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. Epub 2018 Oct 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Furans / chemistry*
  • Humans
  • Purines / chemistry*
  • Pyrroles / chemistry*
  • Ribonucleosides / chemical synthesis*
  • Ribonucleosides / chemistry
  • Ribonucleosides / pharmacology*
  • Structure-Activity Relationship

Substances

  • 7-deazapurine
  • Antineoplastic Agents
  • Antiviral Agents
  • Furans
  • Purines
  • Pyrroles
  • Ribonucleosides
  • furan