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Synthesis of fluorinated nucleosides
Nguyen, Van Hai ; Hocek, Michal (advisor) ; Baszczyňski, Ondřej (referee)
The key intermediate 6-amino-7-iodo-7-deazapurine 3'-deoxy-3'-fluororibonucleoside was synthesized using multistep sequence of several reactions, which started from the commercially available D-xylose and 6-chloro-7-deazapurine. The synthetic strategy was based on fluorination of sugar and glycosylation with corresponding nucleobase afterwards. The fluorination of 5-protected-1,2-isopropylidine xylose with different protecting groups at position 5 always led to elimination. It was later discovered that isopropylidine forces the conformation, which is unfavorable for substitution. During the extensive optimization it was also found out that DAST appears to be an optimal fluorinating agent. Fluorination was performed on 2,3-unprotected xylose, which was subsequently used for glycosylation. After several unsuccessful attempts on "protection group free" glycosylation, Vorbrüggen glycosylation was successful and gave desired 3'-fluoro nucleoside in good yield. However, benzoyl group had to be introduced into position 2'. The protected nucleoside was then aminated and simultaneously deproctected with solution of aqueous NH3 and 1,4-dioxane. The obtained key intermediate was used for synthesis of a small series of desired 6-amino-7-hetaryl nucleoside using Pd-catalyzed Suzuki reaction under aqueous...
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Synthesis of fluorinated nucleosides
Nguyen, Van Hai ; Hocek, Michal (advisor) ; Baszczyňski, Ondřej (referee)
The key intermediate 6-amino-7-iodo-7-deazapurine 3'-deoxy-3'-fluororibonucleoside was synthesized using multistep sequence of several reactions, which started from the commercially available D-xylose and 6-chloro-7-deazapurine. The synthetic strategy was based on fluorination of sugar and glycosylation with corresponding nucleobase afterwards. The fluorination of 5-protected-1,2-isopropylidine xylose with different protecting groups at position 5 always led to elimination. It was later discovered that isopropylidine forces the conformation, which is unfavorable for substitution. During the extensive optimization it was also found out that DAST appears to be an optimal fluorinating agent. Fluorination was performed on 2,3-unprotected xylose, which was subsequently used for glycosylation. After several unsuccessful attempts on "protection group free" glycosylation, Vorbrüggen glycosylation was successful and gave desired 3'-fluoro nucleoside in good yield. However, benzoyl group had to be introduced into position 2'. The protected nucleoside was then aminated and simultaneously deproctected with solution of aqueous NH3 and 1,4-dioxane. The obtained key intermediate was used for synthesis of a small series of desired 6-amino-7-hetaryl nucleoside using Pd-catalyzed Suzuki reaction under aqueous...
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Synthesis of novel cytostatic deazapurine nucleosides and pronucleotides
Perlíková, Pavla ; Hocek, Michal (advisor) ; Jindřich, Jindřich (referee) ; Hlaváč, Jan (referee)
The synthetic routes to three types of phosphate prodrugs of 6-hetaryl-7-deazapurine ribonucleosides based on palladium-catalyzed cross-coupling reactions have been developed. CycloSal- and phosphoramidate pronucleotides and octadecyl phosphates derived from 6- hetaryl-7-deazapurine ribonucleosides were screened for their in vitro cytostatic activity. It was shown that cytostatic activity of cycloSal phosphates was similar or slightly lower compared to the parent nucleosides. Significant drop of cytostatic activity was observed in phosphoramidate pronucleotides. Octadecyl phosphates were devoid of any cytostatic activity. 6-Hetaryl-7-deazapurine ribonucleosides with bulky groups in position 6 showed very strong and selective inhibition of adenosine kinase from Mycobacterium tuberculosis. 2'-Modified 6-hetaryl-7-deazapurine nucleosides: 2'-O-methylribonucleosides, arabinonucleosides and 2'- deoxy-2'-fluororibonucleosides, were prepared by multistep functional group transformations from a ribonucleoside. The synthesis of 2'-deoxy-2',2'-difluoro-erythro-pentofuranosyl nucleosides was based on a glycosylation of 6-chloro-7-deazapurine with a sugar synthon followed by palladium-catalyzed cross-coupling reaction and deprotection. Despite the low yields and laborious separation of the anomers,...
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Hetaryl derivatives of 7-deazapurine ribonucleosides: potent cytostatic agents
Perlíková, Pavla ; Nauš, Petr ; Bourderioux, Aurelie ; Hocek, Michal
A series of novel 7-deazapurine ribonucleosides substituted with aryl and hetaryl groups has been prepared. Suzuki or Stille cross-coupling reactions with 6-chloro-7-deazapurine ribonucleosides substituted with H, F of Cl atom in position 7 were used in the key step of the synthesis. Either cross-coupling of protected ribonucleoside with appropriate (het)arylboronic acid or stannane followed by deprotection, or single-step aqueous-phase Suzuki cross-coupling reaction of unprotected 7-deazapurine ribonucleoside with boronic acid provided target (het)aryl-7-deazapurine ribonucleosides. 6-Furyl- and 6-thienyl-7-deazapurine ribonucleosides showed cytostatic effect in multiple cancer cell lines in nanomolar range. Application of cyclosaligenyl and alanyl-ester phosphoramidate prodrugs did not improved cytostatic activity of parent nucleosides.
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