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Synthesis of magnesium(II) azaphthalocyanines as potential fluorophores
Švandrlíková, Eva ; Zimčík, Petr (advisor) ; Doležal, Martin (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical Chemistry and Drug Control Student: Eva Švandrlíková Supervisor: Doc. PharmDr. Petr Zimčík Ph.D. Title of the diploma thesis: Synthesis of magnesium(II) azaphthalocyanines as potential fluorophores Azaphthalocyanines are macrocyclic compounds, which can exist with or without central metal (i.e. metal-free). Central metal can be chosen from a wide range of cations leading to significant changes in photophysical and photochemical properties of the macrocycle. My work is focused on magnesium complexes because of their significant fluorescence. Magnesium azaphthalocyanines are generally synthesized by cyclotetramerization reaction with magnesium butoxide. However, some azaphthalocyanines may contain labile peripheral substituents that may be cleaved in butoxides or in the case of unsymmetrical azaphthalocyanines the separation must be performed in a metal-free form. For these reasons, my work concerns with direct magnesium insertion into already prepared azaphthalocyanine macrocycle. I investigated possibilities of direct magnesium insertion with different kinds of magnesium salts, in different solvents, under different dryness of solvent, different temperature and different peripheral substitution of the macrocycle....
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Synthesis of symmetrical azaphthalocyanines substituted with bulky aromatic substituents
Vavřičková, Hana ; Zimčík, Petr (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Drug Control Candidate Hana Vavřičková Supervisor Doc. PharmDr. Petr Zimčík, Ph.D. Title of Thesis Synthesis of symmetrical azaphthalocyanines substituted with bulky aromatic substituents In this work, I dealt with synthesis of two types of azaphthalocyanine (AzaPc) with bulky peripheral substituents attached through stable C-C bond. Synthesis was followed by investigation of their photophysical properties. Each AzaPc was prepared in the metal-free form and as complexes with zinc or magnesium cations. The first AzaPc (8) carried eight peripheral phenolic groups sterically hindered by adjacent tert- butyl substituents in ortho positions. These acidic hydroxy groups can be ionized and the resulting negative charge can cause an intramolecular charge transfer (ICT) and quench the fluorescence of this compound. This behavior may find its potential in sensoric applications. Second AzaPc (7) carried eight peripheral methoxy groups with adjacent isopropyl substituents in ortho positions. This AzaPc served as the ICT-negative control. The precursor for 8 was prepared via nucleophilic substitution of 5,6-dichloropyrazine-2,3- dicarbonitrile with 2,6-di(tert-butyl)phenolate. Bulky...
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Synthesis and study of azaphthalocyanine quenchers of fluorescence
Kántor, Michal ; Zimčík, Petr (advisor) ; Kučerová, Marta (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Michal Kántor Supervisor: prof. PharmDr. Petr Zimčík, Ph.D. Consultant: Mgr. Jiří Demuth Title of thesis: Synthesis and study of azaphthalocyanine quenchers of fluorescence Unsymmetrical dialkylamino substituted azaphthalocyanines (AzaPcs) have unique photophysical properties - light absorption between 300 and 700 nm, almost no self-fluorescence and ability to quench fluorescence of other compounds. This makes AzaPcs suitable candidates for universal dark quenchers which can be used in real time PCR. In this work, we tried to evaluate differences in quenching between probes labeled in different positions of oligodeoxynucleotide (ODN) chain. Two quenchers bearing different functional groups suitable for different connection to ODN were synthetized (see Fig.). Following the synthesis of the quencher, three different probes were prepared- the first with the quencher in the middle of ODN chain (Fig. A), the second with the quencher attached at the end of ODN chain (Fig. B), and the third with the quencher in the middle and at the end of ODN chain (Fig. C). All prepared ODN probes were purified on HPLC system. Subsequently, the quenching efficiency of these...
