Novel β-dicarbonyl derivatives as inhibitors of aminopeptidase N (APN)

Bioorg Med Chem Lett. 2013 Sep 1;23(17):4948-52. doi: 10.1016/j.bmcl.2013.06.058. Epub 2013 Jun 28.

Abstract

Most zinc metalloproteases are over-expressed in tumor cells and play a critical role in the genesis, development, and metastasis of tumors. Novel zinc binding groups (ZBGs) represent a novel strategy to obtain optimal potency and selectivity for zinc metalloproteases inhibitors. Here we described the design, synthesis, and biological studies of novel β-dicarbonyl derivatives as aminopeptidase N (APN/CD13) inhibitors. The results demonstrated that some compounds exhibited moderate to good inhibitory activities against APN with compound 5c being the most potent, suggesting that 5c could serve as new lead for the future APN inhibitor development. The results further confirm our design rationale of β-dicarbonyl moiety as a new ZBG, which may provide a new direction for the design and discovery of zinc metalloproteases inhibitors as new anti-tumor agents.

Keywords: Aminopeptidase N; Anti-tumor; Inhibitor; Zinc binding group; β-Dicarbonyl.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD13 Antigens / antagonists & inhibitors*
  • CD13 Antigens / metabolism
  • Humans
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Zinc / metabolism

Substances

  • Protease Inhibitors
  • CD13 Antigens
  • Zinc