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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 and evaluation of transdermal drug permeation enhancers
Kopečná, Monika ; Vávrová, Kateřina (advisor) ; Doležal, Pavel (referee) ; Hampl, František (referee)
Penetration enhancers are compounds that facilitate transdermal drug delivery, which is an advantageous pathway of drug administration (compared to conventional methods). However, skin acts as formidable barrier enabling terrestrial life by protecting the inner body from the environmental conditions, microbes and substances. Thus, for drug administration via this pathway, some approach to temporary increase the skin permeability (e.g. permeation enhancer) should be employed. Despite the existence of many enhancer classes, there is still a need for new compounds enhancing broader spectrum of drugs, with reversible mode of action and better safety profile. One of the promising approaches is to explore natural compounds with low toxicity and irritation potential. In this thesis, I first studied various glucose and galactose derivatives bearing structural fragments that were responsible for enhancing activity of previously studied enhancers (e.g. amino acid derivatives, fatty acids and alcohols, modified ceramides). A detailed examination of these sugar- based compounds revealed potent glucoside and galactoside enhancers (12Glc6N and A15) comparable to or better than Span 20 with reversible mode of action and acceptable toxicity on keratinocyte and fibroblast cell lines. Another part of my work builds...
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Synthesis and evaluation of transdermal permeation enhancers based on terpenes
Kopečná, Monika ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Monika Kopečná Synthesis and evaluation of transdermal permeation enhancers based on terpenes Transdermal drug delivery has many advantages over the conventional routes of administration. It could make a treatment of some diseases more acceptable for patients. Other advantage is a possibility of easy interruption of treatment in case of problems. And profit comes also from the fact that the drug doesn't pass through the gastro-intestinal tract, so it avoids the first-pass effect and doesn't irritate this tract, too. But majority of drugs cannot cross the skin in sufficient amounts. To enable permeation of more drugs through the human skin, substances called transdermal permeation enhancers are used among others, some natural terpenes and amino acid derivatives such as dodecylester of 6-(dimethylamino)hexanoic acid (DDAK) are potent permeation enhancers (1) (2). The purpose of my work was to combine these potent enhancers and prepare esters of 6-(dimethylamino)hexanoic acid with selected terpenes (menthol, citronellol, linalool, farnesol and borneol) and determine their permeation-enhancing activity in vitro using two model drugs (theophylline and hydrocortisone), human skin and Franz diffusion cell. DDAK was able to increase skin flux of theophylline and hydrocortisone 23 and 37 times,...
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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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Evaluation of the in vitro skin permeation of selected compounds using static Franz diffusion cells
Dvořáková, Tereza ; Vávrová, Kateřina (advisor) ; Zbytovská, Jarmila (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic & Organic Chemistry Student: Tereza Dvořáková Title of diploma thesis: EVALUATION OF THE IN VITRO SKIN PERMEATION OF SELECTED COMPOUNDS USING STATIC FRANZ DIFFUSION CELLS The work focuses testing the transdermal permeation of selected substances - tacrine and 7-methoxytacrine (7-Meota). Tacrine is an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease. For its hepatotoxicity and side- effects is no longer used today. Transdermal administration could be a good alternative to reduce those side effects. 7-Meota is tacrine derivative, which in previous in vitro testing demonstrated lower toxicity in comparison with tacrine. The aim of this thesis was to clarify if and to what extent has tacrine and 7-Meota ability for transdermal permeation. Experiments were performed in vitro by using Franz diffusions cells. As receptor fluid was used for tacrine a phosphate buffer solution and for 7-Meota was a phosphate buffer solution for one part of the trial and for a second part was water. Substances were applied in an infinite dose in aqueous solution onto the surface of pig skin, which was cut to a thickness of 500 µm and 1000 µm. For the comparison was part of the experiments conducted in a...
