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

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journal contribution
posted on 03.10.2018, 00:00 by Anna Tokarenko, Barbora Lišková, Sabina Smoleń, Natálie Táborská, Michal Tichý, Soňa Gurská, Pavla Perlíková, Ivo Frydrych, Eva Tloušt’ová, Pawel Znojek, Helena Mertlíková-Kaiserová, Lenka Poštová Slavětínská, Radek Pohl, Blanka Klepetářová, Noor-Ul-Ain Khalid, Yiqian Wenren, Rebecca R. Laposa, Petr Džubák, Marián Hajdúch, Michal Hocek
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.

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