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Synthesis of new nucleosides as potential inhibitors of flaviviral replication
Horkelová, Simona ; Nencka, Radim (advisor) ; Janeba, Zlatko (referee)
Viruses of the Flaviviridae family are the causative agents of many dangerous diseases for which we currently have no known cure, and research into new drugs against them therefore represents one of the major challenges for modern medicinal chemistry. Targeting the proteins encoded by viruses is the most common approach to combat them. For flaviviruses, the non- structural protein NS5 exhibiting methyltransferase (MTase) and RNA-dependent-RNA polymerase (RdRp) enzyme activity appears to be one of the most suitable molecular targets. This bachelor thesis deals with the synthesis of new potential drugs capable of inhibition skill of flaviviral RdRp. C-nucleoside analogues were prepared, containing 2 types of heterocyclical base: 3-fluoropicolamide modified in positions 5 or 6 and pyrido[3,2-d]pyrimidine-4-amine modified in positions 6 or 7 using aryl or heteroaromatic substituent Key words: C-nucleosides, polymerase, flaviviruses, Tick-borne encephalitis virus, Suzuki reaction, Grignard reaction
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Modular synthesis of 5-substituted thiophene and furan C-nucleosides and their analogues
Bárta, Jan ; Hocek, Michal
A new modular and efficient methodology for the preparation of 5-substituted thiophen-2-yl and 5-substituted furan-2-yl C-nucleosides was developed. A Friedel–Crafts-type of C-glycosidation of 2-bromothiophene or 2-bromofuran with bis-toluoyl protected methyl- 2′-deoxyribofuranoside in presence of Lewis acid gave the desired bis-toluoyl protected 5-bromothiophne and 5-bromofuran C-nucleosides in good yields. They were used as key intermediates for Stille or Suzuki coupling whith (hetero)arylstannanes or boronic acids to afford a series of 5-(hetero)aryl thiophene and 5-(heteroaryl)furan C-nucleosides.
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Development of a general and modular approach to C-nucleosides
Kubelka, Tomáš ; Štefko, Martin ; Bárta, Jan ; Joubert, Nicolas ; Urban, Milan ; Chapuis, Hubert Jean ; Hocek, Michal
Highly efficient and modular approach was developed for the synthesis of various types of new (het)aryl C-nucleosides. This protocol consists of the synthesis of haloaryl-C-nucleoside intermediates, followed by a functional group transformation to introduce various substituents. Using this approach protected 2′-deoxy-C-nucleosides bearing halogenated benzene, pyridine, thiophene, furane and pyrimidine were prepared. These intermediates were then submitted to a wide range of palladium-catalyzed reactions. The same approach was also used for preparation of C-nucleosides bearing ribofuranose moiety. Functional ribofuranosides bearing diverse substituted pyridine and benzene nucleobases were prepared in this way.
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Modulární metodika na přípravu 3- a 4- substituovaných benzenových a anilínových C-ribonukleosidů
Štefko, Martin ; Hocek, Michal
A novel modular, efficient and practical methodology for the preparation of 3- and 4-substituted phenyl and aniline C-ribonucleosides was developed. The key intermediates were synthesized in two steps from TBS-protected ribonolactone in 75% and 66% yields, respectively, as pure beta-anomers. The bromophenyl intermediates were subjected to a series of palladium catalyzed cross-coupling, aminations and alkoxylation reactions to give, after deprotection a series of free 1 beta-(3- and 4-alkyl, -aryl, -amino -alkoxyphenyl and -hetaryl substituted phenyl)-C-ribonucleosides (20 examples).
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Modulární syntéza 5-substituovaných thiofen-2-yl C-2'-deoxyribonukleosidů
Bárta, Jan ; Hocek, Michal
A new modular methodology for the preparation of 5-substituted thiophen-2-yl C-nucleosides was developed. A Friedel–Crafts-type of C-glycosidation of 2-bromothiophene with bis-toluoyl protected methylglycoside gave the desired bis-toluoyl protected 1-beta-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose in 60%. Deprotection of the protected product gave free bromothiophene C-nucleoside, which was reprotected to bis-TBDMS protected C-nucleoside. The key intermediates were then subjected to a series of palladium catalyzed cross-coupling reactions to afford, after suitable deprotection, a series of free C-nucleosides. Alternatively, other types of C-nucleosides were prepared directly by aqueous-phase Suzuki cross-coupling reactions of free C-nucleosides with boronic acids.
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