title: Conjugates of podophyllotoxin and norcantharidin as dual inhibitors of topoisomeraseⅡ and protein phosphatase 2A.
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.
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Zhen-Bo
authors: ZB
authors: Tang
authors: Department of Parmaceutics, Gansu Provincial Hospital of TCM, Lanzhou 730050, China.
authors: Yao-Zhang
authors: YZ
authors: Chen
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Jie
authors: J
authors: Zhao
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Xiao-Wen
authors: XW
authors: Guan
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Yong-Xin
authors: YX
authors: Bo
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: chenshw@lzu.edu.cn.
authors: Shi-Wu
authors: SW
authors: Chen
authors: 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.
authors: Ling
authors: L
authors: Hui
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D011034:Podophyllotoxin / Q000737:chemistry*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D059005:Topoisomerase II Inhibitors; C069741:norcantharidin; D054648:Protein Phosphatase 2; D011034:Podophyllotoxin
keywords: Cantharidin; Cell-cycle arrest; PP2A; Podophyllotoxin; TOP-Ⅱ