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Synthesis of ceramide analogues based on 5C sphingosine
Drozen, Tomáš ; Vávrová, Kateřina (advisor) ; Nováková, Veronika (referee)
Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of anorganic and organic chemistry Candidate: Tomáš Drozen Supervisor: Doc. PharmDr. Kateřina Vávrová, Ph.D. Title of Diploma thesis: Synthesis of ceramide analogues based on 5C sphingosine Ceramides are lipids, in particular sphingolipids. They have many important roles in the organism. Ceramides form the main part of lipid matrix in the stratum corneum, the uppermost skin layer, and take an important part in maintaining skin barrier properties. Membranes of eukaryotic cells also contain ceramides, and both ceramides and their derivatives formed in organism are important signalling molecules. They act as both primary and secondary messengers, participating in regulation of cell growth, apoptosis and inflammatory responses. Although ceramides have been investigated for a long time, there are still many unanswered questions. Fo rthe understanding of the ceramide functions, it is necessary to investigate their movement in the organism and study the effects of their analogs with changed structure. Olefin metathesis is often used for synthesis of analogs with varying chain length or different florescent labels. This thesis describes attempts to synthesise ceramide analogs with very short sphingosine chain, which can be used...
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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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Study of azaphthalocyanines as fluorescence quenchers in oligodeoxynucleotide probes
Demuth, Jiří ; Nováková, Veronika (advisor) ; Hocek, Michal (referee) ; Vávrová, Kateřina (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Jiří Demuth Supervisor: doc. PharmDr. Veronika Nováková, Ph.D. Consultant: prof. PharmDr. Petr Zimčík, Ph.D. Doctoral Thesis: Study of azaphthalocyanines suitable for quenching of fluorescence in oligodeoxynucleotide probes Phthalocyanines (Pcs) and azaphthalocyanines (AzaPcs) are planar macrocyclic compounds. These synthetic compounds are derived from naturally occurring dyes - porphyrins. Pcs and AzaPcs have very interesting photophysical properties due to their extensive 18 -electron conjugated system. They are used in electrotechnics, material industry or in medicinal applications. Octaalkylamino substituted tetrapyrazinoporphyrazines (TPyzPzs), which belong to AzaPc family, can quench fluorescence of other molecules due to the ultrafast intramolecular charge transfer. This thesis studies this quenching ability of TPyzPzs with the aim to develop efficient fluorescence probes. Such probes could find application in a variety of experiments across scientific disciplines i.e. - biochemistry, forensic or genetic analysis. Synthetic part of dissertation thesis is a continuation of previous investigation of TPyzPzs in our research group. It describes...
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Synthesis of phytoceramide analogues and evaluation of their effects on the skin barrier properties
Tesař, Ondřej ; Vávrová, Kateřina (advisor) ; Pullmannová, Petra (referee)
Charles University in Prague Faculty of Pharmacy in Hradci Králové Deparment of Inorganic and Organic Chemistry Candidate: Ondřej Tesař Supervisor: doc. PharmDr. Kateřina Vávrová, Ph.D. Title of diploma thesis: Synthesis of phytoceramide analogues and evaluation of their effect on the skin barrier properties. Phytoceramides (FCER) belong to the class of sphingolipids. They are composed of a basic alcohol phytosphingosine (P) and the acyl chain. Together with the other lipids they create the extracellular membrane in human stratum corneum (SC), the uppermost layer of the skin, which protects us against the loss of water and penetration of foreign compounds into our body. The influence of FCER structure on the function of this membrane is unknown yet. Aim of the work: The aim of this work was to examine what role the acyl chain length of FCER plays in this membrane impermeability. Methods: My task was to synthetize FCER with acyl chain length of 2, 4, 6 and 24 carbons and preparation of SC model membranes containing FCER with acyl chain length of 2, 4, 6, 8 or 24 carbons, cholesterol, lignoceric acid and cholesterol sulfate. The permeabilities of the model membranes were evaluated in Franz diffusion cells. Electric impedance and permeability for two model drugs: theophylline (TH) and indomethacin...
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