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

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.