2. Academic Validation
  3. Synthesis and Cytotoxic and Antiviral Profiling of Pyrrolo- and Furo-Fused 7-Deazapurine Ribonucleosides

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

  • J Med Chem. 2018 Oct 25;61(20):9347-9359. doi: 10.1021/acs.jmedchem.8b01258.
Anna Tokarenko 1 2,  Barbora Lišková 3,  Sabina Smoleń 1,  Natálie Táborská 3,  Michal Tichý 1,  Soňa Gurská 3,  Pavla Perlíková 1,  Ivo Frydrych 3,  Eva Tloušt'ová 1,  Pawel Znojek 3,  Helena Mertlíková-Kaiserová 1,  Lenka Poštová Slavětínská 1,  Radek Pohl 1,  Blanka Klepetářová 1,  Noor-Ul-Ain Khalid 4,  Yiqian Wenren 4,  Rebecca R Laposa 4,  Petr Džubák 3 5,  Marián Hajdúch 3 5,  Michal Hocek 1 2
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry , Czech Academy of Sciences , Flemingovo nam. 2 , CZ-16610 Prague 6 , Czech Republic.
  • 2 Department of Organic Chemistry, Faculty of Science , Charles University in Prague , Hlavova 8 , CZ-12843 Prague 2 , Czech Republic.
  • 3 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.
  • 4 Department of Pharmacology and Toxicology , University of Toronto , 1 King's College Circle, Room 4213 , Toronto , Ontario M5S 1A8 , Canada.
  • 5 Cancer Research Czech Republic , Hněvotínská 5 , CZ-775 15 Olomouc , Czech Republic.
PMID: 30281308 DOI: 10.1021/acs.jmedchem.8b01258
Abstract

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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