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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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Ceramides and Dimethylamino Acid Derivatives as Skin Barrier Modulators
Novotný, Jakub ; Vávrová, Kateřina (advisor) ; Sedlák, Miloš (referee) ; Doležal, Pavel (referee)
The purpose of this work is to contribute to the understanding of the structure-activity relationships and behavior of the skin ceramides and transdermal penetration enhancers based on dimethylamino acid esters. First two chapters provide a theoretical background for understanding the main principles of transdermal drug delivery as well as composition and function of stratum corneum barrier. The experimental work is presented in the form of individual publications in chapters three to five. The first chapter describes transport routes through the human skin and gives an overview of enhancers of transdermal permeation with main accent on their chemical structure, mechanism of action, interaction with stratum corneum components and advantages and drawbacks of their use. The second chapter brings more detailed information on the specific content and composition of stratum corneum. The main attention is paid to the ceramides - a complex group of lipids that play a crucial role as cell signaling molecules and skin barrier constituents. In the skin, these sphingolipids form a major part of the stratum corneum intercellular lipid matrix, which is the barrier for penetration of most compounds. The development of such a protective layer was a critical step in the evolution of life on a dry land. Moreover,...
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Effect of ceramide acyl chain length on the skin permeabillity
Lorenc, Petr ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Ceramides that are present in stratum corneum (SC), the uppermost layer of the skin, are responsible for skin barrier function and thus for its permeability for drugs. Their role in the formation of skin barrier has been widely described; however, up to now, their structure-activity relationships have not been fully revealed. Previous studies suggested, that the ceramide acyl chain length is a key factor for the permeability of the skin barrier. The aim of this work was to study the influence of the length of ceramide acyl chain on the permeability of the skin barrier using short ceramides, sphingosine, phytoshingosine and ceramide 2 (NS). Short ceramide analogues contained sphingosine with 18 carbon atoms and the acyl chain ranging from 2 to 18 carbon atoms. Their influence on skin permeability was tested in vitro in Franz diffusion cells on dermatomed porcine skin using two model drugs - theophylline (TH) and indomethacin (IND). Donor samples were prepared as 5% (w/v) suspension of TH and 2.5% (w/v) suspension of IND with addition of 1% (w/v) ceramide in 60% (v/v) propylene glycol. Negative samples for the comparison of the fluxes and the drug concentrations contained 5% (w/v) suspension of TH and 2.5% (w/v) suspension of IND propylene glycol without the addition of ceramide. Phosphate buffer...
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Monosubstituted 5,6-dihydro-2H-pyran-2-ones. Natural occurence, biological activity and synthetic approaches.
Bešťák, Petr ; Špulák, Marcel (advisor) ; Vávrová, Kateřina (referee)
5,6-Dihydro-2H-pyran-2-ones are naturally occurring substances, very widely distributed in the nature. Their biological activities have been known for a long time. In last few decades, along with the development of instrumental equipment and synthetic skills of modern chemistry, systematic research and structure-activity relationship's of these compounds became a challenging task. This review embraces monosubstituted pentenolides, mostly those, substituted in the 6-position. Furthermore, it reveals the possible reason for the generally exclusive natural occurrence of the 6-substituted 5,6-dihydro-2H-pyran-2-ones on the opposite to other - 3, 4 and 5-substituted analogues. This review describes most of known naturally occurring monosubstituted pentenolides, including their structure and confirmed or suspected biological activities. Synthetic approaches to pentenolides have been considered and collected.
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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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Asymetrically substituted ureas as a skin permeation enhancers
Šíma, Martin ; Hrabálek, Alexandr (advisor) ; Vávrová, Kateřina (referee)
PharmDr. Martin Šíma Asymetrically substituted ureas as a skin permeation enhancers ABSTRACT: Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium-5-(dodecyloxycarbo-nyl)pentylcarbamate, T12) is a highly effective skin permeation enhancer. In this rigorous thesis, T12 analogs with urea function group 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 biological activity of T12 and its analogs from previous studies (alkane, ketone, amide, carbamate, and carbonate). Similarly to analogs from previous studies, there was a significant decrease in the enhancing potency. The results thus show that the ester group in the molecule of T12 is essential for its extraordinary effect.
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Anti-adhesive activity of bovine whey oligosaccharides against Neisseria meningitis
Janůšová, Barbora ; Vávrová, Kateřina (advisor) ; Pour, Milan (referee)
RESUME Neisseria meningitidis, je lidský patogen způsobující život ohrožující onemocnění. Tato onemocnění jsou velice závažná a mohou být smrtelná již za několika hodin po manifestaci prvních příznaků. Proto je nezbytně nutná rychlá diagnóza a okamžité nasazení antibiotik. Avšak díky zvýšenému výskytu rezistentních bakteriálních kmenů se stává léčba i prevence velmi obtížná, a jsou tedy hledány nové způsoby terapie. Jedním z nových přístupů může být antiadhesivní terapie využívající glykanů, které zabraňují adhesi bakterií na hostitelské tkáně. Oligosacharidy a glykokonjugáty izolované z kravského a mateřského mléka prokázaly antiadhesivní účinky proti mnoho patogenům, stejně tak i proti N. meningitidis. Tyto komponenty by mohly být tedy využity jako bioaktivní přísada do potravin, a snižovat tak incidenci bakterielních onemocnění. Toto využití je však velmi ekonomicky náročné, a jsou tedy hledány jiné zdroje, které by mohly snížit náklady. Takový zdroj představuje syrovátka vznikající jako odpadní produkt při výrobě sýrů. Cílem této práce tedy bylo izolovat oligosacharidy z kravské syrovátky, separovat je na neutrální a acidické a otestovat jejich antiadhesivní účinky. Pro separaci izolovaných oligosacharidů bylo užito gelové a iontově výměnné chromatografie. Schopnost oligosacharidů zabránit adhesi N....
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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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