2. Academic Validation
  3. Design and synthesis of piperazine acetate podophyllotoxin ester derivatives targeting tubulin depolymerization as new anticancer agents

Design and synthesis of piperazine acetate podophyllotoxin ester derivatives targeting tubulin depolymerization as new anticancer agents

  • Bioorg Med Chem Lett. 2017 Sep 1;27(17):4066-4074. doi: 10.1016/j.bmcl.2017.07.047.
Wen-Xue Sun 1,  Ya-Jing Ji 1,  Yun Wan 1,  Hong-Wei Han 1,  Hong-Yan Lin 1,  Gui-Hua Lu 1,  Jin-Liang Qi 2,  Xiao-Ming Wang 3,  Yong-Hua Yang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: qijl@nju.edu.cn.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: wangxm07@nju.edu.cn.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: yangyh@nju.edu.cn.
PMID: 28757065 DOI: 10.1016/j.bmcl.2017.07.047
Abstract

In this paper, a series of podophyllotoxin piperazine acetate ester derivatives were synthesized and investigated due to their antiproliferation activity on different human Cancer cell lines. Among the congeners, C5 manifested prominent cytotoxicity towards the Cancer cells, without causing damage on the non-cancer cells through inhibiting tubulin assembly and having high selectively causing damage on the human breast (MCF-7) cell line (IC50=2.78±0.15μM). Treatments of MCF-7 cells with C5 resulted in cell cycle arrest in G2/M phase and microtubule network disruption. Moreover, regarding the expression of cell cycle relative proteins CDK1, a protein required for mitotic initiation was up-regulated. Besides, Cyclin A, Cyclin B1 and Cyclin D1 proteins were down-regulated. Meanwhile, it seems that the effect of C5 on MCF-7 cells Apoptosis inducing was observed to be not obvious enough. In addition, docking analysis demonstrated that the congeners occupy the colchicine binding pocket of tubulin.

Keywords

Cell cycle; Cytotoxicity; Microtubule network; Modeling; Podophyllotoxin piperazine acetate ester derivatives.

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