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The development of reliable method for glucosylation and lactosylation of sphingolipids
Hošek, Adam ; Opálka, Lukáš (advisor) ; Karabanovich, Galina (referee)
Title of the master thesis: The development of reliable method for glucosylation and lactosylation of sphingolipids Candidate: Adam Hošek Supervisor: PharmDr. Lukáš Opálka, Ph.D. Consultant: Dr. Georgios Paraskevopoulos, Ph.D. Charles University, Faculty of Pharmacy in Hradec Králové Skin Barrier Research Group, Department of Organic and Bioorganic Chemistry Ceramides are hydrophobic sphingolipids consisting of a sphingoid base and an acyl chain. They are found in the stratum corneum, the uppermost layer of the epidermis, where they are important part of the skin barrier, but they can also be found in brain tissue and inside human cells. Glucosylceramides are the simplest glycosphingolipids, and they contain a single glucose molecule in their structure. They are found in all types of human cells, where they not only serve as precursors for the biosynthesis of other, more complex glycosphingolipids, but also have their own physiological functions. The most significant is their influence on cell growth, development, differentiation and apoptosis. Disruptions in their synthesis or degradation can lead to serious health problems and are also a risk factor for the future development of a wide range of diseases. Their total absence in the body is incompatible with life. A more thorough study of their...
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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 substituted oxadiazoles with potential antimycobacterial activity
Mészárosová, Daniela ; Karabanovich, Galina (advisor) ; Krátký, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Daniela Mészárosová Supervisor: Ing. Galina Karabanovich, Ph.D. Title of Diploma Thesis: Synthesis of substituted oxadiazoles with potential antimycobacterial activity Tuberculosis is an infectious disease caused by mycobacteria Mycobacterium tuberculosis, which is one of the top ten causes of death worldwide. According to the World Health Organization, 10.4 million new cases were reported in 2016 and 1.7 million people died of this disease (including 0.4 million people with HIV). Treatment of tuberculosis caused by drug-susceptible strains of M. tuberculosis is very successful, with up to 82% of patients cured. However, a major problem is the therapy of patients with drug resistant strains of M. tuberculosis. Multidrug-resistant tuberculosis (MDR-TB) is a TB that cannot be cured by isoniazid (INH) or rifampicin (RIF), the two most effective first-line antituberculotics. In this case, TB is treated with second-line antituberculotics, which should be administered for up to two years. However, according to statistics, only 32.2% of patients with MDR-TB are successfully cured in the European Union. Therefore, it is important to look for and develop new drugs that act on MDR-TB and can help...
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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 of aza-analogs of compounds with high antimycobacterial activity
Khajl, Tomáš ; Karabanovich, Galina (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Tomáš Khajl Supervisor: Ing. Galina Karabanovich, Ph.D. Title of Diploma Thesis: Synthesis of aza-analogs of compounds with high antimycobacterial activity Tuberculosis (TB) is widespread disease, caused by bacteria M. tuberculosis. TB is the 13th leading cause of death and was the 2nd leading cause of death from infectious diseases in 2020. TB is also the most common cause of death in HIV-positive people. Due to increasing resistance to 1st line and 2nd line drugs, research into new anti-TB drugs is needed. This diploma thesis is based on previous results obtained at KOBCH FaF UK, where 5-alkyl/aryl-2-((3,5-dinitrobenzyl)sulfanyl)-1,3,4-oxadiazoles were invented. These 1,3,4- oxadiazoles showed excellent antimycobacterial activity with minimal inhibitory concentration (MIC) values of 0.03 μM. This activity is much higher than that of isoniazid, first-line antituberculotic drug, which has MIC values of 0.5 μM. In previous work, it has been shown that the 3,5-dinitrophenyl fragment is crucial to the high antimycobacterial activity and that derivatives with a 1,3,4-oxadiazole cycle show the highest potency compared to 1H/2H-tetrazole and 1,2,4-triazole derivatives. However, the question of...
