Synthesis of {[5-(adenin-9-yl)-2-furyl]methoxy}methyl phosphonic acid and evaluations against human adenylate kinases

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4227-30. doi: 10.1016/j.bmcl.2014.07.036. Epub 2014 Jul 17.

Abstract

AMP mimics constitute an important class of therapeutic derivatives to treat diseases where the pool of ATP is involved. A new phosphonate derivative of 9-(5-hydroxymethylfuran-2-yl)adenine was synthesized in a multi-step sequence from commercially available adenosine. Its ability to behave as a substrate of human adenylate kinases 1 and 2 was assessed. The phosphonate was shown to be a moderate but selective substrate of the mitochondrial human AK2, better than well-known antiviral acyclic phosphonates 9-(2-phosphonomethoxyethyl)adenine (PMEA, Adefovir) and (R)-9-(2-phosphonomethoxypropyl)adenine (PMPA, Tenofovir). Putative binding mode within adenylate kinase NMP site revealed by molecular docking in comparison to AMP native substrate allowed to illustrate this selective behavior.

Keywords: Adenosine; Analogue/AMP mimics; Kinase; Nucleoside; Phosphonate; Phosphotransfer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemical synthesis
  • Adenine / chemistry
  • Adenine / pharmacology
  • Adenylate Kinase / antagonists & inhibitors*
  • Adenylate Kinase / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology*
  • Structure-Activity Relationship

Substances

  • ((5-(adenin-9-yl)-2-furyl)methoxy)methyl phosphonic acid
  • Organophosphonates
  • Adenylate Kinase
  • adenylate kinase 1
  • adenylate kinase 2
  • Adenine