Synthesis and Cytotoxic and Antiviral Profiling of Pyrrolo- and Furo-Fused 7‑Deazapurine Ribonucleosides

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.