Synthesis of amino-hydroxy-benzocycloheptenones as potent, selective, non-peptidic dinuclear zinc metalloaminopeptidase inhibitors

Bioorg Med Chem. 2013 Nov 1;21(21):6447-55. doi: 10.1016/j.bmc.2013.08.044. Epub 2013 Sep 4.

Abstract

Racemic trisubstituted benzocycloheptanes were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. A highly selective nanomolar inhibitor of a prototypical 'two zinc' aminopeptidase from the M28 family was observed with these tridentate species, while bidentate analogs proved to be highly selective for the 'one zinc' M1 family of enzymes. The selectivity profile of these new, low molecular weight structures may guide the design of specific, non-peptidic inhibitors of binuclear aminopeptidases.

Keywords: M1 aminopeptidases; M28 aminopeptidases; Racemic trisubstituted benzocycloheptane derivatives; Selective inhibition; Synthetic inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aeromonas / enzymology
  • Aminopeptidases / antagonists & inhibitors*
  • Aminopeptidases / metabolism
  • Benzocycloheptenes / chemical synthesis
  • Benzocycloheptenes / chemistry*
  • Benzocycloheptenes / metabolism
  • Binding Sites
  • Catalytic Domain
  • Escherichia coli / enzymology
  • Molecular Docking Simulation
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / metabolism
  • Protein Binding
  • Structure-Activity Relationship
  • Zinc / chemistry

Substances

  • Benzocycloheptenes
  • Protease Inhibitors
  • Aminopeptidases
  • Zinc