Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry

Bioorg Med Chem. 2018 Jul 23;26(12):3145-3157. doi: 10.1016/j.bmc.2018.04.041. Epub 2018 Apr 22.

Abstract

The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC50 = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.

Keywords: Aminopeptidase N; Anti-angiogenesis; Anti-metastasis; CD13; Triazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • CD13 Antigens / antagonists & inhibitors*
  • CD13 Antigens / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Click Chemistry
  • Disease Models, Animal
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Leucine / analogs & derivatives*
  • Leucine / pharmacology
  • Leucine / therapeutic use
  • Liver Neoplasms / pathology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / secondary
  • Mice
  • Molecular Docking Simulation
  • Neovascularization, Physiologic / drug effects
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Protease Inhibitors
  • CD13 Antigens
  • Leucine
  • ubenimex