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Acid-base equilibria and tautomerism of nucleobases
Kovács, Jakub ; Dračínská, Helena (advisor) ; Petrželová, Simona (referee)
Nucleic acids and their components belong to the most important molecules essential for life. Hydrogen atom migration across the skeleton of purine or pyrimidine bases of nucleic acids gives rise to their various tautomeric forms. Furthermore, depending on pH of the medium, these bases might become protonated or deprotonated. Protonation/deprotonation of nucleic acid bases is involved in many biochemical processes. These include mainly regulation of replication and gene expression by means of specific secondary structure stabilization or acid- base catalysis of phosphodiester backbone cleavage. Additionally, secondary structures that include ionized bases are also associated with various genetic diseases. However, protonation and deprotonation are very fast dynamic processes and their experimental detection is difficult. Therefore, this work focuses on development of reliable method for relatively fast detection of pyrimidine base derivates primary protonation site. At first, pyrimidine bases with protonation site determined by structure were analyzed in both neutral and ionized state using NMR spectroscopy. In the next step, NMR parameters for both neutral and ionized forms were calculated using quantum-chemical computational methods. Computational method was optimized to produce results which...
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Synthesis of purine and pyrimidine derivatives with potential biological activities.
Jansa, Petr ; Holý, Antonín (advisor) ; Černý, Miloslav (referee) ; Rosenberg, Ivan (referee)
An extensive overview of the current state of the research in the field of the development of acyclic nucleoside phosphonates (ANPs) was elaborated, which quotes from 196 publications in abstracted journals. A new microwave-assisted methodology for the preparation of dialkyl haloalkylphosphonates was developed. Through strict control of the reaction temperatures in microwave reactor, it was possible to lower the amount of the reactants all the way to the ideal ratio of 1:1. With the use of a continuous-flow microwave reactor, it was possible to prepare the key building blocks for the subsequent syntheses of ANPs in large quantities (100 g), which significantly accelerates research in this area. The new method was patented and published. While studying various ANP prodrugs, a new highly effective methodology for the preparation of the diamides of ANPs was developed. The method starts directly from ANP diesters, which react with trimethylsilylbromide to form the corresponding bis(trimethylsilyl)esters of ANPs, which are well soluble in organic solvents and react smoothly during the subsequent introduction of aminoacid esters. Moreover, the reaction with trimethylsilylbromide protects the reactive groups present in the rest of the molecule and thus prevents undesired side reactions. Furthermore, using...
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