2. Academic Validation
  3. Discovery and synthesis of novel magnolol derivatives with potent anticancer activity in non-small cell lung cancer

Discovery and synthesis of novel magnolol derivatives with potent anticancer activity in non-small cell lung cancer

  • Eur J Med Chem. 2018 Aug 5:156:190-205. doi: 10.1016/j.ejmech.2018.06.048.
Huan Tang 1,  Yongguang Zhang 1,  Dan Li 1,  Suhong Fu 1,  Minghai Tang 1,  Li Wan 2,  Kai Chen 3,  Zhuowei Liu 4,  Linlin Xue 1,  Aihua Peng 1,  Haoyu Ye 5,  Lijuan Chen 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.
  • 2 School of Pharmacy, Chengdu University of TCM, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, PR China.
  • 3 School of Chemical Engineering, Sichuan University, Chengdu, 610041, PR China.
  • 4 Guang dong Zhongsheng Pharmaceutical Co., Ltd, Dongguan, Guangdong, 523325, PR China.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China. Electronic address: haoyu_ye@scu.edu.cn.
  • 6 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China; School of Pharmacy, Chengdu University of TCM, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, PR China. Electronic address: chenlijuan125@163.com.
PMID: 30006164 DOI: 10.1016/j.ejmech.2018.06.048
Abstract

EGFR T790 M accounts for 50% to 60% of cases of non-small-cell lung carcinoma (NSCLC) resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs). Hence, identifying novel compounds with activity against TKIs resistant is of great value. In this study, twenty honokiol and magnolol derivatives were isolated from the EtOH extract of Magnolia officinalis and the antiproliferative activity was evaluated on HCC827 (19del EGFR mutation), H1975 (L858 R/T790 M EGFR mutation), and H460 (KRAS mutation) cell lines. Among the isolated compounds, piperitylmagnolol (a 3-substituted magnolol derivative) showed the best antiproliferative activity against those three cell lines with the IC50 values of 15.85, 15.60 and 18.60 μM, respectively, which provided a direction for the structural modification of magnolol. Further structural modification led to the synthesis of thirty-one magnolol derivatives, and compounds A13, C1, and C2 exhibited significant and broad-spectrum antiproliferative activity with the IC50 values ranging from 4.81 to 13.54 μM, which were approximately 4- and 8-fold more potent than those of honokiol and magnolol, respectively. Moreover, their aqueous solubility was remarkably improved with 12-, 400- and 105 fold greater than those of honokiol and magnolol. Anti-tumor mechanism research revealed that these three compounds were able to induce cell cycle arrest at G0/G1 phase, cause efficient Apoptosis in H1975 cells, and also prevent the migration of HUVECs in a dose-dependent manner through CDK2, CDK4, Cyclin E, and Cyclin D1 inhibition as well as up-regulation of cleaved-PARP and cleaved-caspase 3 levels. In in vivo antitumor activity, C2 (10, 30 and 100 mg/kg, po) dose-dependently inhibited the tumor growth in H1975 xenograft model with the tumor inhibition rate of 46.3%, 59.3% and 61.2% respectively, suggesting that C2 is a potential oral Anticancer agent deserving further investigation.

Keywords

Anticancer agent; Honokiol; Magnolia officinalis; Magonolol; Non-small cell lung cancer.

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