Dual carbonic anhydrase/matrix metalloproteinase inhibitors incorporating bisphosphonic acid moieties targeting bone tumors

Bioorg Med Chem Lett. 2014 Jun 15;24(12):2617-20. doi: 10.1016/j.bmcl.2014.04.077. Epub 2014 Apr 30.

Abstract

A set of bisphosphonate matrix metalloproteinase (MMP) inhibitors was investigated for inhibitory activity against several carbonic anhydrase (CA, EC 4.2.1.1) isozymes, some of which are overexpressed in hypoxic tumors. Some of the bisphosphonate revealed to be very potent inhibitors (in the low nanomolar range) of the cytosolic isoform CA II and the membrane-bound CA IX, XII and XIV isozymes, a feature useful for considering them as interesting compounds for bone resorption inhibition applications. We suggest here that it is possible to develop dual enzyme inhibitors bearing bisphosphonate moieties that may target both MMPs and CAs, two families of enzymes involved in tumor formation, growth, and metastasis.

Keywords: Bisphosphonate; Bone resorption inhibitor; Carbonic anhydrase; Enzyme inhibitor; Matrix metalloproteinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / enzymology*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrase Inhibitors / therapeutic use
  • Cell Line
  • Diphosphonates / pharmacology*
  • Diphosphonates / therapeutic use
  • Enzyme Activation / drug effects
  • Humans
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Inhibitory Concentration 50
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Matrix Metalloproteinase Inhibitors / therapeutic use
  • Molecular Structure
  • Zoledronic Acid

Substances

  • Carbonic Anhydrase Inhibitors
  • Diphosphonates
  • Imidazoles
  • Matrix Metalloproteinase Inhibitors
  • Zoledronic Acid