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Synthesis of compounds influencing the nucleic acids chains interactions.
Ondrej, Martin ; Miletín, Miroslav (advisor) ; Opletalová, Veronika (referee)
Substances which can bind selectively to the DNA structures and modify its' functions are in the center of study of many researchers for several decades. A place of their action is the minor groove of DNA. Distamycin A, netropsin, Hoechst 33258 and many other compounds are substances with a potential to interact with DNA sequences, especially with A T base pairs rich ones. My thesis is focused on searching and synthesizing of molecules structurally and functionally similar to compounds mentioned above. In order to find the structure with required properties as well as the method for the synthesis, screening by preparation of various compounds has been made. Each synthesis was performed using various methods confirming that the methodology is not entirely uniform. Common required result of each synthesis was preparation of final compound in a water soluble salt. Many partial reactions were not always successful, but necessary for terminal synthesis of required compounds. Syntheses of four compounds were successful, which were tested by molecular biology methods for increasing the melting temperature. The performed tests have shown low activity of the prepared compounds. N,N'-(1,3-phenylenebis(methylene))bis(4- ((diaminomethylene)amino)-1-methyl-1H-pyrrole-2-carboxamide) seems to be the most...
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Radiosensitization of cancer cells by modulation of autophagy: Phosphoproteomic analysis
Ondrej, Martin ; Tichý, Aleš (advisor) ; Dresler, Jiří (referee) ; Hernychová, Lenka (referee)
(ENG) Lung cancer, and in particular, non-small cell lung cancer (NSCLC), belongs to the most lethal oncological diseases worldwide. Choosing the proper therapeutic approach is, therefore, inevitable for the successful treatment of lung tumors. In this regard, radiotherapy is an essential therapeutic approach. However, like any other treatment option, radiotherapy has its limitations in the form of radioresistance. Autophagy has been generally accepted to be one of the most crucial factors in the radioresistance of tumor cells. It is, therefore, necessary to search for suitable approaches that would lead to the suppression of cytoprotective autophagy and, thus, to the radiosensitization of tumor cells. In this respect, in our study, we employed methods of quantitative phosphoproteomics along with several techniques of molecular biology to examine the underlying molecular mechanisms and signaling pathways involved in the regulation and inhibition of the autophagic process. To inhibit the cytoprotective autophagy, we used a relatively new autophagy inhibitor-Lys05, the analog of a well-described autophagy inhibitor chloroquine. As a model, we chose the radioresistant NSCLC cells (H1299; p53-negative), because they represent the most problematic group of cells within non-small cell lung tumors. The...
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Synthesis of compounds influencing the nucleic acids chains interactions.
Ondrej, Martin ; Miletín, Miroslav (advisor) ; Opletalová, Veronika (referee)
Substances which can bind selectively to the DNA structures and modify its' functions are in the center of study of many researchers for several decades. A place of their action is the minor groove of DNA. Distamycin A, netropsin, Hoechst 33258 and many other compounds are substances with a potential to interact with DNA sequences, especially with A T base pairs rich ones. My thesis is focused on searching and synthesizing of molecules structurally and functionally similar to compounds mentioned above. In order to find the structure with required properties as well as the method for the synthesis, screening by preparation of various compounds has been made. Each synthesis was performed using various methods confirming that the methodology is not entirely uniform. Common required result of each synthesis was preparation of final compound in a water soluble salt. Many partial reactions were not always successful, but necessary for terminal synthesis of required compounds. Syntheses of four compounds were successful, which were tested by molecular biology methods for increasing the melting temperature. The performed tests have shown low activity of the prepared compounds. N,N'-(1,3-phenylenebis(methylene))bis(4- ((diaminomethylene)amino)-1-methyl-1H-pyrrole-2-carboxamide) seems to be the most...
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