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Synthesis and study of deuterated and polyene analogs of selected transdermal permeation enhancers
Psík, Martin ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Martin Psík Charles University in Prague, Faculty of Pharmacy in Hradec Králové 2015 Synthesis and study of deuterated and polyene analogs of selected transdermal permeation enhancers Transdermal drug delivery offers many advantages over traditional routes of administration. Main factor limiting permeation of the drug is barrier property of the skin especially its uppermost layer stratum corneum. One of the approaches to promote drug flux through SC uses permeation enhancers. Most permeation enhancers are not suitable for clinical use due to their toxicity or irritation potential. Interesting family of permeation enhancers are amino acid derivatives, in particular for their low toxicity. Very promising amino acid derivatives seem to be dodecyl 6-dimethylaminohexanoate (DDAK) and dodecyl (S)-N-acetylprolinate (L-Pro2). Their mechanism of action is not fully understood. The main goal of this diploma thesis was to contribute to the understanding of the behavior of these two transdermal permeation enhancers in the skin. In the first part of this thesis deuterated analogues of DDAK and Pro2 with deuterated dodecyl chains (previous studies show no difference between L- and D-Pro2, thus, we only used Pro2) were prepared and then their influence on the SC lipids and proteins were studied by infrared...
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Synthesis of lipophenolic derivatives of hydroxytyrosol, resveratrol and phloroglucinol
Pavlíčková, Tereza ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové, Department of inorganic and organic chemistry University of Montpellier Faculty of Pharmacy Institute of Biomolecules Max Mousseron, UMR5247 CNRS ENSCM, UM Candidate: Tereza Pavlíčková Advisor: Assoc. prof. PharmDr. Kateřina Vávrová, Ph.D. Supervisor: Dr. Céline Crauste Title: Synthesis of lipophenolic derivatives of hydroxytyrosol, resveratrol and phloroglucinol Lipophenols are conjugates of (poly)phenolic derivatives with a lipid moiety that are designed here to access lipophilic antioxidants. First part of this work targets olive oil lipophenols. Three new lipophenolic compounds, conjugates of hydroxytyrosol (most abundant olive oil phenol derivative) and three different unsaturated fatty acids were synthesized in two steps, in good yield and high purity. These products will be used as standards for determination of their presence in extra virgin olive oil (EVOO) and in liver samples of rats being fed by EVOO to examine possible in vivo metabolization. Second part of the work targets lipophenols as potential antioxidant and anti-carbonyl-stress agents in retinal diseases, where those factors are involved in the physiopathology. (Poly)phenols linkage to specific lipophilic FAs can increase their bioavailability, potentially...
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Synthesis of roscovitine analogues derived from [1,2,4]triazolo[4,3-a]pyrazines
Makovec, Jakub ; Roh, Jaroslav (advisor) ; Vávrová, Kateřina (referee)
Charles University in Prague Faculty of Pharmacy Hradec Králové Department of Inorganic and Organic Chemistry Student: Jakub Makovec Supervisor: PharmDr. Jaroslav Roh, Ph.D. Title of diploma thesis: Synthesis of roscovitine analogues derived from [1,2,4]triazolo[4,3-a]pyrazines Cancer affects all ages across the world. This is a very serious disease with high mortality and without universal therapeutic strategy. There are many drugs that inhibit cancer growth, but on the other hand these drugs have very frequent and serious side effects. Therefore there are the attempts to find such substances which have a specific activity only against changed cancerous tissue and minimal effects on healthy tissues. Roscovitine is an experimental drug with potential for the treatment of cancer. The main mechanism of action of roscovitine is inhibition of cyclin-dependent kinases participating in the regulation of cell cycle. Roscovitine is currently undergoing the clinical trials. In my thesis, we focused on the preparation of new analogs of roscovitine based on the structure of 1,2,4-triazolo[4,3-a]pyrazine. In first step, we prepared 5- (benzyl/phenylamino)-6-chloropyrazin-2,3-dicarbonitrile from commercially available 5,6-dichloropyrazin-2,3-dicarbonitrile and aniline or benzylamine. In the next step...
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Synthesis of precursors of fluorescent polyene ceramide
Říha, Michal ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Michal Říha Supervisor: Doc. PharmDr. Kateřina Vávrová, Ph.D. Title of diploma thesis: Synthesis of precursors of fluorescent polyene ceramide Ceramides, a complex group of lipids belonging to sphingolipids, have significant func- tions in many processes in living systems. Their crucial importance consists in the cell signa- lization and co-creation of functional skin barrier. Fluorescently labelled lipid analogues are often used in the lipid research. Polyene-lipids, in which the fluorophore is formed by five conjugated double bonds, represent an advanced way of fluorescent labelling of lipid molecules. Thanks to their structure, the polyene-lipids uniquely mimic their natural counterparts. This thesis studies the possibilities of the synthesis of fluorescent polyene ceramide and describes the precursors, i.e. the key substances, suitable for the preparation of the target labelled ceramide. The fluorophore was planned to be situated in the sphingosine part of the molecule, so as the properties of analogues with variable acyl chain length could be studied in the future. Three synthetic ways have been designed and investigated. The first way (Synthesis A) consists in the...
