Synthesis and biological evaluation of Combretastatin A-4 derivatives containing a 3-O-substituted carbonic ether moiety as potential antitumor agents

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• 作者：Mingyi Ma (1)
  Longru Sun (1)
  Hongxiang Lou (1)
  Mei Ji (1)
  
• 关键词：Combretastatin A ; 4 ; Synthesis ; Antitumor activity ; WST ; 1 ; Cell cycle arrest ; Apoptosis
• 刊名：Chemistry Central Journal
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：7
• 期：1
• 全文大小：581 KB
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• 作者单位：Mingyi Ma (1)
  Longru Sun (1)
  Hongxiang Lou (1)
  Mei Ji (1)
  
  1. Department of Natural Products Chemistry, Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, 250012, PR China
  
• ISSN：1752-153X

文摘

Background Combretastatin A-4 (CA-4), which is an excellent antineoplastic agent, was isolated from Combretum caffrum. To date, structural modification studies of CA-4 have focused predominantly on the construction of new therapeutic agents for drug discovery. As a part of our ongoing work towards the modification of natural products, we have focused on the 3-O-substituent groups in the B-ring of CA-4 under the hypothesis that these novel derivatives will possess good bioactivities and behave as effective antiproliferative pro-drugs. Results A series of novel CA-4 derivatives, which contained a 3-O-substituted carbonic ether moiety, were synthesized and evaluated for their antitumor activities against four tumor cell lines, including MDA-MB-231, MCF-7, K562 and A549 cells. These derivatives exhibited clear antitumor activities, and CA-4E, in particular, showed the highest bioactivity of all of the derivatives tested against all four tumor cell lines, with IC50 values in the range of 1 to 180 nM. Based on its high bioactivity, CA-4E was subsequently selected to investigate the antitumor mechanism of these synthetic compounds. The cell cycle results demonstrated that CA-4E induced time- and dose-dependent G2/M arrest in a similar manner to CA-4, although its effect was more powerful than that of CA-4, and the apoptosis data showed that CA-4E induced cellular apoptosis in a dose-dependent manner. Conclusions The newly synthesized CA-4 derivatives exhibited good antitumor activities in vitro, with CA-4E, in particular, showing the highest bioactivity of all of the compounds tested. Furthermore, CA-4E induced time- and dose-dependent G2/M arrest and cellular apoptosis in a dose-dependent manner. Taken together, these results suggest that CA-4E should be subjected to further investigation as a potential anticancer drug candidate.