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Study of Antiproliferative effects of Novel Iron Chelators
Potůčková, Eliška ; Šimůnek, Tomáš (advisor) ; Boušová, Iva (referee) ; Kuča, Kamil (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Eliška Potůčková Supervisor: Doc. PharmDr. Tomáš Šimůnek, Ph.D. Title of Doctoral Thesis: Study of antiproliferative effects of novel iron chelators Recent studies demonstrate that iron chelators possess marked potential as anticancer agents and also as substances protecting sensitive tissues against oxidative stress. This thesis is dealing mainly with design and synthesis of new antiproliferative iron chelators based on the structure of salicylaldehyde isonicotinoyl hydrazone (SIH) and with a characterization of their pharmacological and toxicological properties. Antiproliferative effects of these substances were studied on human breast adenocarcinoma cell line and human leukemic cell line and the non-specific toxicity on neonatal rat cardiac tissue-derived cells. During these studies some novel structure- activity relationships have been found. Furthermore, the suitability of simultaneous administration of iron chelators with antineoplastic agents used in breast cancer treatment was studied. In this project the anthracycline antibiotic, doxorubicin, and, in particular, the estrogen receptor antagonist, tamoxifen, were identified as the most suitable agents for potential treatment...
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Synthesis and Study of Properties of Aza-analogues of Phthalocyanines
Nováková, Veronika ; Zimčík, Petr (advisor) ; Kuča, Kamil (referee) ; Kubát, Pavel (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Veronika Nováková Supervisor doc. PharmDr. Petr Zimčík, Ph.D. Title of Doctoral Thesis Synthesis and study of properties of aza-analogues of phthalocyanines Phthalocyanines (Pc) and their azaanalogues azaphthalocyanines (Azapc) are planar macrocyclic compounds with significant absorption band at 620-720 nm finding application in the areas such as photodynamic therapy, chemical catalysis and solar cells. Photophysical (fluorescence) and photochemical (singlet oxygen production) parameters are important in above mentioned applications. Peripheral substituents of Pc/AzaPc play key role in this case. Alkylsulfanyl and alkyloxy derivatives exerted high fluorescence quantum yields (ΦF) as well as quantum yields of singlet oxygen (ΦΔ). On the other hand, alkylamino substitution led to almost zero values of both ΦF and Φ∆. These derivatives have recently found new application as dark quenchers in DNA hybridization probes. The first part of this thesis demonstrated that intramolecular charge transfer (ICT) is responsible for zero values of quantum yields of alkylamino AzaPc and that the lone electron pair of peripheral nitrogen is a donor for ICT in AzaPc....
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Study of biological activity of isolated alkaloids from Corydalis cava (Fumariaceae)
Chlebek, Jakub ; Opletal, Lubomír (advisor) ; Drašar, Pavel (referee) ; Kuča, Kamil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany and Ecology Candidate: Mgr. Jakub Chlebek Supervisor: Doc. RNDr. Lubomír Opletal, CSc. Title of Doctoral Thesis: Study of biological activity of isolated alkaloids from Corydalis cava (Fumariaceae). Key words: Corydalis cava, isoquinoline alkaloids, DPPH, AChE, BuChE, BACE1, IMER. Tubers of Corydalis cava were selected on the basis of bio-guided spectrophotometric Ellman's method as a source of isoquinoline alkaloids for study of their selected biological activities. The tubers of Corydalis cava were extracted with ethanol and the mixture of summary tertiary alkaloids (fraction A) was fractionated in silica gel chromatography column using step gradient elution with hexane, chloroform and ethanol. Repeated column chromatography, preparative TLC and crystallization led to the isolation of fifteen isoquinoline alkaloids. The chemical structures of isolated compounds were determined on the basis of spectroscopic techniques and by comparison with literature data. Isolated alkaloids were tested on ability to inhibit AChE, serum BuChE (IC50), BACE1 and for its free-radical scavenging activity (EC50). The cholinesterase inhibitory activity was determined in vitro by modified spectrophotometric Ellman's...
