cycloSal-PMEA and cycloAmb-PMEA: potentially new phosphonate prodrugs based on the cycloSal-pronucleotide approach

J Med Chem. 2005 Dec 15;48(25):8079-86. doi: 10.1021/jm050641a.

Abstract

Two new classes of lipophilic prodrugs of the antiviral active phosphonate 9-[2-phosphonomethoxyethyl]adenine (PMEA 1) have been prepared and were studied with regard to their hydrolysis properties and biological activity. A first series of compounds was prepared on the basis of the cycloSal nucleotide approach. Because of the surprisingly low hydrolysis stability of these cycloSal-PMEA derivatives, more stable derivatives have to be developed. Instead of using salicyl alcohol, in cycloAmb-PMEA derivatives 2-aminobenzyl alcohols were attached to PMEA 1. The latter compounds showed a considerably higher stability compared to the cycloSal counterparts. Stability studies revealed that all lipophilic prodrugs delivered PMEA selectively by chemical means. All compounds proved to be noninhibiting to acetyl- and butyrylcholinesterase, and some of the phosphonate diesters were found to be more active against HIV compared to the parent PMEA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Adenine / analogs & derivatives*
  • Adenine / chemical synthesis
  • Adenine / chemistry
  • Adenine / pharmacology
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Benzyl Alcohols / chemistry*
  • Butyrylcholinesterase / chemistry
  • Cell Line
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-2 / drug effects
  • Humans
  • Hydrolysis
  • Magnetic Resonance Spectroscopy
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Spectrophotometry, Ultraviolet
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Benzyl Alcohols
  • Cholinesterase Inhibitors
  • Organophosphonates
  • Prodrugs
  • 2-aminobenzyl alcohol
  • adefovir
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • salicyl alcohol
  • Adenine