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Synthesis of transdermal permeation enhancers on basis piperidine carboxylic acids derivatives II
Kořínek, Michal ; Hrabálek, Alexandr (advisor) ; Kuneš, Jiří (referee)
Synthesis of transdermal permeation enhancers on basis of piperidine carboxylic acids derivatives II. Michal Kořínek Supervisor: Doc. PharmDr. Alexandr Hrabálek, CSc. Transdermal permeation enhancers are substances facilitating penetration of drugs through the skin. They temporarily influence stratum corneum, the outermost protective layer of epidermis. Highly effective transkarbam 12 served as a model substance. The aim of my work was to find out the effect of cyclization on its enhancing activity. The following derivatives of piperidine-4-carboxylic acid esters were synthesized: 4-(decyloxycarbonyl)piperidinium bromide 4-(dodecyloxycarbonyl)piperidinium bromide 1-acetylpiperidine-4-carboxylic acid decyl ester 1-acetylpiperidine-4-carboxylic acid dodecyl ester 4-(decyloxycarbonyl)piperidinium 4-(decyloxycarbonyl)piperidine-1-carbamate 4-(dodecyloxycarbonyl)piperidinium 4-(dodecyloxycarbonyl)piperidine-1-carbamate These unknown substances were characterized by spectral methods. The biological activity of the prepared compounds was evaluated in vitro on porcine skin in modified Franz diffusion cell with theophylline as a model permeant. The amount of theophylline was measured by HPLC method with UV detection. The results showed a significant permeation-enhancing activity of both the carbamic acid salts and...
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Direct Activation of the C-H Bond in Tetrazoles
Lubojacký, Richard ; Pour, Milan (advisor) ; Hrabálek, Alexandr (referee)
Direct activation of C-H bond in tetrazoles Richard Lubojacký, 5th grade Supervisor: Prof. RNDr. Milan Pour, Ph.D. Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Králové Within the framework of this diploma thesis, direct arylation and alkenylation of 1- substituted tetrazoles at C5 was developed and optimized. An economical preparation of a range of 1,5-disubstituted tetrazoles was thus made possible. In these reactions, Pd-catalysis in the presence of CuI and Cs2CO3 was found as optimal. Contrary to similar reactions of imidazoles and purines, it was necessary to incorporate phosphine ligands in order to stabilize Pd - intermediates and prevent them from a premature decomposition into cyanamides. A library of 1,5-disubstituted tetrazoles with very promising yields has been prepared using this method.
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Isosters of transkarbam 12 as transdermal penetration enhancers
Šíma, Martin ; Hrabálek, Alexandr (advisor) ; Vávrová, Kateřina (referee)
SUMMARY: Diploma thesis - Isosters of Transkarbam 12 as skin penetration enhancers Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium-5-(dodecyloxycarbo- nyl)pentylcarbamate, T12) is a highly effective skin permeation enhancer. In this diploma thesis, T12 analogs with carbamate and carbonate function groups replacing the ester one were synthetised, and evaluated in vitro as skin permeation enhancers on excised porcine skin, using theophiline as a model drug. The results were expressed by an enhancing ratio and compared with the biological activity of T12. The enhancing activity decreases in the following sequence: ester, carbonate, carbamate. The results thus show that it is the ester group in the molecule of T12 which is essential for its extraordinary effect. In addition, homologues with a different length of the ending and connecting carbon chains were evaluated. While the length of the connecting carbon chain does not influence the biological activity significantly, nonyl to decyl ending carbon chains show the highest acceleration ability. It indicates that the length of the carbon chain, and not its lipofility, is important for the enhancing activity.
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Synthesis of ceramides with deuterated sphingosine
Havlíčková, Kateřina ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Ceramides are a complex group of lipids belonging to sphingolipids. They are the most important component of stratum corneum (SC) and thus participate in a barrier function of the skin. In spite of the ceramides are a subject of intensive research, the exact effect of their structure to the barrier function of the skin is poorly understood. For studying the structure, properties and dynamics of SC lipid membranes, analogues of lipids labelled by deuterium are often used. The methods using deuterated molecules include neutron scattering, fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, deuterium nuclear magnetic resonance (2 H-NMR) and time of flight secondary ion mass spectrometry (ToF-SIMS). This work describes the synthesis of the ceramide with a deuterated sphingosine chain. The acquired ceramides with a different acyl chain length (deuterated as well as non-deuterated) should be used for studying their properties in SC lipid membranes in the future. The synthesis was based on methods commonly used for preparation of non-deuterated analogues of ceramides. The most important step of the synthesis was the incorporation of the deuterated chain into the molecule of sphingosine. The deuterated terminal alkyne was prepared from the perdeuterated bromoalkane. Next the deuterated...