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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 of ceramide NS using Grubbs metathesis
Obrdlík, Daniel ; Vávrová, Kateřina (advisor) ; Karabanovich, Galina (referee)
Ceramides are group of lipids which belong to sphingolipids. Skin ceramides have several functions in the organisms. They are important part of the lipid matrix of the stratum corneum, the outermost layer of the epidermis, where they participate in the barrier function of the skin. Furthermore, ceramides are secondary messengers in cell apoptosis and participate in many metabolic processes. Ceramides are composed of sphingoid base, which is N-acylated by fatty acid. Sphingoid base can be sphingosine, phytosphingosine, dihydrosphingosine or 6- hydroxysphingosine. Lower level of ceramides in the stratum corneum is associated with various skin diseases especially atopic dermatitis and psoriasis. Manifestations of these diseases is significantly improved by topical administration of ceramide. Exogenously administered ceramides help regenerate damaged skin and improve hydration of the skin. However, it is not fully known, in which way topically administered ceramides improve the progress of diseases. The aim of this work is synthesize physiological ceramide NS by using Grubbs metathesis reactions and optimize the conditions for achieving the highest yields. Synthesis of ceramide NS was based on pentadecan-1-ol, which was eliminated to terminal alkene. The elimination was carried out in three different...
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Synthesis of analogues of chelator SIH with increased stability towards hydrolysis
Kruchkou, Pavel ; Karabanovich, Galina (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Supervisor: Ing. Galina Karabanovich, Ph.D. Student: Pavel Kruchkou Title of Thesis: Synthesis of analogues of chelator SIH with increased stability towards hydrolysis Excessive amounts of free iron ions in the body can catalyze the formation of hydroxyl radicals, which are involved in the development of various diseases. One of the ways how to protect the body is to chelate free iron ions with chelators, in order to prevent the development of iron- catalyzed oxidative stress. Effective chelators are substances from the group of salicylaldehyde analogues of isonicotinoyl hydrazone. Salicylaldehyde isonicotinoyl hydrazone (SIH) is a chelator that forms complexes with Fe 3+ ions. Due to its high lipophilicity can be administered orally. Its main disadvantage is the low stability in the aqueous environment caused by the rapid hydrolysis of the hydrazone bond. The aim of this work was to synthesize a series of new aroylhydrazones derived from the SIH chelator, which supposed to have an improved ability to chelate iron ions and the associated ability to protect cells from oxidative stress and potentially increased stability to hydrolysis. In the first series of SIH analogs - N...
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Synthesis of dexrazoxane analogs
Macuš, Marek ; Karabanovich, Galina (advisor) ; Špulák, Marcel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Marek Macuš Supervisor: Ing. Galina Karabanovich, Ph.D. Title of the thesis: Synthesis of dexrazoxane analogs Anthracycline antibiotics (ANT), such as daunorubicin, doxorubicin or epirubicin, belong amongst the most effective antineoplastic drugs. They are being used to treat leukemias as well as solid tumors. One of the limiting factors of these highly active substances is their cardiotoxicity. Supposedly, cardiotoxicity can originate in the following basis; either by the interaction with Fe ions which form reactive oxygen species (ROS) or directly caused by the inhibition of topoisomerase IIβ by ANTs in cardiomyocytes. Irreversible damage to heart muscle cells can lead to heart failure. Dexrazoxane (DEX) is the only drug clinically used for ANT-inducted cardiotoxicity prevention. DEX is a bisdioxopiperazine derivative, and its mechanism of action is not fully clear. There are two main hypotheses: 1. chelation of intracellular iron ions and reduction of ROS formation, 2. catalytic inhibition of topoisomerase IIβ. Figure 1: Structure of dexrazoxane and dexrazoxane analogues prepared in this thesis. The thesis aimed to prepare DEX analogues with a modified linker. Namely, the butane-2,3-...
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Synthesis of ceramide NS using Grubbs metathesis
Obrdlík, Daniel ; Vávrová, Kateřina (advisor) ; Karabanovich, Galina (referee)
Ceramides are group of lipids which belong to sphingolipids. Skin ceramides have several functions in the organisms. They are important part of the lipid matrix of the stratum corneum, the outermost layer of the epidermis, where they participate in the barrier function of the skin. Furthermore, ceramides are secondary messengers in cell apoptosis and participate in many metabolic processes. Ceramides are composed of sphingoid base, which is N-acylated by fatty acid. Sphingoid base can be sphingosine, phytosphingosine, dihydrosphingosine or 6- hydroxysphingosine. Lower level of ceramides in the stratum corneum is associated with various skin diseases especially atopic dermatitis and psoriasis. Manifestations of these diseases is significantly improved by topical administration of ceramide. Exogenously administered ceramides help regenerate damaged skin and improve hydration of the skin. However, it is not fully known, in which way topically administered ceramides improve the progress of diseases. The aim of this work is synthesize physiological ceramide NS by using Grubbs metathesis reactions and optimize the conditions for achieving the highest yields. Synthesis of ceramide NS was based on pentadecan-1-ol, which was eliminated to terminal alkene. The elimination was carried out in three different...
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