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Study of transdermal and dermal absorption of 2,6-diaminopurine acyclic nucleoside phosphonates
Diblíková, Denisa ; Vávrová, Kateřina (advisor) ; Zbytovská, Jarmila (referee)
Acyclic nucleoside phosphonates (ANP) are broad-spectrum antivirals highly effective against herpes-, retro- and hepadnaviruses. They also exhibit cytostatic, antiparasitic, immunomodulatory activities. Their transdermal delivery offers an attractive and advantageous route of administration, but is limited due to the polar character of their phosphonate moiety. The aim of this work was to study the possibility of both transdermal and dermal application of a series of 2,6-diaminopurine derivatives including (R)-PMPDAP and (S)-PMPDAP, (S)-HPMPDAP, (S)-8-azaHPMPDAP, cyclic (S)-HPMPDAP and lysolipid prodrugs, i.e., hexadecyloxypropyl (HDP) esters of (R)-HDP-PMPDAP and (S)-HDP- HPMPDAP. Ability of ANP to penetrate trough the skin by themselves is generally very low. For this reason the influence of permeation enhancer dodecylester of 6- (dimethylamino)hexanoic acid (DDAK) through and into human skin was investigated. The evaluation was performed in vitro by using Franz diffusion cells and human skin. The results of this work confirm that ANP (60 mM in 60 % propylene glycol) delivery through the skin is very low (flux 0.53-1.40 nmol/cm2 /h), except for the lysolipid prodrugs (R)-HDP-PMPDAP and (S)-HDP-HPMPDAP), which were not detected in the acceptor phase at all. 1 % DDAK enhanced transdermal flux of...
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Synthesis of 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine and study of its physicochemical properties
Valášková, Lenka ; Roh, Jaroslav (advisor) ; Vávrová, Kateřina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of inorganic and organic chemistry Candidate: Lenka Valášková Supervisor: PharmDr. Jaroslav Roh, PhD, Carine Deleuze-Masquefa Title of diploma thesis: Synthesis of 1-(3-methoxyphenyl)-N-methylimidazo[1,2- a]quinoxalin-4-amine and study of its physicochemical properties Melanoma is malign tumor usually located in the skin, mucous membranes or rarely in other parts of the organism. Every year the prevalence of this tumor is growing. Tumors which are detected in early stages can be successfully removed, but when metastasis appear treatment of this type of cancer is difficult. Some tumors (e.g. on problematic places such as on face) cannot be removed by surgery, even if they are soon detected. In these cases, topically administered anticancer drugs can be used. One of those substances is imiquimod (ALDARA® ; Figure 1), possesses antiviral, immunostimulating and cytotoxic activity. Limiting factor of this substance is its toxicity- it can be used only topically. The research group of prof. Pierre-Antoine Bonnet deals with the synthesis of imiquimod analogues. Synthesized molecules belong to three chemical groups, which differ in the orientation of imidazole moiety. Their lead structures, providing higher in vitro cytotoxic...
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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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The physico-chemical characterization of prospective transdermal absorption enhancers.
Vavrysová, Helena ; Zbytovská, Jarmila (advisor) ; Vávrová, Kateřina (referee)
THE PHYSIOCHEMICAL CHARACTERISATION OF POSSIBLE ENHANCERS FOR ABSORPTION The work is deal with studies of lipid and characterisation of the thermotopic behaviour of selected possible enhancers for transdermal absorption. The thermotropic behaviour was observed by combination DSC and IR spectroscopy of five synthetic compounds with similar structure as skin ceramides. We can deduce that all studied enhancers are highly ordered structures with high numer of trans conformers and triclinical lipid chain packing. With increased temperatur growth number of gauche conformers and increase fluidity of lipid chain. At the same time dissapear hydrogen bounds which form on the polar heads between lipid chains. Temperature differencies of phase transitions of measuring compounds is considerable. It can be caused insuficient heating of ATR crystal but exists linear dependence of correlation. With increased temperature growth measurement error. This dependence can be used for other measurements.
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Synthesis of ceramide and dihydroceramide analogues and evaluation of their effects on the skin barrier properties
Jandovská, Kateřina ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Jandovská, Kateřina: Synthesis of ceramide and dihydroceramide analogues and evaluation of their effects on the skin barrier properties. Ceramides belong to sphingolipids, their molecule is formed by a sphingoid base and long fatty acid. They are known not just as important second messengers playing a significant role in cell differentiation, proliferation and apoptosis, but also as essential part of functional skin barrier. Although these molecules are studied intensively, the exact effect of their structure on barrier function of the skin is poorly understood. The aim of my work was to study the effect of acyl chain length and stereochemistry on C3 of dihydroceramides (ceramides with single bond on C4) on the permeability of model membranes simulating the skin barrier. I have synthetized 3 ceramides with short acyl chain of 4 carbons (derived from dihydrosphingosine (dS), L-threo-dihydrosphingosine (L-dS) and L-threo-sphingosine (L-S)), and prepared model membranes of stratum corneum (SC) containing dihydroceramides with C2, C4, C6, C8 and C24 acyl chain length and stereoisomeres of C4-ceramides and C4-dihydroceramides as well. I have evaluated their electrical impedance and permeability for two model drugs. The effects of the prepared ceramides on the model membrane permeability were evaluated...
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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 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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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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Synthesis of lipophenolic derivatives of hydroxytyrosol, resveratrol and phloroglucinol
Pavlíčková, Tereza ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové, Department of inorganic and organic chemistry University of Montpellier Faculty of Pharmacy Institute of Biomolecules Max Mousseron, UMR5247 CNRS ENSCM, UM Candidate: Tereza Pavlíčková Advisor: Assoc. prof. PharmDr. Kateřina Vávrová, Ph.D. Supervisor: Dr. Céline Crauste Title: Synthesis of lipophenolic derivatives of hydroxytyrosol, resveratrol and phloroglucinol Lipophenols are conjugates of (poly)phenolic derivatives with a lipid moiety that are designed here to access lipophilic antioxidants. First part of this work targets olive oil lipophenols. Three new lipophenolic compounds, conjugates of hydroxytyrosol (most abundant olive oil phenol derivative) and three different unsaturated fatty acids were synthesized in two steps, in good yield and high purity. These products will be used as standards for determination of their presence in extra virgin olive oil (EVOO) and in liver samples of rats being fed by EVOO to examine possible in vivo metabolization. Second part of the work targets lipophenols as potential antioxidant and anti-carbonyl-stress agents in retinal diseases, where those factors are involved in the physiopathology. (Poly)phenols linkage to specific lipophilic FAs can increase their bioavailability, potentially...
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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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