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I.Synthesis of acyclic nucleoside phosphonates with a thiadiazole base mimicking 5-azacytosine as compounds with potential biological activitiesII.Development of small molecules targeting c-MYC oncogene.
Pomeislová, Alice ; Krečmerová, Marcela (advisor) ; Jindřich, Jindřich (referee) ; Voltrová, Svatava (referee)
The first part of the thesis regards synthesis of N-[2-(phosphonomethoxy)ethyl] (PME) and (S)-3-hydroxy-2-(phosphonomethoxy)propyl ((S)-HPMP) derived acyclic nucleoside phosphonate (ANP) analogues carrying 5-amino-1,2,4-thiadiazol-3(2H)-one as a nucleobase that is supposed to mimic cytosine or 5-azacytosine. A series of 1,2,4-thiadiazole derivatives bearing at the N2 position PME- or (S)-HPMP-moiety and NH2-protecting group (benzoyl, ethoxycarbonyl, or Fmoc) were obtained as chemically stable ANP congeners. Their synthesis was performed via stepwise construction of the thiadiazole ring and required the use of two newly prepared synthons, PME-amine and (S)-HPMP-amine. However, all attempts to prepare the intended PME- and (S)-HPMP-thiadiazole phosphonic acids with free amino moiety failed due to instability of the N2 -substituted thiadiazole ring. Biological evaluation of twenty-one selected thiadiazole compounds towards two human cysteine- dependent enzymes, cathepsin K and glycogen synthase kinase 3ß, revealed that several compounds inhibited both enzymes in the low micromolar range. Some of these efficient inhibitors had also favourable toxicity profile at 100 µM, which makes them appropriate for further development of potential drug candidates. In the second part of the dissertation, design and...
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From adenoma to colorectal cancer: The study of DNA methylation profiles
Fabianová, Ivana ; Vymetálková, Veronika (advisor) ; Šmahel, Michal (referee)
Colorectal cancer (CRC) is a major public health problem worldwide and is one of the most common types of cancer in advanced countries. Recent statistics still present that the Czech Republic has a high incidence of CRC worldwide, especially in Czech men. CRC is known to be a disease that is caused not only by genetic and chromosomal abnormalities but also by epigenetic changes with the best-known DNA methylation. Changes in DNA methylation are the most prominent mechanisms that alter gene expression. Loss of gene function by epigenetic silencing of critical genes plays a key role in the development and progression of sporadic human tumors, including CRC. CRC usually develops from a harmless protrusion, known as an adenoma. However, little is known about the exact timing of DNA methylation changes in the transition from a healthy colon, through an adenoma to a malignant state. This bachelor thesis aims to summarize in detail the aberrant changes in DNA methylation in people with adenoma and in patients with CRC and at the same time to summarize the currently used methods of DNA methylation detection. Keywords: colorectal cancer, DNA methylation, adenoma, CpG island methylation phenotype, hypermethylation, hypomethylation
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