Medicinal Chemistry Research

, Volume 27, Issue 2, pp 351–365 | Cite as

Design, synthesis and anti-cancer evaluation of novel podophyllotoxin derivatives as potent tubulin-targeting agents

Original Research
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Abstract

A series of podophyllotoxin derivatives (M1M16) that were selectively acylated by various phenoxy acids at the C-4 position of podophyllotoxin were synthesized, and their biological activities were also evaluated. Among them, compound M4 showed the most potent anti-cancer activity against HeLa cells with an IC50 value of 1.64 ± 0.41 μM. Additionally, flow cytometry analysis results indicated that it could cause a remarkable cell cycle arrest at G2/M phase, but the effect on apoptosis inducing was not significant. Moreover, the expression of cell cycle relative protein CDK1 was up regulated while cyclin B1 and Cdc25C, two proteins required for mitotic initiation were down regulated. Furthermore, the confocal assay and extracellular polymerized tubulin expression analysis also demonstrated that M4 was a potent tubulin polymerization inhibitor and the effect was comparable to that of colchicine. Finally, docking simulation results showed that M4 could nicely bind to the colchicine binding site of tubulin which further comfirmed the tubulin inhibiton activity of M4.

Keywords

Anti-cancer Podophyllotoxin Phenoxy acid Anti-tubulin Cell cycle 

Notes

Acknowledgements

The authors are grateful to the Program for Changjiang Scholars and Innovative Research Team in University (IRT_14R27), the National Natural Science Foundation of China (31470384, 31171161, and 31670298), and the Fundamental Research Funds for the Central Universities (020814380002).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1992_MOESM1_ESM.docx (2.1 mb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Cui Hu
    • 1
    • 2
  • Xiang Zhu
    • 1
    • 2
  • Gu-Hao Wang
    • 1
    • 2
  • Xun Wu
    • 1
    • 2
  • Hong-Wei Han
    • 1
    • 2
  • Gui-Hua Lu
    • 1
    • 2
  • Jin-Liang Qi
    • 1
    • 2
  • Yan-Jun Pang
    • 1
    • 2
  • Rong-Wu Yang
    • 1
    • 2
  • Xiao-Ming Wang
    • 1
    • 2
  • Yong-Hua Yang
    • 1
    • 2
  1. 1.State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular BiologyNanjing UniversityNanjingChina
  2. 2.Co-Innovation Center for Sustainable Forestry in Southern ChinaNanjing Forestry UniversityNanjingChina

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