Deoxyribonucleoside 2'- or 3'-mixed disulfides: prodrugs to target ribonucleotide reductase and/or to inhibit HIV reverse transcription

J Med Chem. 2003 Jun 19;46(13):2565-8. doi: 10.1021/jm0256225.

Abstract

Herein, we report the design, synthesis, and biological effects of nucleosides bearing a disulfide function on the sugar ring as prodrugs of potentially active mercaptonucleotides that can target ribonucleotide reductase or reverse transcriptase. We show that cytidine derivatives efficiently reduce dNTP pools in human CEM/SS cells and that 3'-deoxythymidin-3'-yl methyl disulfide is able to interfere with both cellular dNTP synthesis and HIV reverse transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Cell Division / drug effects
  • Cells, Cultured
  • Deoxyribonucleosides / chemical synthesis*
  • Deoxyribonucleosides / chemistry
  • Deoxyribonucleosides / pharmacology
  • Disulfides / chemical synthesis*
  • Disulfides / chemistry
  • Disulfides / pharmacology
  • HIV-1 / drug effects
  • HIV-2 / drug effects
  • Humans
  • Mice
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Ribonucleotide Reductases / antagonists & inhibitors*
  • Stavudine / analogs & derivatives
  • Stavudine / chemical synthesis*
  • Stavudine / chemistry
  • Stavudine / pharmacology
  • Structure-Activity Relationship
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects

Substances

  • 3'-deoxythymidin-3'-yl methyl disulfide
  • Anti-HIV Agents
  • Deoxyribonucleosides
  • Disulfides
  • Prodrugs
  • Reverse Transcriptase Inhibitors
  • Stavudine
  • Ribonucleotide Reductases