An aza-nucleoside, fragment-like inhibitor of the DNA repair enzyme alkyladenine glycosylase (AAG)

Bioorg Med Chem. 2020 Jun 1;28(11):115507. doi: 10.1016/j.bmc.2020.115507. Epub 2020 Apr 15.

Abstract

The DNA repair enzyme AAG has been shown in mice to promote tissue necrosis in response to ischaemic reperfusion or treatment with alkylating agents. A chemical probe inhibitor is required for investigations of the biological mechanism causing this phenomenon and as a lead for drugs that are potentially protective against tissue damage from organ failure and transplantation, and alkylative chemotherapy. Herein, we describe the rationale behind the choice of arylmethylpyrrolidines as appropriate aza-nucleoside mimics for an inhibitor followed by their synthesis and the first use of a microplate-based assay for quantification of their inhibition of AAG. We finally report the discovery of an imidazol-4-ylmethylpyrrolidine as a fragment-sized, weak inhibitor of AAG.

Keywords: Alkyladenine DNA glycosylase (AAG); Aza-nucleoside; Base excision DNA repair; Ischaemic reperfusion; Methylpurine DNA glycosylase (MPG); Small molecule inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / chemical synthesis
  • Alkylating Agents / chemistry
  • Alkylating Agents / pharmacology*
  • Animals
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Crystallography, X-Ray
  • DNA Glycosylases / antagonists & inhibitors*
  • DNA Glycosylases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry
  • Nucleosides / pharmacology*
  • Structure-Activity Relationship

Substances

  • Alkylating Agents
  • Aza Compounds
  • Enzyme Inhibitors
  • Nucleosides
  • 3-methyladenine-DNA glycosylase
  • DNA Glycosylases