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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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Synthesis and investigation of aminophthalocyanines II.
Mocák, Ivan ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Ivan Mocák Supervisor: prof. PharmDr. Petr Zimčík, Ph.D. Title of diploma thesis: Synthesis and investigation of aminophthalocyanines II. Azaphthalocyanines (AzaPc) are nitrogen analogues of phthalocyanines (Pc) where benzene rings are replaced for pyrazine, pyridine or pyridazine respectively. AzaPc are characterized by broad spectrum of characteristic photophysical and photochemical properties that are responsible for their use in many areas, e.g. as industrial dyes, as photosensitizers in photodynamic therapy or as fluorescent sensors. In recent years, importance of dialkylamino substituted AzaPc has been rising in area of fluorescence quenching. Their broad absorption spectrum makes them suitable candidates to become universal quenchers. Process responsible for their quenching ability is called intramolecular charge transfer (ICT) from peripheral dialkylamino groups. These groups are also responsible for formation of unique supramolecular arrangement - J-dimers. The influence of bulky dialkylamino substituents on formation of J-dimers, which occurrence is rarer than the other possible form - H-dimers, is studied in this work. Results also describe how ICT is...
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Synthesis of novel 5,6-disubstituted derivatives of uracil as potential drugs
Vu, Lien Phuong ; Kučerová, Marta (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Vu Lien Phuong Supervisors: PharmDr. Marta Kučerová, Ph.D. Tanja Bruun, M.Sc. (Pharm.) Prof. Jari Yli-Kauhaluoma Title of diploma thesis: Synthesis of novel 5,6-disubstituted derivatives of uracil as potential drugs In this thesis, uracil was used as the core structure given its many biological activities that were reported such as antitumor, antiviral, antibiotic, hypoglycemic, diuretic and many others. The work was focused on the preparation of new 5,6- disubstituted uracil derivatives as potential biologically active agents. 2,4,6-Trichloropyrimidine was used for the preparation of 6-chlorouracil that was condensed with phenols or anilines to give the respective 6-phenoxyuracils and 6- phenylaminouracils. These intermediates were then modified in position 5 to give the final products. For this very challenging last step, various alkylating and acylating agents were used, e.g. Vilsmeier reagent, alkylchlorides, chloroacetyl chloride, ethyl chlorooxoacetate and ethyl bromoacetate. In the end, ethyl bromoacetate gave the most promising results affording four novel 5,6-disubstituted uracil derivatives. During the experimental work it was found that pH of water used...
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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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The electrochemical reduction of the nitro group in a flow reactor
Jankových, Miroslav ; Kučera, Radim (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Student: Miroslav Jankových Supervisor: doc. PharmDr. Radim Kučera, PhD. Consultant: PharmDr. Tomáš Holas, PhD. Title of diploma thesis: The electrochemical reduction of the nitro group in a flow reactor The aim of this diploma thesis is to study the electrochemical reduction within the flow reactor. The combination of these two methods provides enviromentaly-friendly and interesting method for the manufacturing of active pharmaceutical ingredients. Our object was to find out if the reaction really goes on. After that our goals were to optimize the reaction parameters. We executed some of the experiments to understand the parameters such as: flow rate, voltage, electric current, electrolyte. These parameters we combined to see their effect on the reaction results. The outcome of the thesis is mainly basic information about impact of parameters mentioned above. From the series of experiments the best parameters are flow rate 0,1 ml.min- 1 , voltage 0,8 - 2,0 V, electric current 100 - 150 mA, electrolyte NH4Cl, reaching conversion up to 96%.
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Study of the photodynamic inactivation of prions by phthalocyanines.