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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 fluorescent polyene ceramide
Škarda, Filip ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Filip Škarda Synthesis of fluorescent polyene ceramides Charles University in Prague, Faculty of Pharmacy in Hradec Králové 2014 Ceramides are lipid compounds that belong to the sphingolipid family. These molecules play a crucial role in many biological processes e.g. they are secondary messengers during apoptosis and other cellular signaling pathways, are involved in the synthesis of sphingomyelin and play very important role in the lipid matrix of stratum corneum, which is the epidermal barrier. Recent results showed that ceramides are affecting, or are being affected by various skin diseases. In the case of atopic dermatitis, a major decrease of ceramides in the stratum corneum is observed. On the other hand, the manifestation of psoriasis or atopic dermatitis can be reduced with topically administered ceramides. The topical ceramides repair the skin lipid barrier and prevent further water loss and aggravation of the disease. The mechanism of action of topically administered ceramides has not been fully elucidated yet. This is one of the reasons why the selection of the right methodology in order to clarify the mechanism of action is crucial. One of the possibilities is the introduction of a fluorophore into the ceramide molecule. Currently, various fluorophores (NBD, Bodipy, Rhodamine) are used...
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Enantioselective synthesis of homoallylic alcohols using chiral N-oxide organocatalysts
Mikušek, Jiří ; Pour, Milan (advisor) ; Roh, Jaroslav (referee)
In order to extend the earlier work in the group,1 we endeavored to explore the ability of the terpene-derived pyridine N-oxide organocatalyst (+)-METHOX to catalyze allylations of non-aromatic, α,β-conjugated aldehydes with allyltrichlorosilane in CH3CN. This thesis describes the synthesis of 5 novel homoallylic alcohols of high enantioselectivities (≤ 96% ee). O HR + SiCl3 METHOX 10 mol% CH3CN -30 řC R OH * (S) 96% ee N+ O- OMe OMe OMe (+)-METHOX 1 Malkov, A. V.; Bell, M.; Castelluzzo, F.; Kočovský, P. Org. Lett. 2005, 7, 3219
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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...
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Synthesis of Ortho-fused Heterocycles as the Precursors of Azaphthalocyanine Dyes
Gela, Petr ; Roh, Jaroslav (advisor) ; Kopecký, Kamil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of inorganic and organic chemistry Candidate Mgr. Petr Gela Consultant PharmDr. Jaroslav Roh, Ph.D. Title of Thesis Synthesis of ortho-fused heterocycles as the precursors of azaphthalocyanine dyes Chemical compounds containing tetrazole in recent years display an unprecedented boom. They exhibit a wide area of implementation in many areas especially in the pharmaceutical industry. The tetrazole group in these compounds acts as a bioisosteric surrogate for the functional group of carboxylic acid mainly because of close physical and chemical properties. The most important drugs containing tetrazole are used in the treatment of hypertension. In presented work we focused on the conversion of the tetrazole cycle into a different heterocyclic compound. The tetrazole can be used to the formation of other heterocycles with different number of cycles and hetero atoms. Moreover, the newly formed cycle can be also part of ortho-condensed system. In this work, we delt with the reactions of 5-substituted tetrazole with 6-substituted 5-chloropyrazine-2,3-dicarbonitrile, resulting in corresponding [1,2,4]triazolo[4,3-a]pyrazin-5,6-dicarbonitrile. Eight new and previously undescribed compounds were prepared. Synthetised compounds were used as a...
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Synthesis of benzothiazole derivatives as potential DNA Gyrase-B inhibitors
Gottsteinová, Iva ; Špulák, Marcel (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry University of Ljubljana Faculty of Pharmacy Department of Medicinal Chemistry Candidate: Iva Gottsteinová Supervisors: assoc. prof. Dr. Janez Ilaš, PharmDr. Marcel Špulák, Ph.D. Title of thesis: Synthesis of benzothiazole derivatives as potential DNA Gyrase-B inhibitors Aim of this diploma thesis was the synthesis of benzothialoze derivatives as potential inhibitors of Gyrase-B. First suggested structures were designed as analogues of alkaloid oroidin gained from marine sponge Angelas oroides. Successful series with high inhibitory activity were derivatives of 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole. To increase inhibitory activity, series of benzothiazole derivatives were designed. 6-nitrobenzo[d]thiazole-2-amine was used as starting compound and substituted in position 2 and 6 for different substitution. In second part, this diploma thesis is focused on preparation of 3,4-dichloro-5-methyl- 1H-pyrrole-2-carboxylate in large quantity as a key substituent for further reactions.
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