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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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