2. Academic Validation
  3. Synthesis, and evaluation of in vitro and in vivo anticancer activity of 14-substituted oridonin analogs: A novel and potent cell cycle arrest and apoptosis inducer through the p53-MDM2 pathway

Synthesis, and evaluation of in vitro and in vivo anticancer activity of 14-substituted oridonin analogs: A novel and potent cell cycle arrest and apoptosis inducer through the p53-MDM2 pathway

  • Eur J Med Chem. 2019 Jul 1:173:15-31. doi: 10.1016/j.ejmech.2019.04.005.
Qing-Kun Shen 1,  Hao Deng 1,  Shi-Ben Wang 2,  Yu-Shun Tian 3,  Zhe-Shan Quan 4
Affiliations

Affiliations

  • 1 Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China.
  • 2 School of Pharmacy, Liaocheng University, LiaoCheng, Shandong, 252059, China.
  • 3 Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China. Electronic address: ystian@ybu.edu.cn.
  • 4 Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, 133002, China. Electronic address: zsquan@ybu.edu.cn.
PMID: 30981113 DOI: 10.1016/j.ejmech.2019.04.005
Abstract

A series of novel oridonin derivatives bearing various substituents on the 14-OH position were designed and synthesised. Their antitumour activity was evaluated in vitro against three human Cancer cell lines (HCT116, BEL7402, and MCF7). Most tested derivatives showed improved anti-proliferative activity compared to the lead compound oridonin and the positive control drug 5-fluorouracil (5-Fu). Among them, compound C7 (IC50 = 0.16 μM) exhibited the most potent anti-proliferative activity against HCT116 cells; it was about 43- and 155-fold more efficacious than that of oridonin (IC50 = 6.84 μM) and 5-Fu (IC50 = 24.80 μM) in HCT116 Cancer cells. Interestingly, the IC50 value of compound C7 in L02 normal cells was 23.6-fold higher than that in HCT116 cells; it exhibited better selective anti-proliferative activity and specificity than oridonin and 5-Fu. Furthermore, compound C7 possibly induced cell cycle arrest and Apoptosis by regulating the p53-MDM2 signalling pathway. Notably, C7 displayed more significant suppression of tumour growth than oridonin in colon tumour xenograft models where the tumour growth inhibition rate was 85.82%. Therefore, compound C7 could be a potential lead compound for the development of a novel antitumour agent.

Keywords

Antitumour; Apoptosis; Cell cycle arrest; In vivo; Oridonin.

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