2. Academic Validation
  3. Synthesis, anticancer evaluation and pharmacokinetic study of novel 10-O-phenyl ethers of dihydroartemisinin

Synthesis, anticancer evaluation and pharmacokinetic study of novel 10-O-phenyl ethers of dihydroartemisinin

  • Eur J Med Chem. 2017 Dec 1:141:584-595. doi: 10.1016/j.ejmech.2017.10.023.
Shenglin Luan 1,  Hang Zhong 1,  Xuan Zhao 2,  Jinyu Yang 1,  Yongkui Jing 2,  Dan Liu 3,  Linxiang Zhao 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, China.
  • 3 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sammyld@163.com.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: linxiang.zhao@vip.sina.com.
PMID: 29102180 DOI: 10.1016/j.ejmech.2017.10.023
Abstract

Twenty hybrid compounds, tethering dihydroartemisinin (DHA) with diaryl-pyrazoline/diaryl-pyrazole through ether linkage, were synthesized based on hybridization strategy and assessed for their Anticancer activity. The representative compound 6f exhibited significantly elevated antiproliferative activity compared with DHA against a panel of Cancer cell lines. Unexpected sensitivity of 6f in Adriamycin-resistant MCF-7 cells (MCF-7/Adr) inspired subsequent research on Anticancer activity of these DHA derivatives against breast Cancer cell lines. All the novel compounds exhibited potent activity in three breast Cancer cells including MDA-MB-231, MCF-7 and MCF-7/Adr. Most of them exerted almost 10-fold higher potency in MCF-7/Adr than in MCF-7 and MDA-MB-231 cells. Compound 5f, the most potent compound against MCF-7/Adr (GI50 = 18 nM), was used for mechanism research which revealed that compound 5f arrested MCF-7 and MCF-7/Adr cells in G0/G1 phase with decreased levels of cyclin D1 and increased levels of p27. Preliminary pharmacokinetic properties of 5f and 6f were investigated in rats after a single intravenous administration. The high sensitivity of MCF-7/Adr indicates that these compounds have potential to be developed as therapeutic agents to treat drug-resistant Cancer.

Keywords

10-O-phenyl ethers of dihydroartemisinin; Anticancer activity; G0/G1 phase cell cycle arrest; Multidrug resistance; Pharmacokinetic study.

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