A structure-activity study for the inhibition of metalloprotease-9 activity and gene expression by analogues of gallocatechin-3-gallate

Catechins modulate the gelatinolytic activity of matrix metalloproteinase-9 (MMP-9) by reducing its release from macrophages and by lowering MMP-9 promoter activity and mRNA levels. The effect appears to be dependent on some structural and stereochemical requirements. In this study, the relationship between chemical structure and activity was studied by synthesizing analogues of (-t-)-gallocatechin-3-gallate selectively deprived of hydroxyl groups. The compounds were added to murine macrophages at concentrations ranging from 1 to 30 uM, and the effect on MMP-9 activity, transcription, and secretion was measured by standard techniques. Our results indicate that the compound containing all the hydroxyl groups was the most effective in inhibiting directly MMP-9 activity (80% inhibition, p<0.001), and this inhibitory effect decreased with the increasing of hydroxyl groups number. Conversely, when transcription was the target, (-t-)-trans-3-flavanol-3-benzoate, lacking all the hydroxyl groups, was the most effective both in lowering MMP-9 promoter activity (62%, p<0.001) and consequently protein secretion (68%, p<0.001) and in inhibiting nucleax-factor-kB-driven transcription (72%, p<0.001). The results of the present study supply new insights on how catechin derivatives can act at the transcriptional or at enzyme level, indicating that the structural features required for the enzymatic inhibition are different from those necessaxy for the down regulation of gene expression. These data may provide new tools for designing potent and selective agents for the modulation of MMP-9 activity and gene expression.