title: Biphenyl sulfonylamino methyl bisphosphonic acids as inhibitors of matrix metalloproteinases and bone resorption.
abstract: 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.
authors.affiliation: Dipartimento Farmaco-Chimico, Università degli Studi Aldo Moro, Via Orabona 4, 70126 Bari, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Rubino
authors.forename: Mariangela
authors.initials: M
authors.lastname: Agamennone
authors.forename: Cristina
authors.initials: C
authors.lastname: Campestre
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.forename: Viviana
authors.initials: V
authors.lastname: Cremasco
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
authors.forename: Dariana
authors.initials: D
authors.lastname: Maggi
authors.forename: Emilia
authors.initials: E
authors.lastname: Panza
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
mesh_terms: D001665:Binding Sites; D050071:Bone Density Conservation Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004164:Diphosphonates / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2