期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 4, 页码 1449-1468出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01652
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资金
- National Natural Science Foundation of China [81373280, 81673306]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZCX201404]
- China Postdoctoral Science Foundation [2015M581903]
The cytotoxicity of the natural ent-kaurene diterpenoid,, oridonin, has been extensively studied. However, the application of oridonin for cancer therapy was hampered primarily by its moderate potency. In this study, a series of oridonin A-ring modified analogues, and their derivatives bearing various substituents on 14-OH position, were designed, synthesized, and evaluated for anticancer efficacy. Some of the derivatives were significantly more potent than oridonin against both drug-sensitive and drug-resistant cancer cells. The most potent compound, 13p, was 200-fold more efficacious than oridonin in MCF-7 cancer cells. Furthermore, 13p induced apoptosis and cell cycle arrest at the G2/M phase. A decrease in mitochondrial membrane potential and an increase in Bax/Bcl-2 ratio, accompanied by activated caspase-3 cleavage, were observed in MCF-7 cells after treatment with 13p, suggesting that the mitochondrial pathway was involved in the 13p-mediated apoptosis. Moreover, 13p significantly inhibited tumor growth in mouse xenograft models and had no observable toxic effect.
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