Discovery of dehydroabietic acid sulfonamide based derivatives as selective matrix metalloproteinases inactivators that inhibit cell migration and proliferation

摘要

Abstract A series of dehydroabietic acid (DHAA) dipeptide derivatives containing the sulfonamide moiety were designed, synthesized and evaluated for inhibition of MMPs as well as the effects of in?vitro cell migration. These compounds exhibited relatively good inhibition activity against MMPs with IC 50 values in low micromolar range. A docking study of the most active compound 8k revealed key interactions between 8k and MMP-3 in which the sulfonamide moiety and the dipeptide group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU. In particular, compound 8k appeared to be the most potent compound against the HepG2 cell line, at least partly, by inhibition of the activity of MMP-3 and apoptosis induction. The treatment of HepG2 cells with compound 8k resulted in inhibition of in?vitro cell migration through wound healing assay and G1 phase of cell cycle arrested. In addition, 8k -induced apoptosis was significantly facilitated in HepG2 cells. Thus, we conclude that DHAA dipeptide derivatives containing the sulfonamide moiety may be the potential MMPs inhibitors with the ability to suppress cells migration. Graphical abstract Display Omitted Highlights ? A novel series of DHAA dipeptide derivatives containing the sulfonamide moiety were synthesized. ? Compound 8k exhibited potential inhibitory activity against MMP-3. ? Molecular modeling suggested that 8k tightly binds to the active site of MMP-3. ? The inhibitors efficiently inhibit the cell migration of human liver cancer cells. ? 8k induced apoptosis and arrested cell cycle at G1 phase in HepG2 cells.