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Synthesis and study of hyaluronic acid derivatives modified on carboxyl
Volfová, Gabriela ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Gabriela Volfová Supervisors: Mgr. Radovan Bu a, Ph.D. doc. PharmDr. Jaroslav Roh, Ph.D. Title: Synthesis and study of hyaluronic acid derivatives modified on carboxyl Abstract: Hyaluronic acid (HA) is a naturally occurring linear polysaccharide. Due to its biocompatibility and non-immunogenicity, HA and its derivatives are widely used in various biological and medical applications. The e cacy of each formulation is strongly related to the molecular weight (MW) of the HA used. Unfortunately, various factors can a ect the MW during the manufacturing process. Elevated tem- perature required during the sterilization process is one significant example, which can lead to a reduction in molecular weight and result in a loss of some desired properties of the final product. This work focuses on the synthesis of HA amides formed on its free carboxyl group and subsequently studying the e ect of this modifi- cation on the degradation rate at elevated temperature. Three final compounds were prepared by reacting HA with various amines using 4-(4,6-dimethoxy-1,3,5-triazin-2- yl)-4-methylmorpholinium chloride (DMTMM), all of which underwent degradation noticeably faster than native HA.
Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid
Šůs, Jan ; Roh, Jaroslav (advisor) ; Špulák, Marcel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mgr. Jan Šůs Supervisors: Assoc. Prof. PharmDr. Jaroslav Roh, Ph. D. Title of rigorosum thesis: Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid Anthracyclines (ANTs) such as doxorubicin or daunorubicin are widely used anticancer drugs. However, their administration is associated with high risk of cardiotoxicity. Chronic ANT cardiotoxicity is characterized by dilated cardiomyopathy, with subsequent development of left ventricular contractile dysfunction and congestive heart failure. It is supposed that the complexation of ANTs with intracellular iron ions leads to the formation of reactive oxygen species, which causes serious tissue damage especially in myocardium. However, recent studies showed that the mechanism of action is more complex and the inhibition of topoisomerase IIβ (TOP2β) may play a crucial role. The only drug preventing cardiotoxicity of ANTs with established clinical efficacy is dexrazoxane (DEX). The mechanism of action of DEX is not fully elucidated, it probably involves either chelation of intracellular ions by its metabolite ADR-925 (Fig. 1) or the inhibition of TOP2β by the parent compound. Fig. 1. Dexrazoxane and its...
Synthesis of novel cardioprotectants and metabolites of potent anticancer drug - Bp4eT
Eisner, Tomáš ; Roh, Jaroslav (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mgr. Tomáš Eisner Supervisor: Assoc. Prof. PharmDr. Jaroslav Roh, Ph. D. Title of rigorosum thesis: Synthesis of novel cardioprotectants and metabolites of potent anticancer drug Bp4eT Anthracyclines (ANT) such as doxorubicin, daunorubicin, or epirubicin rank among the most effective anticancer drugs. However, their major side effect is chronic cardiotoxicity leading to irreversible cardiac damage and congestive heart failure. It is assumed that this side effect is caused by reactive oxygen species, whose formation is catalyzed by the complexes of anthracyclines with iron ions. The only clinically used drug preventing ANT cardiotoxicity is dexrazoxane (DXZ, Figure 1). In this work we dealt with the synthesis of novel DXZ analogues, because the structure-activity relationship studies have not been performed yet. The main analogue named ES-5 (Figure 1) was synthesized and its cardioprotective effect was evaluated both in vitro and in vivo. Fig. 1. Structures of DXZ and ES-5 Furthermore, thiosemicarbazone Bp4eT (2-benzoylpyridine 4-ethyl-3- thiosemicarbazone, Figure 2), a potent anticancer iron chelator and its metabolites were synthesized. These compounds were used as standards in metabolic...
Synthesis of novel cardioprotective iron chelators
Hrušková, Kateřina ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Oxidative stress participates in patophysiology of many serious cardiovascular diseases. Free intracellular iron occurs as a catalyst of Haber-Weiss and Fenton reaction between superoxides and peroxides increasing the formation of highly toxic hydroxyl radicals, which cause cell damage. Iron chelators diminish the pool of free iron and thus become perspective agents in therapy of various diseases, e.g. anthracycline-induced cardiotoxicity. Aroylhydrazones group, such as salicylaldehyde-isonicotinoylhydrazone (SIH), appear to be highly efficient chelators. Unfortunately, pharmacokinetic studies focused on these compounds revealed their low stability in plasma. Therefore, I synthesised a series of SIH analogs in order to increase their stability together with preserving the ability to chelate free intracellular iron and to define their structure-activity relationships. A basic hypothesis in design of the novel chelators was using substituted ketone instead of aldehyde, leading potentially to an enhanced stability of hydrazone bond. SIH Two different methods were used during the reactions, a conventional heating in an oil bath and heating in a microwave reactor. The latter caused a significant shortening of the reaction time. In vitro studies of novel compounds showed their higher stability in plasma,...
Synthesis of new types of succinimides as a potential adjuvant
Božiková, Slavomíra ; Roh, Jaroslav (advisor) ; Opálka, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Slavomíra Božiková Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Consultant: RNDr. Dávid Maliňák, PhD Title of Diploma Thesis: Synthesis of new types of succinimides as a potential adjuvant Adjuvants represent a big group of the compounds used for the increased immune response to vaccines. This whole concept of these helper substances is more than 80 years old. The first finding that started the research of more substances was the alternative system of the aluminium salt. Important group of adjuvants are substances, which activate the immunity system to increased reaction after stimulation of toll-like receptors (TLRs) that are present in the human body. These receptors are considered as one of the most important immunity molecules. The best examined receptors of this group is the TLR4 receptor that binds various ligands. The most important ligands are the lipopolysaccharide of Gram-negative bacteria. Mechanisms of the interaction of these ligands with TLR4 are being examined recently. In my thesis I focused on the TLR4 receptors and on the synthesis of new molecules of the succinimide type, which eventually can stimulate these receptors and be potential adjuvants.
Synthesis of azaphthalocyanines substituted with moieties derived from trimesic acid
Kollár, Jan ; Zimčík, Petr (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Author: Jan Kollár Supervisor: Doc. PharmDr. Petr Zimčík, PhD. Title of diploma thesis: Synthesis of azaphthalocyanines substituted with moieties derived from trimesic acid Aim of this work was a synthesis of new photosensitizers from the group of water- soluble azaphthalocyanines (AzaPc) with future potential to be used in PDT. The starting compound for synthesis, trimesic acid, was esterified by ethanol and the triester was partially hydrolysed to mono carboxylic acid. Subsequently, the carboxyl group was selectively reduced to hydroxyl followed by oxidation to aldehyde. Benzoin condensation of this aldehyde gave acyloin that was oxidized to tetraethyl 5,5'-oxalyldiisophthalate. Substituted pyrazine-2,3-dicarbonitrile, a precursor for AzaPc, was obtained by condensation of diaminomaleonitirile with this vicinal diketon. Cyclotetramerization using magnesium butoxide as initiator gave magnesium(II) AzaPc substituted with sixteen butoxycarbonyl groups. Magnesium complexes were converted to metal-free AzaPc in acidic medium and then to zinc(II) AzaPc by reaction with anhydrous zinc acetate. Tetraethyl 5,5'-oxalyldiisophthalate was also hydrolyzed to diketon with four free...
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...
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...
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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