Synthesis, antiretrovirus effects, and phosphorylation kinetics of 3'-isocyano-3'-deoxythymidine and 3'-isocyano-2',3'-dideoxyuridine

J Med Chem. 1990 Feb;33(2):845-8. doi: 10.1021/jm00164a059.

Abstract

The silylated AzddThd 5 and AzddUrd 6 prepared from 2,3'-anhydronucleoside derivatives 3 and 4 were transformed to formamides 7 and 8 by using the sequence RN3----RN = P(C6H5)----RNHCHO. Formamides 7 and 8 were dehydrated to the protected 3'-isocyano derivatives 9 and 10; deblocking gave 11 and 12. Neither 3'-isocyano-3'-deoxythymidine (11) nor 3'-isocyano-2',3'-dideoxyuridine (12) showed anti-HIV activity at noncytotoxic concentrations. ddThd derivative 11 was considerably more toxic to MT-4 cells than ddUrd derivative 12; it also had a much greater affinity (Ki) for MT-4 cell dThd kinase than ddUrd derivative 12. Both compounds appear to be linear mixed-type inhibitors of MT-4 cell dThd kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites / chemical synthesis
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / metabolism
  • Cell Survival / drug effects
  • Chemical Phenomena
  • Chemistry
  • Dideoxynucleosides / chemical synthesis*
  • Dideoxynucleosides / metabolism
  • Dideoxynucleosides / pharmacology
  • HIV / drug effects*
  • Kinetics
  • Phosphorylation
  • Thymidine / analogs & derivatives*
  • Thymidine / chemical synthesis
  • Thymidine / metabolism
  • Thymidine / pharmacology
  • Thymidine Kinase / antagonists & inhibitors*
  • Virus Replication / drug effects

Substances

  • Antimetabolites
  • Antiviral Agents
  • Dideoxynucleosides
  • 3'-isocyano-3'-deoxythymidine
  • 3'-isocyano-2',3'-dideoxyuridine
  • Thymidine Kinase
  • Thymidine