2. Academic Validation
  3. Conjugates of podophyllotoxin and norcantharidin as dual inhibitors of topoisomeraseⅡ and protein phosphatase 2A

Conjugates of podophyllotoxin and norcantharidin as dual inhibitors of topoisomeraseⅡ and protein phosphatase 2A

  • Eur J Med Chem. 2016 Nov 10:123:568-576. doi: 10.1016/j.ejmech.2016.07.031.
Zhen-Bo Tang 1,  Yao-Zhang Chen 2,  Jie Zhao 1,  Xiao-Wen Guan 1,  Yong-Xin Bo 1,  Shi-Wu Chen 3,  Ling Hui 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
  • 2 Department of Parmaceutics, Gansu Provincial Hospital of TCM, Lanzhou 730050, China.
  • 3 School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: chenshw@lzu.edu.cn.
  • 4 Experimental Center of Medicine, General Hospital of Lanzhou Military Command, Lanzhou 730050, China; Key Laboratory of Stem Cells and Gene Drug of Gansu Province, General Hospital of Lanzhou Military Command, Lanzhou 730050, China. Electronic address: zyhuil@hotmail.com.
PMID: 27517805 DOI: 10.1016/j.ejmech.2016.07.031
Abstract

A series of novel conjugates of podophyllotoxin and norcantharidin was designed using association strategy, and synthesized by coupling 4'-demethylepipodophyllotoxin with N-amino acid norcantharimides, and their cytotoxicitiy was evaluated against four human tumor cell lines (A-549, HepG2, HeLa and HCT-8) and normal human diploid fibroblast line WI-38. These compounds exhibited potent cytotoxic effects on tumor cell lines, whereas it was less toxic to WI-38 cells than Anticancer drug VP-16 or its parent compound norcantharidin. Furthermore, conjugates 7a, 7c, 7f, 7j, 7k and 7l displayed excellent PP2A inhibition activity with IC50 values of 0.49-9.52 μM. The most potent compound 7l also exhibited topoisomeraseⅡinhibition activity. In addition, compound 7l induced cell-cycle arrest in the G2/M phase in HepG2 by regulating levels of cyclinB1 and cdc2.

Keywords

Cantharidin; Cell-cycle arrest; PP2A; Podophyllotoxin; TOP-Ⅱ.

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