α-Biphenylsulfonylamino 2-methylpropyl phosphonates: Enantioselective synthesis and selective inhibition of MMPs

Biasone, Alessandro; Tortorella, Paolo; Campestre, Cristina; Agamennone, Mariangela; Preziuso, Serena; Chiappini, M.; Nuti, Elisa; Carelli, Paolo; Rossello, Armando; Mazza, F.; Gallina, Carlo

doi:10.1016/j.bmc.2006.10.047

Cited by 38 publications

(24 citation statements)

References 26 publications

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“…MMP and ADAM Inhibition Assays-MMP inhibition assays have been previously described (36). Recombinant ADAM-10 and ADAM-17 were purchased from R&D Systems.…”

Section: Histological Analysis and Immunofluorescence-wild-type And Mmentioning

confidence: 99%

Collagenase-2 Deficiency or Inhibition Impairs Experimental Autoimmune Encephalomyelitis in Mice

Folgueras¹,

Fueyo

García‐Suárez

et al. 2008

Journal of Biological Chemistry

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Matrix metalloproteinases (MMPs) have been implicated in a variety of human diseases, including neuroimmunological disorders such as multiple sclerosis. However, the recent finding that some MMPs play paradoxical protective roles in these diseases has made necessary the detailed study of the specific function of each family member in their pathogenesis. To determine the relevance of collagenase-2 (MMP-8) in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, we have performed two different analyses involving genetic and biochemical approaches. First, we have analyzed the development of EAE in mutant mouse deficient in MMP-8, with the finding that the absence of this proteolytic enzyme is associated with a marked reduction in the clinical symptoms of EAE. We have also found that MMP-8 ؊/؊ mice exhibit a marked reduction in central nervous system-infiltrating cells and demyelinating lesions. As a second approach, we have carried out a pharmacological inhibition of MMP-8 with a selective inhibitor against this protease (IC 50 ‫؍‬ 0.4 nM). These studies have revealed that the administration of the MMP-8 selective inhibitor to mice with EAE also reduces the severity of the disease. Based on these findings, we conclude that MMP-8 plays an important role in EAE development and propose that this enzyme may be a novel therapeutic target in human neuro-inflammatory diseases such as multiple sclerosis.

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“…MMP and ADAM Inhibition Assays-MMP inhibition assays have been previously described (36). Recombinant ADAM-10 and ADAM-17 were purchased from R&D Systems.…”

Section: Histological Analysis and Immunofluorescence-wild-type And Mmentioning

confidence: 99%

Collagenase-2 Deficiency or Inhibition Impairs Experimental Autoimmune Encephalomyelitis in Mice

Folgueras¹,

Fueyo

García‐Suárez

et al. 2008

Journal of Biological Chemistry

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“…an MMP8-specific inhibitor (Biasone et al, 2007) completely prevented LPS-induced death in MMP8 ϩ/ϩ mice (Fig. 1e,f ).…”

Section: Mmp8 Inhibition Protects Against Systemic Inflammationmentioning

confidence: 78%

“…Mice were injected intraperitoneally with 17.5 mg/kg body weight lipopolysaccharide (LPS) from Salmonella enterica serotype abortus equi (Sigma), an LD 100 dose for wild-type C57BL/6 mice. BB-94 (British Biotech), dissolved in PBS containing 0.01% Tween 20 and MMP8-specific inhibitor (Biasone et al, 2007) dissolved in PBS containing 5% DMSO, were injected intraperitoneally 3 and 6 h before LPS challenge, at 50 mg/kg body weight. Control animals received intraperitoneal injections of vehicle or nothing at all.…”

Section: Animals C57bl/6j Mmp8mentioning

confidence: 99%

Matrix Metalloprotease 8-Dependent Extracellular Matrix Cleavage at the Blood-CSF Barrier Contributes to Lethality during Systemic Inflammatory Diseases

Vandenbroucke¹,

Dejonckheere²,

Lint³

et al. 2012

Journal of Neuroscience

102

116

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Systemic inflammatory response syndrome (SIRS) is a highly mortal inflammatory disease, associated with systemic inflammation and organ dysfunction. SIRS can have a sterile cause or can be initiated by an infection, called sepsis. The prevalence is high, and available treatments are ineffective and mainly supportive. Consequently, there is an urgent need for new treatments. The brain is one of the first organs affected during SIRS, and sepsis and the consequent neurological complications, such as encephalopathy, are correlated with decreased survival. The choroid plexus (CP) that forms the blood-CSF barrier (BCSFB) is thought to act as a brain "immune sensor" involved in the communication between the peripheral immune system and the CNS. Nevertheless, the involvement of BCSFB integrity in systemic inflammatory diseases is seldom investigated. We report that matrix metalloprotease-8 (MMP8) depletion or inhibition protects mice from death and hypothermia in sepsis and renal ischemia/reperfusion. This effect could be attributed to MMP8-dependent leakage of the BCSFB, caused by collagen cleavage in the extracellular matrix of CP cells, which leads to a dramatic change in cellular morphology. Disruption of the BCSFB results in increased CSF cytokine levels, brain inflammation, and downregulation of the brain glucocorticoid receptor. This receptor is necessary for dampening the inflammatory response. Consequently, MMP8 ϩ/ϩ mice, in contrast to MMP8 Ϫ/Ϫ mice, show no anti-inflammatory response and this results in high mortality. In conclusion, we identify MMP8 as an essential mediator in SIRS and, hence, a potential drug target. We also propose that the mechanism of action of MMP8 involves disruption of the BCSFB integrity.

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“…Most compounds present a diphenyl or a phenoxyphenyl residue, based on the results obtained by our previous works in which these groups were linked to typical ZBGs 3,4,19,22,[31][32][33][34] . The relative position of sulfonamide linking group as well as the importance of hydroxyl groups were evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…To a stirred suspension of the appropriate intermediate (29)(30)(31)(32)(33) (0.41 mmol) in THF/MeOH (16 mL, 3:1), 10% Pd/C (26 mg) was added. After stirring overnight under hydrogen atmosphere (6 atm), the reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure affording the desired product.…”

Section: Ms (Esi) M/z (%): 324 [M-h]mentioning

confidence: 99%

Catechol-based matrix metalloproteinase inhibitors with additional antioxidative activity

Tauro

Laghezza

Loiodice

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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New catechol-containing chemical entities have been investigated as matrix metalloproteinase inhibitors as well as antioxidant molecules. The combination of the two properties could represent a useful feature due to the potential application in all the pathological processes characterized by increased proteolytic activity and radical oxygen species (ROS) production, such as inflammation and photoaging. A series of catechol-based molecules were synthesized and tested for both proteolytic and oxidative inhibitory activity, and the detailed binding mode was assessed by crystal structure determination of the complex between a catechol derivative and the matrix metalloproteinase-8. Surprisingly, X-ray structure reveals that the catechol oxygens do not coordinates the zinc atom.

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α-Biphenylsulfonylamino 2-methylpropyl phosphonates: Enantioselective synthesis and selective inhibition of MMPs

Cited by 38 publications

References 26 publications

Collagenase-2 Deficiency or Inhibition Impairs Experimental Autoimmune Encephalomyelitis in Mice

Collagenase-2 Deficiency or Inhibition Impairs Experimental Autoimmune Encephalomyelitis in Mice

Matrix Metalloprotease 8-Dependent Extracellular Matrix Cleavage at the Blood-CSF Barrier Contributes to Lethality during Systemic Inflammatory Diseases

Catechol-based matrix metalloproteinase inhibitors with additional antioxidative activity

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