Journal
CHEMMEDCHEM
Volume 6, Issue 7, Pages 1258-1268Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201000540
Keywords
bisphosphonates; inhibitors; matrix metalloproteinases; metalloproteins; zinc binding groups
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Funding
- Ministero dell' Istruzione, dell'Universite della Ricerca (MIUR) [JERJPC_003]
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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.
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