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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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Study of Effect of Ceramide Hydroxylation on Permeability and Microstructure of Model Lipid Membranes
Kováčik, Andrej ; Vávrová, Kateřina (advisor) ; Uhriková, Daniela (referee) ; Šklubalová, Zdeňka (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Organic and Bioorganic Chemistry Candidate Mgr. Andrej Kováčik Supervisor prof. PharmDr. Kateřina Vávrová, Ph.D. Title of Doctoral Thesis Study of Effect of Ceramide Hydroxylation on Permeability and Microstructure of Model Lipid Membranes Ceramides (Cer) occur in intracellular spaces of the stratum corneum, the outermost mammalian epidermal layer, where they along with other lipids (free fatty acids, cholesterol) form a skin lipid barrier. Besides sphingosine- (Cer NS) and dihydrosphingosine-based Cer (Cer NdS), in the healthy mammalian epidermis some polar Cer are present, i.e., Cer based on phytosphingosine (with hydroxyl group in position 4, i.e., phytoceramides) and Cer based on 6-hydroxysphingosine (with hydroxyl group in position 6, i.e., 6- hydroxyceramides). However, the role of phytoceramides (Cer NP) and 6 hydroxyceramides (Cer NH) in the skin barrier function has not been clarified. Moreover, 6 hydroxyceramides are not commercially available. Therefore, the first aim of this work was to synthesize physiological 6-hydroxyceramides. The synthesis of 6- hydroxylated Cer, i.e., Cer NH with long (C24:0) and Cer EOH with ultralong acyl with ester-linked linoleic acid is reported. The triple bond was reduced...
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The permeability and microstructure of model stratum corneum lipid membranes: comparison of non-hydroxylated and (R)- and (S)-α-hydroxylated ceramides
Šilarová, Michaela ; Vávrová, Kateřina (advisor) ; Zbytovská, Jarmila (referee)
Ceramides are lipid components in the uppermost layer of the skin, stratum corneum and they are essential for correct function of a skin barrier. In the stratum corneum, ceramides with cholesterol and free fatty acids are in equimolar ratio. Ceramides contain sphingoid bases, which are amino alcohols sphingosine, phytosphingosine, dihydrosphingosine or 6- hydroxysphingosine. These sphingoid bases are N-acylated by non-hydroxylated, α- hydroxylated or ω-hydroxylated fatty acid, mostly by lignoceric (C24) acid. The aim of this work was to study the permeability and microstructure of the model membranes containing non-hydroxylated ceramides. Moreover, we aimed to study the effect of additional α-hydroxyl group in ceramides including the effect of stereochemistry in position 2. We prepared model membranes based on Cer, free fatty acids (C16-24), cholesterol and a small amount of cholesteryl sulfate (5 wt%). We investigated four permeability markers: electrical impedance, water loss through the membrane, flux of theophylline and flux of indomethacin. The microstructure and miscibility of ceramides with other lipids were studied by infrared spectroscopy and X-ray powder diffraction. The results from experiments showed some differences between ceramides. For example the effect of the type of sphingoid...
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Dissolution testing of tablets containing theophylline and mixtures of two types of calcium hydrogen phosphates and microcrystalline cellulose
Vávrová, Kateřina ; Ondrejček, Pavel (advisor) ; Svačinová, Petra (referee)
Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of Pharmaceutical technology Consultant: PharmDr. Pavel Ondrejček, Ph.D. Student: Kateřina Vávrová Title of Thesis: Dissolution testing of tablets containing theophylline and mixtures of two types of calcium hydrogen phosphates and microcrystalline cellulose The aim of this thesis was the dissolution testing of tablets containing theophylline, the mixture of two dicalcium phosphate types and microcrystalline cellulose. The influence of tablet composition on the dissolution profiles was evaluated. The tablets were prepared from the mixtures containing microcrystalline cellulose, dicalcium phosphate anhydrous and dihydrate. These substances were used as fillers. Prepared mixtures contained theophylline as a model active ingredient and magnesium stearate as lubricant. Afterwards, the dissolution tests were done. For these tests, the basket method was utilized. As a dissolution medium the 0,1M hydrochloric acid solution was used. From the results of this experiment we concluded that we can influence the total amount of released theophylline and the speed of its release by the different ratio of microcrystalline cellulose and one of dicalcium phosphate types. The fastest theophylline dissolution was in tablets with high...
