Adenosine analogs bearing phosphate isosteres as human MDO1 ligands

Bioorg Med Chem. 2018 May 1;26(8):1588-1597. doi: 10.1016/j.bmc.2018.02.006. Epub 2018 Feb 13.


The human O-acetyl-ADP-ribose deacetylase MDO1 is a mono-ADP-ribosylhydrolase involved in the reversal of post-translational modifications. Until now MDO1 has been poorly characterized, partly since no ligand is known besides adenosine nucleotides. Here, we synthesized thirteen compounds retaining the adenosine moiety and bearing bioisosteric replacements of the phosphate at the ribose 5'-oxygen. These compounds are composed of either a squaryldiamide or an amide group as the bioisosteric replacement and/or as a linker. To these groups a variety of substituents were attached such as phenyl, benzyl, pyridyl, carboxyl, hydroxy and tetrazolyl. Biochemical evaluation showed that two compounds, one from both series, inhibited ADP-ribosyl hydrolysis mediated by MDO1 in high concentrations.

Keywords: Adenosine analogs; Adenosine diphosphate ribose; Human macrodomain-containing protein 1; MDO1; Macrodomain; Mono-ADP-ribosylhydrolase; Phosphate isosteres.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / chemical synthesis
  • Adenosine / chemistry
  • Adenosine / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • N-Glycosyl Hydrolases / antagonists & inhibitors*
  • N-Glycosyl Hydrolases / metabolism
  • Phosphates / chemistry
  • Phosphates / pharmacology*
  • Protein Processing, Post-Translational / drug effects
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Phosphates
  • N-Glycosyl Hydrolases
  • ADP-ribosylarginine hydrolase
  • Adenosine