treatment
Voláková, Eliška ; Opálka, Lukáš (advisor) ; Roh, Jaroslav (referee)
Charles University, Faculty of pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Eliška Voláková Supervisor: PharmDr. Lukáš Opálka, Ph.D. Title of diploma thesis: Quantification of skin ceramides in patients after oncological treatment Ceramides are one of the three basic lipid components present in the stratum corneum of human skin. Alterations in the ratio of individual ceramides are associated with disruption of skin barrier function. Such changes have been observed not only in skin diseases of the non-cancerous type, but also as a consequence of cancer. The main aim of the present study was to investigate the difference in the representation of skin ceramides in the stratum corneum of healthy patients and patients after cancer. Samples were collected from five groups of patients, four of which represented cancer patients with different types of treatment: tumor resection, chemotherapy, radiation or a combination of chemotherapy and radiation. The remaining fifth group consisted of control samples from volunteers without a diagnosis of cancer. Samples were obtained by tape-stripping from an identical site on patient forearm, followed by protein determination. Cancer patient samples were compared with control samples in terms of different water loss through the...
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