N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity

J Med Chem. 2015 Sep 24;58(18):7224-40. doi: 10.1021/acs.jmedchem.5b00367. Epub 2015 Aug 28.

Abstract

Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9, and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to the previously discovered compound 1. A new series of hydroxamates was designed, synthesized, and tested for their antiangiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9, and MMP-14 inhibitor was identified, compound 3, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound 3 in order to investigate its binding mode to MMP-9 and MMP-14.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry*
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / physiology
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry*
  • Hydroxamic Acids / pharmacology
  • Matrix Metalloproteinase 14 / chemistry
  • Matrix Metalloproteinase 14 / metabolism
  • Matrix Metalloproteinase 2 / chemistry
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / chemistry
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / chemistry*
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Mice
  • Molecular Docking Simulation
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology

Substances

  • Angiogenesis Inhibitors
  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Sulfonamides
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 14

Associated data

  • PDB/4WZV
  • PDB/4XCT