Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5232-6. doi: 10.1016/j.bmcl.2015.09.062. Epub 2015 Sep 26.

Abstract

Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1.79Å resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further structurally modified to identify promising lead structures of novel GCPII inhibitors.

Keywords: Carborane; Glutamate carboxypeptidase II; X-ray crystal structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Boron Compounds / chemical synthesis*
  • Boron Compounds / chemistry
  • Boron Compounds / pharmacology
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Glutamate Carboxypeptidase II / ultrastructure
  • Humans
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / chemistry
  • Urea / pharmacology

Substances

  • Boron Compounds
  • Enzyme Inhibitors
  • Urea
  • Glutamate Carboxypeptidase II