Nucleotide Analogues Bearing a C2' or C3'-Stereogenic All-Carbon Quaternary Center as SARS-CoV-2 RdRp Inhibitors

Molecules. 2022 Jan 17;27(2):564. doi: 10.3390/molecules27020564.

Abstract

The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2' or C3' is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2' was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.

Keywords: COVID-19; RdRp; SARS-CoV-2; epoxidation; glycosylation; nucleoside analogues; quaternary stereocenter; triphosphorylation.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Carbon / chemistry*
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Nucleotides / chemical synthesis
  • Nucleotides / chemistry
  • Nucleotides / pharmacology*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / enzymology*
  • Stereoisomerism

Substances

  • Antiviral Agents
  • Heterocyclic Compounds, 4 or More Rings
  • Nucleotides
  • Carbon
  • RNA-Dependent RNA Polymerase