Kostelanská, Marie ; Holada, Karel (advisor) ; Zimčík, Petr (referee) ; Kolářová, Hana (referee)
Transmissive spongiform encephalopathies, also called prion disorders, are fatal neurodegenerative diseases affecting mammals. In patients, the pathological prion protein (PrPTSE ) accumulates in CNS and causes death. Prions possess high binding affinity to surfaces. Moreover, they are highly resistant to conventional sterilization procedures which rise the risk of nosocomial transmission from patients in subclinical stage of prion disease through medical tools. In the thesis, we evaluate the efficiency of photodynamic inactivation (PDI) for prion decontamination. The PDI is induced by photoactivation of phthalocyanine (Pc) derivates AlPcOH(SO3)2, SiPc(OH)2(SO3)1-3 or ZnPc(SO3)1-3. Pc exposed to light generate reactive oxygen species, mainly singlet oxygen (O2(1 ∆g)). Production of O2(1 ∆g) in aqueous solution was confirmed by iodide method, quenching by NaN3 and oxidative degradation of uric acid. The photoactivation of Pc in infectious brain homogenate led to elimination of PrPres signal (= proteinase K-resistant PrPTSE fragment) below the detection limit of western blot by using nanomolar AlPcOH(SO3)2 concentration. The complete elimination of PrPres signal was accompanied with total protein concentration decrease by a maximum of 20% in brain homogenate No signs of protein fragmentation or...
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Construction of modified DNAs with selected reactive or protective groups
Vaníková, Zuzana ; Hocek, Michal (advisor) ; Křen, Vladimír (referee) ; Zimčík, Petr (referee)
This PhD thesis is focused on the synthesis of DNA modified with photocleavable 2- nitrobenzyl protecting groups in major groove and its applications in the regulation of gene expression in the level of transcription. In the first part of my thesis, the synthesis of photocaged 2'-deoxyribonucleosides triphosphates and their photolysis to unprotected 5-hydroxymethylated nucleotides is described. All prepared nucleoside triphosphates were good substrates for their enzymatic incorporation into DNA. Synthesized 5-(2-nitrobenzyloxy)methyl-2'-deoxyuridine-5'- monophosphate (dUNBMP) and DNA with one 5-(2-nitrobenzyloxy)methyl- modification in the sequence were used for the detailed kinetic studies of photocleavage reactions. In the second part of the thesis, the series of modified DNAs with specific sequences were prepared by primer extension (PEX) and/or polymerase chain reaction (PCR). A cleavage of prepared modified DNAs was studied by selected restriction endonucleases (REs). In all cases, the nitrobenzylated DNA fully resist the cleavage by REs. The deprotection/ photocleavage conditions for nitrobenzylated DNA were studied in the case of DNAs with positive restriction endonuclease digestion of hydroxymethylated DNA. The resulting photocleaved DNA was fully digested by REs, therefore 2-nitrobenzyl...
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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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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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Study of barrier lipids in the skin and skin models
Sochorová, Michaela ; Vávrová, Kateřina (advisor) ; Zimčík, Petr (referee) ; Salavec, Miloslav (referee)
1 Abstract Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Mgr. Michaela Sochorová Supervisor: prof. PharmDr. Kateřina Vávrová, Ph.D. Title of doctoral thesis: Study of barrier lipids in the skin and skin models The barrier lipids are found in the intercellular spaces of the uppermost layer of epidermis - stratum corneum (SC). These lipids comprise an approximately equimolar mixture of ceramides (Cer), fatty acids (FA) and cholesterol (Chol). The composition and organization of the lipid mixture is unique and provides a barrier, which protects organism against harmful effects from the surroundings and, at the same time, it protects body from excessive water loss and contributes to homeostasis maintenance. Skin barrier disruption, including altered barrier lipid composition and organization, was described in many skin diseases, for example atopic dermatitis, psoriasis or skin cancer. Study and therapy of these diseases are limited by their complex pathophysiology and a lack of biological material (human skin). Therefore, skin models are appropriate and useful tools for study of skin diseases. The skin models differ in their simplicity/complexity and their preparation therefore they can provide different information. Model lipid membranes are...
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