2. Academic Validation
  3. Discovery of novel antitumor nitric oxide-donating β-elemene hybrids through inhibiting the PI3K/Akt pathway

Discovery of novel antitumor nitric oxide-donating β-elemene hybrids through inhibiting the PI3K/Akt pathway

  • Eur J Med Chem. 2017 Jul 28:135:414-423. doi: 10.1016/j.ejmech.2017.04.045.
Jichao Chen 1,  Tianyu Wang 1,  Shengtao Xu 1,  Pengfei Zhang 1,  Aijun Lin 1,  Liang Wu 2,  Hequan Yao 1,  Weijia Xie 1,  Zheying Zhu 3,  Jinyi Xu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
  • 2 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: wul2004@hotmail.com.
  • 3 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK. Electronic address: Zheying.Zhu@nottingham.ac.uk.
  • 4 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: jinyixu@china.com.
PMID: 28463784 DOI: 10.1016/j.ejmech.2017.04.045
Abstract

A series of novel furoxan-based NO-donating β-elemene hybrids were designed and synthesized to improve the Anticancer efficacy of natural β-elemene. The bioassay results indicated that all of the target compounds exhibited significantly improved antiproliferative activities against three Cancer cell lines (SGC-7901, HeLa and U87) compared to parent compound β-elemene. Interestingly, these compounds displayed excellent sensitivity to U87 cells with IC50 values ranging from 173 to 2 nM. Moreover, most compounds produced high levels of NO in vitro, and the antitumor activity of 11a in U87 cells was markedly attenuated by an NO scavenger (hemoglobin or carboxy-PTIO). Further mechanism studies revealed that 11a caused the G2 phase arrest of the cell cycle and induced Apoptosis of U87 cells by preventing the activation of the PI3K/Akt pathway. Moreover, 11a significantly suppressed the tumor growth in H22 liver Cancer xenograft mouse model with a tumor inhibitory ratio (TIR) of 64.8%, which was superior to that of β-elemene (TIR, 49.6%) at the same dose of 60 mg/kg. Together, the remarkable biological profiles of these novel NO-donating β-elemene derivatives may make them promising candidates for the intervention of human cancers.

Keywords

Antitumor activity; Apoptosis; Furoxan; PI3K/Akt pathway; β-Elemene.

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