Design and semisynthesis of oleanolic acid derivatives as VEGF inhibitors: Inhibition of VEGF-induced proliferation, angiogenesis, and VEGFR2 activation in HUVECs.
10.1016/S1875-5364(22)60159-6
- Author:
Ning MENG
1
;
Hong-Xu XIE
2
;
Jia-Rong HOU
2
;
Yan-Bin CHEN
2
;
Meng-Jun WU
3
;
Yue-Wei GUO
4
;
Cheng-Shi JIANG
5
Author Information
1. School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: mls_mengn@ujn.edu.cn.
2. School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ywguo@simm.ac.cn.
5. School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: bio_jiangcs@ujn.edu.cn.
- Publication Type:Journal Article
- Keywords:
Angiogenesis;
Oleanolic acid;
Structural modification;
VEGF inhibitor;
VEGFR2
- MeSH:
Cell Movement;
Cell Proliferation;
Human Umbilical Vein Endothelial Cells;
Humans;
Oleanolic Acid/pharmacology*;
Vascular Endothelial Growth Factor A/metabolism*
- From:
Chinese Journal of Natural Medicines (English Ed.)
2022;20(3):229-240
- CountryChina
- Language:English
-
Abstract:
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, possessing α,β-unsaturated 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 VEGFR2 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.
