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.
- 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: [email protected].
- 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: [email protected].
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.