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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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