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Effects of antidepressants and depressive disorders on mitochondrial functions
Hroudová, Jana ; Fišar, Zdeněk (advisor) ; Martásek, Pavel (referee) ; Kuča, Kamil (referee)
Mood disorders are serious diseases. Nevertheless, their pathophysiology is not sufficiently clarified. Biological markers that would facilitate the diagnosis or successful prediction of pharmacotherapy are still being sought. The aim of the study was to find out whether mitochondrial functions are affected by antidepressants, mood stabilizers and depression. Our research is based on recent hypotheses of mood disorders, the advanced monoamine hypothesis, the neurotrophic hypothesis, and the mitochondrial dysfunction hypothesis. We assume that impaired function of mitochondria leads to neuronal damage and can be related to the origin of mood disorders. Effects of antidepressants and mood stabilizers on mitochondrial functions can be related to their therapeutic or side effects. In vitro effects of pharmacologically different antidepressants and mood stabilizers on the activities of mitochondrial enzymes were measured in mitochondria isolated from pig brains (in vitro model). Activity of monoamine oxidase (MAO) isoforms was determined radiochemically, activities of other mitochondrial enzymes were measured spectrophotometrically. Overall activity of the system of oxidative phosphorylation was measured electrochemically using high- resolution respirometry. Methods were modified to measure the same...
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Electrosynthesis of Delta-Valero Lactones
Pochopová, Lenka ; Kubíček, Vladimír (advisor) ; Kuča, Kamil (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of pharmaceutical chemistry Candidate: Mgr. Pochopová Lenka Consultant: Ing. Kubíček Vladimír, CSc. Tittle of Thesis: ,,ELECTROSYNTHESIS OF DELTA-VALERO LACTONES" In this project electrolysis has been used as a method for a synthesis of new compounds. The main aim is cathodic reduction of the carbon-chlorine bond in a series of aldol trichloroacetates. Formed carbanion would form a 6 member ring by attaching the carbonyl group. Two structures can be formed: α, α-dichloro-β-hydroxy-δ-lactones and α, β-unsaturated-α-chloro -δ-lactones from the starting esters using electrolysis. The whole process was performed at controlled potential in a separated cell, on mercury pool as a cathode and platinum as an anode in an argon atmosphere with dichloromethane/tetraethylamonium system. During the process two electrons have been passed. The synthesized lactones are completely new compounds. In this report also electrochemical and spectroscopy properties of those compounds have been characterized to provide for their other use.
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Synthesis of bisquaternary asymmetrical reactivators of acetylcholinesterase
Komlóová, Markéta ; Doležal, Martin (advisor) ; Kuča, Kamil (referee)
Markéta Komlóová: Synthesis of bisquarternary asymmetrical reactivators of acetylcholinesterase Nine potential bisquaternary reactivators of AChE have been prepared and their reactivation activity against paraoxon or tabun-inhibited enzyme has been tested in vitro. Three reactivators of AChE proved to be suitable for further testing against paraoxon. One of these compounds also demonstrated satisfactory efficiency when reacting against tabun. The reactivation abilities of prepared compounds depend on structural factors such as the presence of oxime group, its location, the presence of quaternary nitrogen and other functional groups. Also four monoquaternary inhibitors have been prepared and their inhibitive activity tested in vitro.
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Cholinesterase activity following experimentally induced organophosphorus poisoning.
Svobodová, Irena ; Herink, Josef (advisor) ; Kuča, Kamil (referee)
The aim of present work was a comparison of effectiveness of oximes chosen in the experimental therapy of nerve agents intoxication (soman and russian VX). All experiments were performed in male Wistar rats. All oximes tested were administered intramuscularly either in a separate injection or in combination with atropine. The preparation of the brain parts for determination of acetylcholinesterase was performed in several time intervals after drugs tested administration. Antidotal potency of oxime HI-6 was superior in comparison with the rest of oximes tested.
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Synthesis of precursors for biologically active lactones IV.
Bémová, Hana ; Kuča, Kamil (referee) ; Opletalová, Veronika (advisor)
Charles University in Prague, Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical Chemistry and Drug Control SYNTHESIS OF PRECURSORS FOR BIOLOGICALLY ACTIVE LACTONES IV. Rigorous Thesis Hana Piskacova A high width of biological activity of natural or synthetic unsaturated five membered lactones from the family of furan-2(5H)-ones, is the main reason why to synthesize new substances of this structure. The introductory part of the thesis deals with antineoplastic natural compounds of this type. Except of antitumour activity some unsaturated five membered lactones exhibit antifungal, antiviral, antibacterial effects, or inhibit the synthesis of cholesterol, for example. The experimental project is an extension of my diploma thesis concerned with the synthesis of precursors for lactones. These precursors - methyl (E)- and (Z)-2-bromo-5- (subst.)arylpent-2-en-4-ynoates - were prepared by Sonogashira couplings. The parent substances for couplings were arylethynes (1-ethynyl-4-(methoxymethoxy)benzen, 1-ethynyl-2-nitrobenzene, 3-ethynylaniline, 2-ethynylpyridine) and methylesters of dihalogenated prop-2-enoic acid. The dominant products of the couplings were β-monoalkynylated esters, apart from them side products of homocouplings were obtained. Reactions of E-methylesters of dihalogenated...
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