Angiogenesis inhibitors targeting the VEGF signaling pathway are developed into drugs for the treatment of vaious diseases,such as cancer,rheumatoid arthritis,and age-related macular degeneration.Recent studies have r...Angiogenesis inhibitors targeting the VEGF signaling pathway are developed into drugs for the treatment of vaious diseases,such as cancer,rheumatoid arthritis,and age-related macular degeneration.Recent studies have revealed that oleanolic acid(OA),a natural pentacyclic triterpenoid,inhibited the VEGF/VEGFR2 signaling pathway and angiogenesis in HUVECs,which may represent an attractive VEGF inhibitor.In this paper,rational structural modification towards OA was performed in order to improve its inhibitory effects aganist VEGF and anti-angiogenesis potential.As a result,a series of novel OA derivatives,possessingα,β-unsat-urated ketone system in ring A and amide functional group at C-28,were prepared and evaluated for cytotoxicity and their ability to inhibit VEGF-induced abnormal proliferation of HUVECs.The results showed that two promising derivatives,OA-1 and OA-16,exhibited no in vitro cytotoxicity against HUVECs but showed more potent inhibitory activity against VEGF-induced proliferation and angiogenesis in HUVECs,compared with OA.The results of Western blot indicated that OA-1 and OA-16 inhibited VEGF-induced VE-GFR2 activation.Furthermore,small interfering RNA experiments were performed to confirm that both compounds inhibited VEGF-induced angiogenesis via VEGFR2.Thus,the present study resulted in the discovery of new promising OA-inspired VEGF inhibitors,which can serve as potential lead compounds for the treatment of angiogenesis-related diseases.展开更多
基金supported by the National Natural Science Foundation of China(Nos.21672082 and 31671214)the Natural Science Foundation of Shandong Province(Nos.ZR2019YQ31,ZR2020YQ52,and ZR2020MB103)+1 种基金the Project of Shandong Province Higher Educational Youth Innovation Science and Technology Program(No.2020KJE006)the Science and Technology Project of University of Jinan(No.XKY2004).
文摘Angiogenesis inhibitors targeting the VEGF signaling pathway are developed into drugs for the treatment of vaious diseases,such as cancer,rheumatoid arthritis,and age-related macular degeneration.Recent studies have revealed that oleanolic acid(OA),a natural pentacyclic triterpenoid,inhibited the VEGF/VEGFR2 signaling pathway and angiogenesis in HUVECs,which may represent an attractive VEGF inhibitor.In this paper,rational structural modification towards OA was performed in order to improve its inhibitory effects aganist VEGF and anti-angiogenesis potential.As a result,a series of novel OA derivatives,possessingα,β-unsat-urated ketone system in ring A and amide functional group at C-28,were prepared and evaluated for cytotoxicity and their ability to inhibit VEGF-induced abnormal proliferation of HUVECs.The results showed that two promising derivatives,OA-1 and OA-16,exhibited no in vitro cytotoxicity against HUVECs but showed more potent inhibitory activity against VEGF-induced proliferation and angiogenesis in HUVECs,compared with OA.The results of Western blot indicated that OA-1 and OA-16 inhibited VEGF-induced VE-GFR2 activation.Furthermore,small interfering RNA experiments were performed to confirm that both compounds inhibited VEGF-induced angiogenesis via VEGFR2.Thus,the present study resulted in the discovery of new promising OA-inspired VEGF inhibitors,which can serve as potential lead compounds for the treatment of angiogenesis-related diseases.
