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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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Carbocyclic analogues of nucleosides containing substituted bicyclic systems.
Šála, Michal ; Hřebabecký, Hubert (advisor) ; Černý, Miloslav (referee) ; Moravcová, Jitka (referee)
Charles University in Prague Faculty of Science Department of Organic and Nuclear Chemistry Carbocyclic analogues of nucleosides containing substituted bicyclic systems Michal Šála Ph.D. Thesis Abstract Prague 2010 Introduction Nucleoside and nucleotide analogues are of fundamental importance for all organisms. Therefore, nucleoside analogues are interesting target for drug discovery and development, mainly as potential antiviral and antitumor agents. A crucial disadvantage of natural nucleosides analogues is cleavage of the N-glycosidic bond by phosphorylases. Modification which increases resistance against enzymatic degradation is substitution of the sugar moiety furanose ring by a hydrocarbon ring. Many of such modified analogues - carbocyclic nucleosides1 - exhibit interesting antiviral activity. Several analogues containing conformationally locked bicyclic systems were also synthesized. Well known are carbocylic nucleosides with a fused cyclopropane moiety2 (bicyclo[3.1.0]hexane). Recently, novel conformationally locked carbocyclic nucleosides based on 2-oxabicyclo[2.2.1]heptane ring system were described3 (as precursors for carbocyclic locked nucleic acids). This thesis concerns the synthesis of biologically active compounds related to the carbocyclic nucleoside analogues. First part of the work is...
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Carbocyclic analogues of nucleosides and nonnucleoside inhibitors of thymidine phosphorylase
Nencka, Radim ; Hřebabecký, Hubert (advisor) ; Černý, Miloslav (referee) ; Ledvina, Miroslav (referee) ; Kefurt, Karel (referee)
!ntroduction Analogues ofnucleic acid components belong to the most successful classes oftherapeutics. Extensive modifications ofnucreobases, nucreosides and nucleotides led to the discovery ofa huge group of compounds with remarkable biological activity. The most important are perhaps the effects on various severe diseases such as cancer, leukemia or viral infectrons. The essential aim ofthis Thesis was the preparation ofbiologically active compounds related to the nucleic acid components. Since the carbocyclic anďogues ofnucleosides have been a long-time interest of our group, the first part of this work was devoted to the development of practical synthetic routes towards their new derivatives and to the synthesis of the novel analogues for further biological activity screening. However, the preliminary biological tests of the prepared compounds uncovered very promising lead to the compretely different field than it was expected. During the primer studies, I synthesized several 5,6-disubstituted uracils, initially prepared just as moder compounds for development of nover synthetic approaches towards carbocyclic nucleosides, that showed to posses outstanding inhibitory activity against thymidine phosphorylase. Therefore, the development of novel derivatives based on these findings was estabrished as a new...
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Synthesis of Prolinol-Based Phosphonate Nucleotide Analogues
Vaněk, Václav ; Rosenberg, Ivan (advisor) ; Černý, Miloslav (referee) ; Moravcová, Jitka (referee) ; Pour, Milan (referee)
4. Conclusion A series ofnovel isosteric 3'-nucleotide analogues (9a-e and l0a-e) was synthesized, cr-t-- and B-t--prolinol nucleoside N-methylphosphonic acids distinguished for the loss of unambiguously defined configuration at the nitrogen atom in 3'-position of prolinol nng. Remarkable conformational differences between cr-L- and B-l-prolinol nucleotides determined by NMR study suggest some similarity with the natural 5'-o-nucleotide. The same conformational changes in o-series of prolinol nucleotides fit even better the 3'- and 5'-o- nucleotides. In addition, a series of four diastereoisomeric synthons 5-8 was prepared from the commercially available lrans-4-hydroxy-l-proline, giving access to a complete set of prolinol-derived nucleotide analogues bearing cr.L-, B-t--, o.o- and p-o-conÍiguration. In order to constrain the conformational flexibility of the N-phosphonomethyl moiety, seveÍal protected compounds were subjected to N-oxidation or N-methylation which gave chiral N-oxides or quatemary ammonium salts. However, the synthesis of the respective unprotected phosphonic acids was unsuccessful, probably due to their fast decomposition. Acylation ofthe pyrrolidine ring nitrogen atom by several acylphosphonic acid derivatives led to the novel N.phosphonoformyl, /y'.phosphonoacetyl and...
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