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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 and study of 1-O-acylceramides
Jon, Vojtěch ; Vávrová, Kateřina (advisor) ; Opálka, Lukáš (referee)
The extracellular matrix of the uppermost layer of the skin, the stratum corneum (SC), consists of ceramides (Cer), cholesterol (Chol), free fatty acids (FFA) and cholesteryl sulfate (CholS). Cer play an important role in the correct barrier function of mammalian epidermis. A new type of sphingolipids, i.e., 1-O-acyl-Cer, have been found in human SC very recently; however, their role in the SC is unknown. These Cer species contain sphingosine (S) that is N- acylated with non-hydroxylated or α- hydroxylated fatty acid, and moreover, hydroxyl group at C1 in sphingosine is esterified by an additional fatty acid (lignoceric acid, C24 or palmitic acid, C16). Because 1-O-acyl-Cer are not commercially available, we aimed to synthesize physiological 1-O-acyl Cer, i.e., Cer-24NS16, Cer-16NS16 and Cer-24AS16. Moreover, we aimed to study their behaviour on permeability and microstructure of model skin lipid membranes. The 1-O-acyl-Cer were synthesized by an acylation of Cer-NS16 or Cer-AS16 with palmitic or lignoceric acid using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and 4- dimethylaminopyridine. Cer-AS16 was prepared by α-bromination of palmitic acid, substitution of bromine by hydroxyl and N-acylation of sphingosine by the prepared acid in the presence N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide...
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Synthesis of human ω-O-acylceramides and evaluation of their effects on barrier properties of skin lipid membranes
Opálka, Lukáš ; Vávrová, Kateřina (advisor) ; Hampl, František (referee) ; Kučerka, Norbert (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic chemistry Candidate: Mgr. Lukáš Opálka Supervisor: doc. PharmDr. Kateřina Vávrová, Ph.D. Title of doctoral thesis: Synthesis of human ω-O-acylceramides and evaluation of their effects on barrier properties of skin lipid membranes The main objective of this work was to synthesize and study human acylceramides (acylCer, ceramides of the EO type) with the focus on the relationships between the acylCer concentration , structure of their polar head, their ability to form lamellar phases and permeability of model lipid membranes. Another objective was to synthesize ceramide-1-phosphates for the study of their signaling role in skin barrier and an analogue of ganglioside GM1 with shorter acyl chain as a standard for analysis of these lipids. Ceramides (Cer) belong to the family of sphingolipids. They are the central molecules in sphingolipid metabolism, they participate on cell regulatory processes and the formation of human skin lipid barrier. The main skin barrier is situated in the stratum corneum (SC), which is the uppermost layer of skin. The purpose of SC is to maintain homeostasis of the inner environment and to prevent the penetration of exogenous substances, allergens and bacteria to the...
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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 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 and study of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanoic acid derivatives as transdermal permeation enhancers
Kučera, Ondřej ; Vávrová, Kateřina (advisor) ; Nováková, Veronika (referee)
Ondřej Kučera Charles University in Prague, Faculty of Pharmacy in Hradec Králové Synthesis and study of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanoic acid derivatives as transdermal permeation enhancers Transdermal permeation enhancers are used to increase absorption of drugs through skin or, more importantly, through the stratum corneum, which is the uppermost layer of the skin. Mechanism of action of enhancers is not fully understood. In general the most active enhancers consist of hydrophilic and hydrophobic parts. In this work, we prepared and studied fluorescent permeation enhancers. Fluorescent dye NBD (7-nitrobenzo[c][1,2,5]oxadiazol) is fairly hydrophilic, so we used it as a hydrophilic head of potential enhancers based on dodecyl 6- (dimethylamino)hexanoate (DDAK). Such fluorescent enhancers could help us understand more about the mechanism of action. It enables determination of this enhancer and imaging of its penetration pathways in the skin. We synthesized three esters of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-hexanoic acid (NBD-acid) with ester-linked C8-C12 alkyls. 6-Aminocaproic acid reacted with 4-chloro- NBD and then with a series of alcohols to give us different lengths of alkyl chains. We applied these enhancers to human skin in Franz diffusion cells using two...
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