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Biphenyl Sulfonylamino Methyl Bisphosphonic Acids as Inhibitors of Matrix Metalloproteinases and Bone Resorption
Author(s) -
Rubino Maria Teresa,
Agamen Mariangela,
Campestre Cristina,
Campiglia Pietro,
Cremasco Viviana,
Faccio Roberta,
Laghezza Antonio,
Loiodice Fulvio,
Maggi Dariana,
Panza Emilia,
Rossello Armando,
Tortorella Paolo
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000540
Subject(s) - bisphosphonate , matrix metalloproteinase , bone resorption , osteoclast , diphosphonates , chemistry , bone remodeling , in vitro , matrix metalloproteinase inhibitor , bone metastasis , pharmacology , biochemistry , cancer research , osteoporosis , metastasis , medicine , cancer
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.