Substrate/inhibition studies of bacteriophage T7 RNA polymerase with the 5'-triphosphate derivative of a ring-expanded ('fat') nucleoside possessing potent antiviral and anticancer activities

Bioorg Med Chem. 1999 Dec;7(12):2931-6. doi: 10.1016/s0968-0896(99)00235-7.

Abstract

As part of an effort to explore the mechanism of potent, broad spectrum antiviral and anticancer activities of a number of ring-expanded ('fat') nucleosides that we recently reported, a representative 'fat' nucleoside 4,6-diamino-8-imino-8H-1-beta-D-ribofuranosylimidazo[4,5-e][1,3]di azepine (1) was converted to its 5'-triphosphate derivative (2), and biochemically screened for possible inhibition of nucleic acid polymerase activity, employing synthetic DNA templates and the bacteriophage T7 RNA polymerase as a representative polymerase. Our results suggest that 2 is a moderate inhibitor of T7 RNA polymerase, and that the 5'-triphosphate moiety of 2 appears to be essential for inhibition as nucleoside 1 alone failed to inhibit the polymerase reaction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Base Sequence
  • DNA / genetics
  • DNA-Directed RNA Polymerases / antagonists & inhibitors*
  • DNA-Directed RNA Polymerases / metabolism
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Nucleotides / chemical synthesis
  • Nucleotides / chemistry
  • Nucleotides / pharmacology*
  • Structure-Activity Relationship
  • Transcription, Genetic / drug effects
  • Viral Proteins

Substances

  • 4,6-diamino-8-imino--8H-1-ribofuranosylimidazo(4,5-e)(1,3)diazepine-5'-phosphate
  • 4,6-diamino-8-imino-8H-1-ribofuranosylimidazo(4,5-e)(1,3)diazepine
  • Antineoplastic Agents
  • Antiviral Agents
  • Azepines
  • Enzyme Inhibitors
  • Nucleosides
  • Nucleotides
  • Viral Proteins
  • DNA
  • bacteriophage T7 RNA polymerase
  • DNA-Directed RNA Polymerases