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Compounds combining pyrazinamide and 4-aminobenzoic acid fragments as potential antituberculars
Žecová, Jana ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Author: Jana Žecová Supervisor: PharmDr. Jan Zitko, Ph.D. Title of diploma thesis: Compounds combining pyrazinamide and 4-aminobenzoic acid fragments as potential antituberculars Tuberculosis is a severe infectious disease, which has been afflicting the human world population for centuries. It's figuring in the scale of the deadliest diseases as well as the occurring of strains resistant to therapy requires a serious approach to this problem and the research of new therapeutic means. Among the actual antituberculars figure two compounds, PZA and PAS. Pyrazinamide is a first line drug, and its derivatives are subject of the research in the Department of Pharmaceutical chemistry and Pharmaceutical analysis. Structurally similar to 4-aminobenzoic acid, PAS is a second line antitubercular, which is again actual in the therapy of resistant form of TBC. This diploma thesis treats about possibilities of the use of compounds combining fragments of PZA and 4-aminobenzoic acid as potential antituberculars. Furthermore, this thesis evaluates the influence of PAS fragment in the derivatives prepared with this antimycobacterial purpose. The theoretical part describes the actual state of...
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Oxadiazoles as potential drugs II.
Kolčárková, Lucie ; Kučerová, Marta (advisor) ; Zimčík, Petr (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Kolčárková Lucie Supervisor: PharmDr. Marta Kučerová, Ph.D. Title of diploma thesis: Oxadiazoles as Potential Drugs II. My work was focused on finding new potential drugs with antibacterial and antifungal activity, from the reason of increasing microbial resistance against current drugs. 3-Pyrazin-2-yl-1,2,4-oxadiazole was chosen as the structural scaffold for the research. In the theoretical part of this diploma thesis I have reviewed various procedures of the preparation of 1,2,4-oxadiazoles. The methods of preparation have been assorted according to the starting material used. In the experimental part of this study several different ways of preparation to synthesize these compounds were explored and then improvement of reaction conditions in order to gain the pure product in good yields were tested. None of compounds has been reported so far. They have been characterized by IR and NMR spectra and by melting points as well. Their purity was checked by TLC and elemental analysis. Six of the synthesized compounds have been tested in vitro for their antibacterial and antifungal activity. One of the compounds has shown medium antifungal activity and another one has...
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Studying the distribution of substituents in derivatives based on hyaluronane
Sedláček, Jakub ; Šatínský, Dalibor (advisor) ; Zimčík, Petr (referee) ; Chmelař, Josef (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Analytical Chemistry Candidate Ing. Jakub Sedláček Supervisor doc. RNDr. Dalibor Šatínský, Ph.D. Title of Doctoral Thesis Studying the distribution of substituents in derivatives based on hyaluronan Derivatives based on hyaluronan have found applications in various areas of medicine. Prepared derivatives are commonly characterized by their molar mass and their degree of substitution, however, such parameters are unable to distinguish among derivatives with different distributions of substituents along the chain, which may exhibit different macroscopic properties. For this reason, methods to determine the distribution of substituents along the chain are needed. The presented thesis deals with the determination of distribution of amino groups in deacetylated hyaluronan. The theoretical part starts with a description of hyaluronan structure and of its derivatives. Next, the application, the preparation, and the characterization of deacetylated hyaluronan are discussed, focusing particularly on its depolymerisation into oligosaccharides using deaminative cleavage or enzymes that degrade hyaluronan. Finally, examples of liquid chromatographic methods used to analyse hyaluronan oligosaccharide are presented. The experimental part...
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Derivatives combining the fragment of pyrazinamide and 4-aminosalicylic acid as antimycobacterial compounds
Šlechta, Petr ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Author: Petr Šlechta Supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: MSc. Ghada Basem Bouz, Ph.D. Title of diploma thesis: Derivatives combining the fragment of pyrazinamide and 4-aminosalicylic acid as antimycobacterial compounds According to WHO, tuberculosis (TB) is the leading cause of death from a single infectious organism worldwide and the number of cases with drug resistant TB is still increasing, creating the need for new antituberculotics. Therefore, we report design, synthesis and antimicrobial evaluation of a series of hybrid compounds combining different pyrazinamide derivates and p- aminosalicylic acid as potential antituberculotic agents. The compounds were prepared by mixing different pyrazinecarboxylic acids, after activation by 1,1'-carbonyldiimidazole, with p- aminosalicylic acid in dimethylsulfoxide as a solvent. Obtained compounds were in vitro tested for their antimycobacterial activity against M. tuberculosis H37Rv, M. tuberculosis H37Ra and four other mycobacterial strains. Prepared compounds were also in vitro screened for antibacterial, antifungal, and cytotoxic (HepG2) activity. Most compounds showed antimycobacterial activity in range of...
