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Synthesis of unsymmetrical derivatives of azaphthalocyanines V.
Nejedlá, Marcela ; Zimčík, Petr (advisor) ; Miletín, Miroslav (referee)
Title of diploma thesis: Synthesis of usymmetrical derivates of azaphthalocyanines V. Author: Marcela Nejedlá The aim of diploma thesis was synthesis of unsymmetrical derivates of azaphthalocyanines (Aza- Pc) with carboxy or hydroxy group, and the preparation of suitable precursors of Aza-Pc. Required zinc and magnesium complexes were synthesized using statistical condensation of two different precursors. The desired complex was isolated from the mixture, purified and characterized. The preparation of the precursor 6-(3-tert-butylsulfanyl-5,6-dicyanopyrazine-2- ylamino)hexanoic acid was successful. The cyclization of two precursors yielded the following Aza-Pc: 3-carboxy[2',3'-b]quinoxalino-11,12,18,19,25,26-hexakis(tert- butylsulfanyl)tripyrazino[g,l,q]porphyrazinato zinc (II); 3-carboxy[2',3'-b]quinoxalino- 11,12,18,19,25,26-hexakis(tert-butylsulfanyl)tripyrazino[g,l,q]porphyrazinato magnesium (II). The modification of the preparation of precursor 5,6-dioxo-1,4,5,6-tetrahydropyrazine-2,3- dicarbonitrile by decreasing the reaction temperature has shown to be unsuitable
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Synthesis of low-symmetry azaphthalocyanine for the labeling of DNA probes increasing the susceptibility of the molecular-biological methods
Schimmerová, Aneta ; Nováková, Veronika (advisor) ; Miletín, Miroslav (referee)
1. ABSTRACT Charles University, Faculty of Pharmacy in Hradec Králové Department Department od Biophysics and Physical Chemistry Student Aneta Schimmerová Supervisor Assoc. Prof. PharmDr. Veronika Nováková, Ph.D. Title of thesis Synthesis of low-symmetry azaphthalocyanine for the labeling of DNA probes increasing the susceptibility of the molecular- biological methods Azaphthalocyanines (AzaPc) are planar macrocyclic compounds. The alkylamino substituted derivatives can be used as dark quenchers in DNA-hybridization assays. A probe usually contains a quencher and a fluorophore. If these two moieties are close enough, the emitted fluorescence is quenched by the quencher. After the hydrolysis of the oligonucleotide probe, the fluorescence appears because of the long distance between the quencher and fluorophore. Thanks to the large system of conjugated double bounds, AzaPc absorb over a wide range of wavelengths from 300 nm to 750 nm. Such absorption covers all fluorophores used in hybridization assays nowadays, thus AzaPc may serve as universal dark quenchers. The aim of this study was to prepare an AzaPc, that will be possible to attach inside an oligonucleotide strand. Furthermore, a planar moiety bounded to AzaPc will intercalate into DNA and improve the strength of binding of the probe to DNA. First, the...
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Derivatives of Rhodanine as Potential Drugs I.
Vlčková, Martina ; Opletalová, Veronika (advisor) ; Miletín, Miroslav (referee)
Příloha 3 Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Chemistry and Drug Control Diploma paper Rhodanine derivatives as potential drugs II. Martina Vlčková Compounds containing a rhodanine motive create a perspective group of molecules that are studied as antimicrobial and antiprotozoic drugs or as substances with influence on inflammatory and proliferative processes. This paper describes the condensation of rhodanine with aromatic aldehydes in alkaline medium and the biological activity of the products: 5-[4-(dimethylamino)benzylidene]-2-thioxothiazolidin-4-one, 5-(2,4-dihydroxy- benzylidene)-2-thioxothiazolidin-4-one, 5-(4-chlorbenzylidene)-2-thioxothiazolidin- 4-one and 5-pyrazin-2-ylmethylene-2-thioxothiazolidin-4-one. These products don't show significant antifungal activity except 5-(4-chlorbenzylidene)-2-thioxothiazolidin-4-one. This substance shows some inhibition effect on Trichosporon asahii (MIC/IC80/12 h = 62.5 μmol.l-1 ), Trichophyton mentagrophytes (MIC/IC80/72 h = 15.62 μmol.l-1 ), Aspergillus fumigatus (MIC/IC80/12 h = 15.62 μmol.l-1 ) and Absidia corymbifera (MIC/IC80 /12 h = 15.62 μmol.l-1 ). The inhibition activity of these compounds on Mycobacterium tuberculosis wasn't found sufficient for further investigation. The strongest...
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The effect of substitution on the basicity of azomethine nitrogens of phthalocyanines
Ludvová, Lucie ; Nováková, Veronika (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Lucie Ludvová Supervisor: assoc. prof. PharmDr. Veronika Nováková, Ph.D. Title of Thesis: The effect of substitution on the basicity of azomethine nitrogens of phthalocyanines This work deals with the effect of substituents on the basicity of azomethine nitrogens in phthalocyanines, which are macrocyclic compounds with wide system of conjugation bounds. Substituents differed in their position at the macrocycle (attached at peripheral or non-peripheral positions) and in the type of substituents (alkylsulfanyl-, alkyloxy- or alkyl groups). Three zinc phthalocyanines were prepared in this project to complete the above mentioned series. In the first step, appropriate precursors were prepared by multi-step procedure using e.g. nucleophilic substitution or Negishi coupling reaction. These precursors were further used for cyclotetramerization reaction to get metal free phthalocyanines. Finally, the zinc cation was coordinated into the center of phthalocyanines. The second part of the project focused on the determination of the basicity of this series of zinc phthalocyanines by the mean of the absorption spectroscopy. The highest basicity showed...
