Three series of isomeric pyrrolo- and furo-fused 7-deazapurine ribonucleosides were synthesized and screened for cytostatic and antiviral activity. The synthesis was based on heterocyclizations of hetaryl-azidopyrimidines to form the tricyclic heterocyclic bases, followed by glycosylation and final derivatizations through cross-coupling reactions or nucleophilic substitutions. The pyrrolo[2',3':4,5]pyrrolo[2,3- d]pyrimidine and furo[2',3':4,5]pyrrolo[2,3- d]pyrimidine ribonucleosides were found to be potent cytostatics, whereas the isomeric pyrrolo[3',2',4,5]pyrrolo[2,3- d]pyrimidine nucleosides were inactive. The most active were the methyl, methoxy, and methylsulfanyl derivatives exerting submicromolar cytostatic effects and good selectivity toward cancer cells. We have shown that the nucleosides are activated by intracellular phosphorylation and the nucleotides get incorporated to both RNA and DNA, where they cause DNA damage. They represent a new type of promising candidates for preclinical development toward antitumor agents.

Department of Pharmacology and Toxicology University of Toronto 1 King's College Circle Room 4213 Toronto Ontario M5S 1A8 Canada

Faculty of Medicine and Dentistry Institute of Molecular and Translational Medicine Palacky University and University Hospital in Olomouc Hněvotínská 5 CZ 775 15 Olomouc Czech Republic

Faculty of Medicine and Dentistry Institute of Molecular and Translational Medicine Palacky University and University Hospital in Olomouc Hněvotínská 5 CZ 775 15 Olomouc Czech Republic Cancer Research Czech Republic Hněvotínská 5 CZ 775 15 Olomouc Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nam 2 CZ 16610 Prague 6 Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nam 2 CZ 16610 Prague 6 Czech Republic Department of Organic Chemistry Faculty of Science Charles University Prague Hlavova 8 CZ 12843 Prague 2 Czech Republic

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