Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors.
The complexity of matrix metalloproteinase inhibitors (MMPIs) design derives from the difficulty in carefully addressing their inhibitory activity towards the MMP isoforms involved in many pathological conditions. In particular, specific metalloproteinases, such as MMP-2 and MMP-9, are key regulators of the 'vicious cycle' occurring between tumor metastases growth and bone remodeling. In an attempt to devise new approaches to selective inhibitor derivatives, we describe novel bisphosphonate bone seeking MMP inhibitors (BP-MMPIs), capable to be selectively targeted and to overcome undesired side effects of broad spectrum MMPIs. In vitro activity (IC50 values) for each inhibitor was determined against MMP-2, -8, -9 and -14, because of their relevant role in skeletal development and renewal. The results show that BP-MMPIs reached IC50 values of enzymatic inhibition in the low micromolar range. Computational studies, used to rationalize some trends in the observed inhibitory profiles, suggest a possible differential binding mode in MMP-2 that explains the selective inhibition of this isoform. In addition, survival assay was conducted on J774 cell line, a well known model system used to evaluate the structure-activity relationship of BPs for inhibiting bone resorption. The resulting data, confirming the specific activity of BP-MMPIs, and their additional proved propensity to bind hydroxyapatite powder in vitro, suggest a potential use of BP-MMPIs in skeletal malignancies.
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi 'Aldo Moro' di Bari, Via Orabona 4, 70126 Bari, Italy.
Marilena
M
Tauro
Antonio
A
Laghezza
Fulvio
F
Loiodice
Mariangela
M
Agamennone
Cristina
C
Campestre
Paolo
P
Tortorella
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D017886:Durapatite / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D004164:Diphosphonates; D061965:Matrix Metalloproteinase Inhibitors; D017886:Durapatite; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14
Bisphosphonates; Bone targeting; Matrix metalloproteinase inhibitors; Zinc binding group