Aim: Oxidative stress-induced endothelial injury is a main risk factor in the pathogenesis of cardiovascular diseases. Tanshinone IIA (Tan IIA) exerts protective functions on endothelial cells in response to oxidative stress. To exploit new bioactive compounds from this natural product, 12 derivatives were first synthesized and evaluated for endothelial protective activities.
Materials & methods: Title compounds were prepared according to high-yielded synthetic routes, and their protective effects on human endothelial EA.hy926 cells were evaluated. To explore the mechanism, their inhibition on apoptosis of endothelial cells and Nrf2 activating activities were investigated. Furthermore, computational ADME prediction and water solubility assay were carried out for active compounds.
Results: Most of them exhibited potent endothelial protective effects on EA.hy926 cells injured by H2O2. In particular, compounds I-2 and II showed increased activity and water solubility compared with Tan IIA. Moreover, they reduced H2O2-induced apoptosis of EA.hy926 cells. A further exploration on the two compounds suggested that their actions were mediated by upregulation of antioxidant genes through activating Nrf2 pathway.
Conclusion: These Tan IIA derivatives clearly showed related activities for the development of a new type of endothelial protective agents. [Formula: see text].
Keywords: Nrf2; apoptosis; derivatives; endothelial protective activity; oxidative stress; tanshinone IIA.