Modular assembly of purine-like bisphosphonates as inhibitors of HIV-1 reverse transcriptase

J Med Chem. 2014 Sep 11;57(17):7435-49. doi: 10.1021/jm501010f. Epub 2014 Aug 29.

Abstract

Bisphosphonates can mimic the pyrophosphate leaving group of the nucleotidyl transfer reaction and effectively inhibit RNA/DNA polymerases. In a search of HIV-1 reverse transcriptase (RT) inhibitors, a new chemotype of nonhydrolyzable purine diphosphate mimic was synthesized. A modular synthetic protocol was developed, utilizing 2-amino-6-(methylthio)-4-(trimethylsilyl)nicotinonitrile as the key synthon in the preparation of highly substituted 2-aminonicotinonitriles. These building blocks were subsequently elaborated to the pyrido[2,3-d]pyrimidine bisphosphonates (PYPY-BPs). Biochemical screening identified analogs of PYPY-BPs that inhibit HIV-1 RT-catalyzed DNA synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diphosphonates / chemical synthesis
  • Diphosphonates / chemistry
  • Diphosphonates / pharmacology*
  • Dose-Response Relationship, Drug
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • Models, Chemical
  • Molecular Structure
  • Mutation
  • Purines / chemistry
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Diphosphonates
  • Purines
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • purine