Synthesis and biological evaluation of norcantharidin derivatives as protein phosphatase-1 inhibitors

Jie Zhao; Xiao-Wen Guan; Shi-Wu Chen; Ling Hui

doi:10.1016/j.bmcl.2014.11.032

Synthesis and biological evaluation of norcantharidin derivatives as protein phosphatase-1 inhibitors

Bioorg Med Chem Lett. 2015 Jan 15;25(2):363-6. doi: 10.1016/j.bmcl.2014.11.032. Epub 2014 Nov 18.

Authors

Jie Zhao¹, Xiao-Wen Guan¹, Shi-Wu Chen², Ling Hui³

Affiliations

¹ School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
² School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: chenshw@lzu.edu.cn.
³ 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.

PMID: 25466711
DOI: 10.1016/j.bmcl.2014.11.032

Abstract

Cantharidin and norcantharidin display anticancer activity against a broad range of tumor cell lines. In this study, we have synthesized a series of norcantharidin derivatives and evaluated their cytotoxic effects on four human tumor cell lines together with the genetically normal human diploid fibroblast line WI-38. One of our compounds (1S,4R)-3-((4-(4-(4-fluorophenyl)piperazin-1-ylsulfonyl) phenyl)carbamoyl)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (12) exhibited potent cytotoxic effects on the tumor cell lines A-549, HepG2, HeLa, and HCT-8, whereas it was less toxic to WI-38 cells than its parent compound, norcantharidin. In addition, this compound inhibited protein phosphatase-1 activity and microtubule formation in HeLa cells, and it also interacts with calf thymus DNA.

Keywords: Cytotoxicity; Microtubules; Norcantharidin; Protein phosphatase-1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / chemistry*
Cell Proliferation / drug effects*
Cells, Cultured
DNA / metabolism
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Fibroblasts / cytology
Fibroblasts / drug effects
Heterocyclic Compounds, 2-Ring / chemical synthesis*
Heterocyclic Compounds, 2-Ring / pharmacology*
Humans
Inhibitory Concentration 50
Microtubules / drug effects
Molecular Structure
Neoplasms / drug therapy*
Neoplasms / pathology
Protein Phosphatase 1 / antagonists & inhibitors*
Structure-Activity Relationship
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacology*

Substances

3-((4-(4-(4-fluorophenyl)piperazin-1-ylsulfonyl)phenyl)carbamoyl)-7-oxabicyclo(2.2.1)heptane-2-carboxylic acid
Antineoplastic Agents
Bridged Bicyclo Compounds, Heterocyclic
Enzyme Inhibitors
Heterocyclic Compounds, 2-Ring
Sulfonamides
norcantharidin
DNA
calf thymus DNA
Protein Phosphatase 1