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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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Syntéza (purin-6-yl)acetátů a jejich transformace
Hasník, Zbyněk ; Hocek, Michal
A novel approach to the synthesis of (purin-6-yl)acetates was developed based on Pd-catalysed cross-coupling reactions of 6-chloropurines with the Reformatsky agent. These intermediates were converted into various products by functional group transformations. Amides were prepared by amidation of ester group with amines, 6-(hydroxyethyl)purines by reduction by NaBH4, and beta-substituted 6-ethylpurines by mesylation of 6-(hydroxyethyl)purines and subsequent nucleophilic substitution.
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Přímá C-H arylace purinů a purinových nukleosidů
Čerňa, Igor ; Hocek, Michal
Direct C–H arylation of purines to position 8 by diverse aryl halides was achieved using Pd catalysis in the presence of CuI and Cs2CO3. The methodology was applied in consecutive regioselective synthesis of 2,6,8-trisubstituted purines bearing three different C-substituents in combination with two cross-coupling reaction. In addition, direct arylation of unprotected purine nucleosides with aryl iodides at position 8 was developed to allow straightforward single-step introduction of diverse aryl groups.
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