Inhibitory effects of nine dibenzylbutyrolactone lignans on a human matrix metalloproteinase, matrilysin, were examined. All of the lignans examined inhibited matrilysin with the IC(50) values ranging from 50 to >280 microM. Matairesinol, which has the basic structure of the other lignans, showed the weakest inhibition. Lignans with methylenedioxy ring(s) or a hydroxyl group at the C5-position inhibited matrilysin more strongly than matairesinol. 5-Hydroxypluviatolide, which has both a methylenedioxy ring and a hydroxyl group at the C5-position, was the most potent inhibitor (IC(50) = 50 microM), suggesting that the introduction of these two elements might enhance synergistically the inhibitory activity of lignans. 5-Hydroxypluviatolide inhibited matrilysin in a competitive manner, and its inhibitory effect was greatly suppressed by the presence of another competitive inhibitor, dimethyl sulfoxide. The precursors of matairesinol, coniferyl alcohol and secoisolariciresinol, had no inhibitory activity, indicating that the dibenzylbutyrolactone structure is essential for the inhibition. It has been shown that lignans have the potential to inhibit matrilysin, and the knowledge of their structure-activity relationship might be beneficial to developing selective inhibitors for matrix metalloproteinases.

MMPs are considered to be involved in the tumor metastasis and invasion, and potent and safe MMP inhibitors have been desired for tumor therapy. The inhibitors could be also useful tool to regulate the enzyme activity and to explore the enzyme reaction mechanism. In this study, inhibitory effect of 10 catechins and 9 dibenzylbutyrolactone lignans on MMP-7 activity was examined in the hydrolysis of a synthetic substrate, MOCAc-PLGL(Dpa)AR, in 50 mM HEPES buffer (pH 7.5) containing 10 mM CaCl2. The catechins examined were classified into three groups according to their inhibition potency: (+) and (-)-catechins, and (+) and (-)-epicatechins (EC) had Ki of > 1 mM; (-)-gallocatechin (GC) and (-)-epigallocatechin (EGC) had Ki of > 0.05 mM; and catechins with a galloyl group at the 3 position [(-)-catechin-3-gallate (CG), (-)-epicatechin-3-gallate (ECG), (-)-gallocatechin-3-gallate (GCG), and (-)-epigallocatechin-3-gallate (EGCG)] had Ki values of 400-1600 nM. The inhibitory potency of ECG was the strongest among them. A major component of green tea chatechin, EGCG, is in the third group. The inhibition manner of the catechins in the third group against MMP-7 was shown to be non-competitive. The potency of EGCG was not affected by the presence of an inhibitor ZnCl2, suggesting that the inhibitions of MMP-7 by EGCG and by ZnCl2 might be independent of each other. The inhibitory effects of green tea catechins suggest that a high intake of green tea might be effective for the prevention of tumor metastasis and invasion in which MMP-7 is concerned. All of the lignans examined inhibited MMP-7 with the IC50 ranging from 0.05 to >0.28 mM. Matairesinol, which has the basic structure of the other lignans, showed the weakest inhibition. Lignans with methylenedioxy ring(s) or a hydroxyl group at the C5-position inhibited MMP-7 more strongly than matairesinol. 5-Hydroxypluviatolide, which has both a methylenedioxy ring and a hydroxyl group at the C5-position, was the most potent inhibitor (IC50 = 0.05 mM), suggesting that the introduction of these two elements might enhance synergistically the inhibitory activity of lignans. 5-Hydroxypluviatolide inhibited MMP-7 in a competitive manner, and its inhibitory effect was greatly suppressed by the presence of another competitive inhibitor, dimethyl sulfoxide. The precursors of matairesinol, coniferyl alcohol and secoisolariciresinol, had no inhibitory activity, indicationg that the dibenzylbutyrolactone structure is essential for the inhibition. Lignans were shown to have the potential to inhibit MMP-7, and the knowledge of their structure-function relationship might be beneficial to developing selective inhibitors for MMPs. It should be noted that the inhibitory manner of catechins was non-competitive, whereas that of lignans was competitive. This suggests that there must be an activity-regulatory site, which accommodates catechins specifically but not lignans, other than the active site which accommodates lignans specifically but not catechins. Catechins and lignans must be suitable pr...