B-Ring-modified and/or 5-demethylated nobiletin congeners: inhibitory activity against pro-MMP-9 production.

Three metabolites and 12 analogues of nobiletin (1) were synthesized. Whereas nobiletin derivatives 2-4 inhibited pro-MMP-9 production similarly in both PMA- and TNF-α-stimulated human lens epithelial cells, the 2'-hydroxylated analogue 5a exerted marked inhibitory effects (IC(50): 0.4 μM) on PMA-treated cells, which were 170-fold more potent than those on TNF-α-treated cells. This activity may be closely related to PKC-mediated transcriptional regulation of pro-MMP-9.