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
  • 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: [email protected].
  • 3. Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK. Electronic address: [email protected].
  • 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: [email protected].
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.