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Synthesis of phosphoramidate prodrugs "ProTides" as novel potential therapeutic agents for the treatment of congenital disorders of glycosylation and mitochondrial DNA depletion syndrome
Sedláková, Jana ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic And Bioorganic Chemistry Candidate: Jana Sedláková Supervisors: Dr. Fabrizio Pertusati doc. PharmDr. Jaroslav Roh, Ph.D. Title of diploma thesis: Synthesis of phosphoramidate prodrugs "ProTides" as novel potential therapeutic agents for the treatment of congenital disorders of glycosylation and mitochondrial DNA depletion syndrome At the present time, no effective treatment is available neither for the most of the congenital disorders of glycosylation (CDGs) nor the mitochondrial DNA depletion syndrome (MDS). Regarding the CDG therapy, D-mannose-1-phosphate (Man-1-P) offers considerable pharmacological potential to improve the pathological patterns in patients affected by phosphomannomutase 2 deficiency (PMM2-CDG), similarly as N-acetyl-D-mannosamine-6-phosphate (ManNAc-6-P) in case of GNE myopathy (GNEM). Administration of selected deoxyribonucleotides was proposed as a potential pharmacological strategy for the treatment of MDS. Unfortunately, the problematic membrane penetration of such polar molecules reduces their effect and limits their clinical application. Hydrophobic, membrane permeable derivatives of the sugar monophosphates and nucleotides, might represent more efficient potential therapeutics for CDGs and...
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Synthesis of phosphoramidate prodrugs "ProTides" as novel potential therapeutic agents for the treatment of congenital disorders of glycosylation and mitochondrial DNA depletion syndrome
Sedláková, Jana ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic And Bioorganic Chemistry Candidate: Jana Sedláková Supervisors: Dr. Fabrizio Pertusati doc. PharmDr. Jaroslav Roh, Ph.D. Title of diploma thesis: Synthesis of phosphoramidate prodrugs "ProTides" as novel potential therapeutic agents for the treatment of congenital disorders of glycosylation and mitochondrial DNA depletion syndrome At the present time, no effective treatment is available neither for the most of the congenital disorders of glycosylation (CDGs) nor the mitochondrial DNA depletion syndrome (MDS). Regarding the CDG therapy, D-mannose-1-phosphate (Man-1-P) offers considerable pharmacological potential to improve the pathological patterns in patients affected by phosphomannomutase 2 deficiency (PMM2-CDG), similarly as N-acetyl-D-mannosamine-6-phosphate (ManNAc-6-P) in case of GNE myopathy (GNEM). Administration of selected deoxyribonucleotides was proposed as a potential pharmacological strategy for the treatment of MDS. Unfortunately, the problematic membrane penetration of such polar molecules reduces their effect and limits their clinical application. Hydrophobic, membrane permeable derivatives of the sugar monophosphates and nucleotides, might represent more efficient potential therapeutics for CDGs and...
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Optimization of the synthesis of 32-hydroxydotriacontanoic acid
Sommerová, Veronika ; Opálka, Lukáš (advisor) ; Roh, Jaroslav (referee)
1 Abstract Acylceramides belong to the subgroup of ultralong chain ceramides. They are essential components of the extracellular lipid matrix of stratum corneum, where they play a crucial role in proper function of skin barrier (they help preventing the excessive water loss and penetration of exogenous substances and pathogens to the organism). The 32-hydroxydotriacontanoic acid is one of the fatty acids forming the backbone of all the acylceramides. In the molecule of acylceramide, the carboxyl group of this acid is bound to a primary amino group of the sphingoid base and the ω-hydroxy group is esterified with linoleic acid. In the stratum corneum, 32-hydroxydotriacontanoic acid may remain as a part of free acylceramides or it can be covalently linked to the surface of corneocytes and form the "first lamela", which then serves as a basis for the orientation of other lipids in the matrix. The recent literature describes the synthesis of 32-hydroxydotriacontanoic acid but only with relatively small overall yields. The most problematic part of the synthesis seems to be the connection of two shorter fragments leading to the ultralong chain. The main aim of this research project was to optimalise the reaction conditions to increase the yield of formation of the utralong acid, focusing on the most complicated...
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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 novel acetylcholinesterase reactivators of isoquinolinic type
Hozová, Miroslava ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Miroslava Hozová Supervisor: PharmDr. Jaroslav Roh, Ph.D. Consultant: RNDr. Dávid Maliňák, Ph.D. Title of Diploma Thesis: Synthesis of novel acetylcholinesterase reactivators of isoquinolinic type Organophosphates are worldwide the most common cause of poisoning, whether in the field of agriculture, attempted suicide, accidental contact or abuse as organophosphorus nerve agents. They can be absorbed by all paths - inhaled, ingest or by transdermal penetration. For over 50 years the only causal antidotes on the market have been acetylcholinesterase reactivators. However, bioavailability is inadequate, therapy is ineffective, and there is no broad-spectrum reactivator able to efficiently restore AChE activity after intoxication by different types of organophosphates. All available reactivators are charged oximes with one or two pyridinium rings. These are pralidoxime, methoxime, trimedoxime, obidoxime, HI-6 and Hlö-7. Effective structure require functional oxime group (R-CH = NOH) which is able to bind the organophosphate agent from enzyme and restore its function. In this thesis, we focused on preparation, identifying structure and specifying physical and chemical properties of new...
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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 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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Substituted benzoxazoles - synthesis and biological activity
Opálka, Lukáš ; Vinšová, Jarmila (advisor) ; Vávrová, Kateřina (referee)
There were 14 compounds prepaired, including 7 Schiff bases and 7 substitued benzoxazoles. The compounds were characterised by 1 H NMR, 13 C NMR, IR, TLC and by melting point. All the new compounds aren't described in Reaxys or in Chemical Abstracts, so they can be considered as original compounds. The reaction was done in two steps. First, the Schiff base was made by the condensation of proper aminophenol and benzaldehyde and in second step, the Schiff base was cyclized by lead (IV) acetate.
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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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