Design and semisynthesis of oleanolic acid derivatives as VEGF inhibitors: Inhibition of VEGF-induced proliferation, angiogenesis, and VEGFR2 activation in HUVECs

Angiogenesis inhibitors targeting VEGF signaling pathway could be developed into drugs for the treatment of several diseases, such as cancer, rheumatoid arthritis, and age-related macular degeneration. Recent study has revealed that oleanolic acid (OA), a natural pentacyclic triterpenoid, inhibited VEGF/VEGFR2 signaling and angiogenesis in HUVECs, and therefore might represent an attractive VEGF inhibitor. In this paper, the rational structural modification towards OA was performed in order to improve its VEGF inhibitory and anti-angiogenesis activity. As a result, a series of novel OA derivatives, possessing α,β-unsaturated ketone system in ring A and amide functional group at C-28, was prepared and evaluated for cytotoxicity and their ability of inhibiting VEGF-induced abnormal proliferation of HUVECs. The results showed that two promising derivatives, OA-1 and OA-16, had no in vitro cytotoxicity against HUVECs but more potent inhibitory activity against the VEGF-induced proliferation and angiogenesis in HUVECs, compared with the OA. The results of western blot experiment indicated that OA-1 and OA-16 inhibited VEGF-induced VEGFR2 activation. Furthermore, small interfering RNA experiments were performed to confirm both compounds inhibited VEGF-induced angiogenesis through VEGFR2. Thus, the present study resulted in the discovery of new promising OA-inspired VEGF inhibitors, which could serve as potential lead compounds for the treatment of angiogenesis-related diseases.