Synthesis and antiviral evaluation of 6-(alkyl-heteroaryl)furo[2,3-d]pyrimidin-2(3H)-one nucleosides and analogues with ethynyl, ethenyl, and ethyl spacers at C6 of the furopyrimidine core

J Med Chem. 2007 Aug 9;50(16):3897-905. doi: 10.1021/jm070210n. Epub 2007 Jul 10.

Abstract

Sonogashira coupling strategies were employed to synthesize new furo[2,3-d]pyrimidin-2(3H)-one (FuPyrm) 2'-deoxynucleoside analogues. Partial or complete reduction of ethyne-linked compounds afforded ethenyl- and ethyl-linked derivatives. Levels of inhibition of varicella-zoster virus (VZV), human cytomegalovirus (HCMV), a broad range of other DNA and RNA viruses, and several cancer cell lines were evaluated in cell cultures. The anti-VZV potency decreased with increasing rigidity of the side chain at C6 of the FuPyrm ring in the order dec-1-yn-1-yl < dec-1-en-1-yl < decan-1-yl. In contrast, compounds with a rigid ethynyl spacer between C6 of the FuPyrm ring and a 4-alkylphenyl moiety were more potent inhibitors of VZV than the corresponding derivatives with an ethyl spacer. Replacement of the phenyl moiety in 6-(4-alkylphenyl) derivatives with a pyridine ring (in either regioisomeric orientation) gave analogues with increased solubility in methanol but reduced anti-VZV potency, and replacement with a pyrimidine ring reduced the anti-VZV activity even further. The pyridine-ring-containing analogues were approximately 20-fold more potent inhibitors of VZV than acyclovir but were approximately 6-fold less potent than BVDU and approximately 60-fold weaker than the most active 6-(4-pentylphenyl)-substituted prototype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemical synthesis
  • Alkenes / chemistry
  • Alkenes / pharmacology
  • Alkynes / chemical synthesis
  • Alkynes / chemistry
  • Alkynes / pharmacology
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • Cytomegalovirus / drug effects
  • Cytomegalovirus / genetics
  • DNA Viruses / drug effects
  • Furans / chemical synthesis*
  • Furans / chemistry
  • Furans / pharmacology
  • Herpesvirus 3, Human / drug effects
  • Herpesvirus 3, Human / genetics
  • Humans
  • Molecular Structure
  • Pyrimidine Nucleosides / chemical synthesis*
  • Pyrimidine Nucleosides / chemistry
  • Pyrimidine Nucleosides / pharmacology
  • RNA Viruses / drug effects
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thymidine Kinase / genetics

Substances

  • Alkenes
  • Alkynes
  • Antineoplastic Agents
  • Antiviral Agents
  • Furans
  • Pyrimidine Nucleosides
  • Thymidine Kinase