Phosphodiester amidates of unsaturated nucleoside analogues: synthesis and anti-HIV activity

J Med Chem. 1997 Jul 4;40(14):2191-5. doi: 10.1021/jm970069q.

Abstract

The effect of introduction of a lipophilic phosphodiester amidate moiety on the HIV activity of inactive unsaturated nucleoside analogues was investigated. Phosphodiester alaninates 5a, 5b, and 6 derived from unsaturated nucleoside analogues 3b, 3c, and 4a were synthesized and investigated as inhibitors of cytopathic effect and replication of HIV-1 in ATH-8 cells. Compound 5a is an inhibitor of HIV-1 whereas analogue 6 is inactive with cytotoxicity appearing above 10 microM and 5b is both inactive and nontoxic. Alkaline or enzymic hydrolysis of 5a gave phosphomonoester alaninate 14, a putative product of intracellular metabolism. Compound 14 as well as adenallene derivative 15c were devoid of anti-HIV activity, and they also failed to inhibit HIV reverse transcriptase. A new regioselective method for preparation of (Z)-4-(benzoyloxy)-1-hydroxy-2-butene, 7, a key intermediate for the synthesis of unsaturated nucleoside analogues of cis configuration such as 3a, 3b, and 3c, is also described.

Publication types

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

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Esterases / metabolism
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • HIV-1 / pathogenicity
  • HIV-1 / physiology
  • Humans
  • Liver / enzymology
  • Molecular Structure
  • Nucleosides / chemical synthesis*
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / pharmacology
  • Purines / chemical synthesis*
  • Purines / chemistry
  • Purines / pharmacology
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Structure-Activity Relationship
  • Swine
  • Virus Replication / drug effects*

Substances

  • Anti-HIV Agents
  • Nucleosides
  • Organophosphorus Compounds
  • Purines
  • Pyrimidinones
  • HIV Reverse Transcriptase
  • Esterases