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Synthesis of transdermal permeation enhancers based on piperidine carboxylic acids
Fratričová, Veronika ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Transdermal permeation enhancers are chemical compounds, which promote drug absorption through the skin via the barrier resistance decrease. The model structure was molecule of transkarbam 12. I have synthesized these compounds: 2-(decyloxycarbonyl)piperidinium bromide 2-(dodecyloxycarbonyl)piperidinium bromide 1-acetylpiperidine-2-carboxylic acid decyl ester 1-acetylpiperidine-2-carboxylic acid dodecyl ester (R)-N -acetylpiperidin-2-carboxylic acid decyl ester (R)-N -acetylpiperidin-2-carboxylic acid dodecyl ester (R)-N -acetylpiperidin-3-carboxylic acid decyl ester (R)-N -acetylpiperidin-3-carboxylic acid dodecyl ester 2-(decyloxycarbonyl)piperidinium 2-(decyloxycarbonyl)piperidine-1-carbamate 2-(dodecyloxycarbonyl)piperidinium 2-(dodecyloxycarbonyl)piperidine-1-carbamate Transdermal permeation-enhancing activity of the prepared compounds was evaluated on the porcine skin in the Franz diffusion cells using theophylline as the model drug. The enhancement ratio values were compared with the results of structurally related compounds synthesized in the previous diploma theses. The results showed that the least active substances were the hydrobromides, N-acetylderivatives were more active, comparable with model enhancer transkarbam 12. No significant difference between racemates and (R)-izomers of N-...
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Synthesis of ceramide analogs with various sphingosine length and evaluation of their effects on the skin barrier
Školová, Barbora ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Ceramides are a complex group of lipids, naturally occurring in the uppermost layer of the epidermis, in the stratum corneum (SC). They constitute a major component of extracellular matrix and they are responsible for the skin barrier properties. Diseases such as atopic dermatitis or psoriasis are associated with the decline in content and changes in the composition of ceramides, which lead to the reduction in the protective functions of the skin. Although the importance of ceramides is known, the relationship between their structure and effect on the barrier function is not yet fully elucidated. Earlier studies indicate that the length of ceramide acyl chain affects the skin permeability. It appears that ceramides with short acyl lose the protective properties. First, I have prepared a series of analogues of ceramides with fifteen carbon atoms chain in the sphingosine part and the acyl part of a length of 2, 4 and 6 carbons. Starting substance of the synthesis was N-protected L-serine methyl ester, which was further protected by the formation of a cyclic acetal and subjected to the reduction of the ester to aldehyde. The resulting aldehyde reacted with 1-alcynide in the presence of HMPA. The triple bond was subsequently reduced to a trans-double bond by lithium in ethylamine. After deprotection of...
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Detergents based on quarternized nitrogenous heterocycles.
Marek, Jan ; Hrabálek, Alexandr (advisor) ; Jun, Daniel (referee)
This thesis is divided into three subsections. In the first part, there is described synthesis of seven already known benzalkonium homologues (C8-C20), which were used as a standard compounds for synthesis and analyzes of amphiphilic substances. The second part deals with preparation for other series of quartenary detergents having heteroaromatic rings (pyridine, isoquinoline, quinoline, acridine) in their structures. According to the analysis of the newly prepared compounds, we have prepared all pyridinium, quinolinium, isoquinolinium homoloques only. Our future forts will by focus on acridinium salts, which we were not able to prepare. Moreover, further biological activity evaluation was managed and its results will be obtained within several month. In the third part, the measurement of inhibition activity compared with acetylcholinesterase and critical micellar concentration was realized.
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The synthesis of the derivatives of 2-aryl-4-methylcyclopent-2-en-1-one with potential antifungal activity
Matoušová, Eliška ; Kuneš, Jiří (advisor) ; Hrabálek, Alexandr (referee)
THE SYNTHESIS OF THE DERIVATIVES OF 2-ARYL-4-METHYLCYKLOPENT-2-EN-1-ONE WITH POTENTIAL ANTIFUNGAL ACTIVITY Eliška Matoušová ABSTRACT Several series of compounds with potential antifungal activity related to a national product incrustoporine have been synthesized in last years. The aim of this thesis was to prepare the set of carbanalogues of incrustoporine (2-arylderivatives of 4-methylcyklopent-2-en-1-one) to find whether the substitution of oxygen atom in lactone group by methylen would have any influence on the activity. We found that the antifungal effect of these compounds was very low. It means that the lactone group is necessary for the activity. All the compounds was also tested for cytotoxic activity but they did not display any significant effect. Z O 2-subst.phenyl-4-methylcyklopent-2-en-1-one O O (-) incrustoporine
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Synthesis of aroylhydrazone iron chelators
Špirková, Iva Agneta ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Name: Iva Agneta Špirková Thesis: Synthesis of aroylhydrazone iron chelators Anthracyclines are often used in the therapy of breast, prostate and other cancers. One of the side effects of the therapy is the development of cardiomyopathy. Iron ions catalyse intracellular Fenton and Haber-Weiss reaction, which produces free hydroxyl radicals. The hydroxyl radicals cause the oxidative stress in myocardium. Possible way to prevent the oxidative stress is to chelate free iron ions. The most potent iron chelators are derived from salicylaldehyde isonicotinoyl hydrazone. The purpose of this work is to improve the ability of aroylhydrazone chelators to prevent the cardiomyocytes against damage while maintaining their chelation ability and low toxicity. We are also interested in their antiproliferative activity-especially the selectivity of this cytotoxic action. The aim of my work was to prepare a series of novel aroylhydrazones, including derivatives of 7-hydroxyindanone, 2-acetylpyridine, brominated and nitrated 2- hydroxypropiophenone.These compounds were prepared by Schiff base condensation. In case of nitrated derivatives, the starting ketones were first prepared by electrophilic nitration. Another series was prepared by reduction of the double hydrazone bond in salicylaldehyde isonicotinoyl hydrazone...
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