Excessive breakdown of extracellular matrix by metalloproteinases (MMPs) may lead to atherosclerosis complications. Broad-spectrum MMPs inhibitors caused adverse events due to their lack of selectivity. In the search for more selective inhibitors, we have synthesized a new compound named MS560 (alpha-trifluoromethyl-alpha-amino-beta-sulphone hydroxamate). MS560 inhibited directly the gelatinolytic activity of MMP-2 and -9 (IC50 MMP-2 970nM; MMP-9 87nM, p<0.01), but was much less effective in inhibiting MMP- 1 activity (IC50 of 6.99uM). Substitution on the amino group of MS560 with methyl, ethyl and prophyl groups showed that increasing the steric hindrance of amino group residue reduces the inhibitory activity on MMP-9. MS560 (from 0.05 to 25uM) only slightly affected MMP-9 secretion by macrophages while it did not alter MMP-2 levels in human smooth muscle cells. Interestingly, MS560 significantly reduced MMP-1 secretion by interfering with MMP-1 promoter activity, at concentrations similar to those required to inhibit its catalytic activity, while MS560 derivatives significantly inhibited the secretion of MMP-9 (IC50 from 260nM to 67nM) without affecting MMP-9 promoter activity leading to increased MMP-9 accumulation. In conclusion, our results show that MS560 or derivatives inhibit the gelatinolytic activity of MMP-2 and -9, and of MMP-9 secretion, at nanomolax concentrations while micromolar concentrations are needed to significantly affect MMP-1 action. The selective inhibitory action of these type of compounds might have beneficial effect in the therapeutic control of excessive matrix breakdown.
|Titolo:||Selective inhibition on gelatinase A and B versus collagenase-1 by an amino-sulphone-hydroxamate derivative|
BELLOSTA, STEFANO (Ultimo)
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2006|
|Appare nelle tipologie:||01 - Articolo su periodico|