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Solubilisation systems for potential photodynamic compounds III.
Grandová, Milada ; Miletín, Miroslav (advisor) ; Kopecký, Kamil (referee)
This graduation thesis is engaged in searching for solubilisation systems for potentially photodynamically active substances. The effort was focused on fading of systems with the smallest particles, transparent or modestly opalescent with the acceptable cytoxicity. Three systems satisfying the requirements for transparency (and so the particle size) were found but only two systems were used further for the solubilization of the photosenzitizers, the third one did not conform to the cytotoxicity tests. Another aim was to find, whether the photosensitizers, while solubilized using the selected systems, will not precipitate and will not be aggregated and therefore they would be usable in cell culture tests. Both the systems complying with the cytotoxicity tests proved to be usable. Photosenzitizers emulsified in them did not embody the aggregation or precipitation of the system. Finally measurements of the particles size of the systems with emulsified photosenzitizers were performed.
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Design and Synthesis of Hybrid Compounds Based on Tacrin/Resveratrol Derivatives
Jeřábek, Jakub ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jakub Jeřábek Supervisors: Prof. PharmDr. Martin Doležal, Ph.D. Prof. Maria Laura Bolognesi Title of Thesis: Design and Synthesis of Hybrid Compounds Based on Tacrine/Resveratrol Derivatives Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder, in which a progressive dementia appears. The cause of AD is currently unknown, however, scientific research has revealed several pathological hallmarks - β-amyloid plaques and neurofibrillary tangles. These changes cause gradual disintegration of nerve cells and they change the metabolism in the brain. The current drugs are not able to treat the cause of the disease, being able only to delay the onset of severe symptoms. The basic drugs for AD treatment are acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitors and, more recently approved, N-methyl- D-aspartate (NMDA) receptor antagonist memantine. These drugs are able to increase cholinergic activity or preventing glutamate excitotoxicity in the patient's brain, thus improving cognitive functions and delaying severe stages of the disease. One of the emerging approaches in drug synthesis represents multi-target-directed ligands (MTDLs). Apart from the ability...
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Synthesis of cationic phthalocyanines
Cidlina, Antonín ; Zimčík, Petr (advisor) ; Miletín, Miroslav (referee)
CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF PHARMACEUTICAL CHEMISTRY AND DRUG CONTROL Author: Antonín Cidlina Supervisor: Assoc. Prof. PharmDr. Petr Zimčík PhD. Title: Synthesis of cationic phthalocyanines In my thesis, I dealt with the preparation of cationic phthalocyanines containing quaternary ammonium groups in peripheral chains that are attached to α or β positions of the macrocycle. The synthesis of precursors for cyclotetramerization was the first step of this work. They were prepared by nucleophilic substitution of aromatic dicarbonitriles by 2- (diethylamino)ethanthiolate. These precursors were used to cyclotetramerization in presence of magnesium butoxide. Magnesium phthalocyanines were prepared by this procedure. Magnesium complexes were converted to metal-free phthalocyanines in acidic medium. Then, they reacted with anhydrous zinc acetate to form zinc phthalocyanines. Subsequently, alkylation of peripheral amino groups by ethyliodide led to quaternized Pc. In addition, the derivates with substitution in α positions did not aggregate in aqueous media. Furthermore, zinc phtalocyanine substituted in α positions had very good photochemical properties. That is why it may become potential photosensitizer with promising photodynamic activity.
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Synthesis of Isozaleplon Studies
Blahovcová, Michaela ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
SYNTHETIC STUDIES CONNECTED WITH THE PREPARATION OF N-[3-(3-CYANOPYRAZOLO[1,5-a]PYRIMIDIN-5-YL)PHENYL]- N-ETHYLACETAMIDE, A ZALEPLON REGIOISOMER Rigorous Thesis Mgr. Michaela Blahovcová Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Chemistry and Drug Control, Heyrovského 1203, Hradec Králové This thesis is a continuation of my master thesis and further develops the subject of zaleplon impurities. The main subject of the work is the zaleplon regioisomer, N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide called isozaleplon, which is the most problematic impurity of zaleplon. The purpose of this thesis was to propose a synthetic way leading to isozaleplon based on the available literature. Then this substance was intended to be used as a standard for determination of this impurity in preparation of zaleplon by various methods. The studied approaches to the isozaleplon synthesis were based on Suzuki- Miyaura cross-coupling reaction of the corresponding boronic acids and/or boronates, mainly with 5-chloropyrazolo[1,5-a]pyrimidin-3-carbonitrile. Various methods of preparation of both components are described, as well as approaches based on the final modification of the 5-(3-aminophenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile moiety...
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