Biphenyl Sulfonylamino Methyl Bisphosphonic Acids as Inhibitors of Matrix Metalloproteinases and Bone Resorption

Maria Teresa Rubino, Mariangela Agamennone, Cristina Campestre, Pietro Campiglia, Viviana Cremasco, Roberta Faccio, Antonio Laghezza, Fulvio Loiodice, Dariana Maggi, Emilia Panza, Armando Rossello, Paolo Tortorella

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44 Scopus citations


A number of matrix metalloproteinases (MMPs), proteins important in the balance of bone remodeling, play a critical role both in cancer metastasis and in bone matrix turnover associated with the presence of cancer cells in bone. Here, we report the synthesis and biological evaluation of a new class of MMP inhibitors characterized by a bisphosphonate function as the zinc binding group. Since the bisphosphonate group is also implicated in osteoclast inhibition and provides a preferential affinity to biological apatite, the new molecules can be regarded as bone-seeking medicinal agents. Docking experiments were performed to clarify the mode of binding of bisphosphonate inhibitors in the active site of MMP-2. The most promising of the studied bisphosphonates showed nanomolar inhibition against MMP-2 and resulted in potent inhibition of osteoclastic bone resorption in vitro. Bone resorption inhibition: A series of biphenyl sulfonylamino methyl bisphosphonic acids were synthesized and tested both as matrix metalloproteinase (MMP) and bone resorption inhibitors. The most promising compound (15) showed nanomolar activity against MMP-2 and good selectivity over MMP-8, -9, and -14; furthermore, it showed a very good antiresorptive activity comparable with that of zolendronic acid.

Original languageEnglish
Pages (from-to)1258-1268
Number of pages11
Issue number7
StatePublished - Jul 2011


  • Bisphosphonates
  • Inhibitors
  • Matrix metalloproteinases
  • Metalloproteins
  • Zinc binding groups


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