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Synthesis of isoprenoid naringenin derivatives
Kernal, Jakub ; Zimčík, Petr (advisor) ; Demuth, Jiří (referee)
5 Abstract Charles University, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate Jakub Kernal Supervisor prof. PharmDr. Consultant Hubert Chapuis, Ph.D. Title of Thesis Synthesis of Isoprenoid Naringenin Derivatives Naringenin as a member of flavanone subclass of flavonoids and its derivatives have been subjects of intensive study for their antibacterial, antifungal, and antineoplastic properties. Recent development in current methods of synthetic chemistry allows us to satisfy the increasing demand for these molecules by providing an alternative source of these naturally occurring substances in the means of chemical synthesis. The aim of this work was synthesis and characterization of naringenin derivatives with increased lipophilic profile which will serve in future research as potential cytotoxic agents. Two major approaches have been developed in the process of obtaining lipophilic derivatives of naringenin (Fig. 2) where the lipophilic moiety consists of terpene or terpenoid part, which is believed to increase the uptake of the desired product by cells. In the first approach, we focused on the modification of the B phenolic ring by esterification of the hydroxyl group on the 4 carbon or on the modification of both A and B...
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Synthesis and delivery of novel fluorescently-labelled nucleotides and their nucleic acids for bio-analytical applications
Güixens Gallardo, Pedro ; Hocek, Michal (advisor) ; Zimčík, Petr (referee) ; Klán, Petr (referee)
1 Abstract The goals of the thesis were to synthesise novel fluorescently labelled nucleotides and the corresponding nucleic acids for bio-analytical applications as well as their delivery into cells. The thesis also aimed at the development of an effective method to inhibit non-templated incorporation of nucleotides. The problematic non-templated enzymatic incorporation of nucleotides is addressed by using several commercially available 5'-modified-oligonucleotides. The oligonucleotides (ONs) that we tested bore ortho twisted intercalating nucleic acid (oTINA), a trityl group, or biotin at the 5'-end. The modified ONs were used as templates in the enzymatic primer extension (PEX) experiments in the presence of either modified nucleotides or only natural deoxynucleoside triphosphates (dNTPs). The oTINA templates underwent PEX reaction using natural dNTPs and different DNA polymerases of the A or B family. In parallel, two types of fluorescent nucleoside derivatives were independently designed and synthesised. Firstly, we envisaged new fluorescent nucleotide tags containing the hexamethylated BODIPY moiety as a bright fluorescent label. Conversely, we focused on the improvement of fluorescent nucleotide probes sensitive to the viscosity or polarity. The fluorescently labelled methylated BODIPY nucleotides...
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Synthesis of anionic phthalocyanines as potential photodynamic active photosensitizers
Kollár, Jan ; Zimčík, Petr (advisor) ; Mosinger, Jiří (referee) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Jan Kollar Supervisor: prof. PharmDr. Petr Zimcik, Ph.D. Advisor: doc. PharmDr. Veronika Novakova, Ph.D. Doctoral Thesis: Synthesis of anionic phthalocyanines as potential photodynamic active photosensitizers Phthalocyanines (Pcs) and their aza-analogues (e.g. tetrapyrazinoporphyrazines, TPyzPzs) represent a promising group of organic dyes with interesting photophysical properties (strong absorption in area 650-750 nm, strong singlet oxygen production) highly suitable for the use in photodynamic therapy (PDT) of cancer. However, they have also some drawbacks lowering their potential use in PDT (low solubility in water, strong tendency to aggregate). The topic of my dissertation thesis closely follows the topic of my diploma thesis, during which TPyzPz with sixteen carboxylate groups in rigid arrangement was prepared and in which we have disclosed strong negative effect of low pH and serum proteins on photodynamic activity. In the first part of this thesis I prepared new zinc TPyzPz with eight sulfonate groups on periphery, which was characterised by good solubility in water. Sulfonates were chosen as stronger acids than carboxylic groups, so they were...
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