Beta-aminoketones as prodrugs for selective irreversible inhibitors of type-1 methionine aminopeptidases

Bioorg Med Chem Lett. 2014 Nov 15;24(22):5310-4. doi: 10.1016/j.bmcl.2014.09.047. Epub 2014 Sep 23.

Abstract

We identified and characterized β-aminoketones as prodrugs for irreversible MetAP inhibitors that are selective for the MetAP-1 subtype. β-Aminoketones with certain structural features form α,β-unsaturated ketones under physiological conditions, which bind covalently and selectively to cysteines in the S1 pocket of MetAP-1. The binding mode was confirmed by X-ray crystallography and assays with the MetAPs from Escherichia coli, Staphylococcus aureus and both human isoforms. The initially identified tetralone derivatives showed complete selectivity for E. coli MetAP versus human MetAP-1 and MetAP-2. Rational design of indanone analogs yielded compounds with selectivity for the human type-1 versus the human type-2 MetAP.

Keywords: Beta-aminoketone; Enzyme inhibition; Irreversible inhibitors; Methionine aminopeptidase; Prodrug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / antagonists & inhibitors*
  • Aminopeptidases / metabolism
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Escherichia coli / enzymology
  • Glycoproteins / antagonists & inhibitors
  • Glycoproteins / metabolism
  • Humans
  • Ketones / chemistry*
  • Ketones / metabolism
  • Methionyl Aminopeptidases
  • Molecular Docking Simulation
  • Prodrugs / chemistry*
  • Prodrugs / metabolism
  • Protein Structure, Tertiary
  • Staphylococcus aureus / enzymology
  • Structure-Activity Relationship

Substances

  • Bacterial Proteins
  • Enzyme Inhibitors
  • Glycoproteins
  • Ketones
  • Prodrugs
  • Aminopeptidases
  • METAP1 protein, human
  • METAP2 protein, human
  • Methionyl Aminopeptidases