Th-W57:3 A structure-activity study for the inhibition of metalloproteinase-9 activity and gene expression by analogues of gallocatechin-3-gallate

Abstract

Catechins are able to modulate the gelatino- lytic activity of matrix metalloproteinase-9 (MMP-9) by reducing its release from macrophages. Gallocatechins decrease MMP-9 secretion by lowering MMP-9 promot- er activity and mRNA levels. The effect appears to be de- pendent on some structural and stereochemical require- ments. In this study, the relationship between chemical structure and activity was studied by testing the effect of analogues of (±)-gallocatechin-3-gallate (±)-GCG, selec- tively deprived of hydroxyl groups, on MMP-9 activity, transcription, and secretion. Our results indicate that (±)- GCG and (±)-catechin-3-gallate are characterized by a substitution pattern compatible with direct inhibition of MMP-9 activity. Conversely, when transcription was the target, (±)-trans-3-fl avanol-3-benzoate, lacking all the hydroxyl groups, was the most effective both in lower- ing MMP-9 promoter activity and consequently protein secretion, and in inhibiting nuclear-factor-kB-driven transcription. Our results suggest that the structural requirements for enzyme inhibition are different from those necessary for targeting gene expression.