A Novel Potent Anticancer Compound Optimized from a Natural Oridonin Scaffold Induces Apoptosis and Cell Cycle Arrest through the Mitochondrial Pathway

  • J Med Chem. 2017 Feb 23;60(4):1449-1468. doi: 10.1021/acs.jmedchem.6b01652.
Shengtao Xu  1 ,  Hong Yao  1 ,  Shanshan Luo  2 ,  Yun-Kai Zhang  3 ,  Dong-Hua Yang  3 ,  Dahong Li  1  4 ,  Guangyu Wang  1 ,  Mei Hu  1 ,  Yangyi Qiu  1 ,  Xiaoming Wu  1 ,  Hequan Yao  1 ,  Weijia Xie  1 ,  Zhe-Sheng Chen  3 ,  Jinyi Xu  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
  • 2. Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai 201203, P. R. China.
  • 3. College of Pharmacy and Health Sciences, St. John's University , 8000 Utopia Parkway, Queens, New York 11439, United States.
  • 4. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , 103 Wen Hua Road, Shenyang 110016, China.
PMID: 28165738 DOI: 10.1021/acs.jmedchem.6b01652
Abstract

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.