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

A no. of matrix metalloproteinases (MMPs), proteins important in the balance of bone remodeling, play a crit. role both in cancer metastasis and in bone matrix turnover assocd. with the presence of cancer cells in bone. Here, we report the synthesis and biol. 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 biol. apatite, the new mols. can be regarded as bone-seeking medicinal agents. Docking expts. 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.