alpha-Tocopheryl succinate as a scaffold to develop potent inhibitors of breast cancer cell adhesion.

Dasheng Wang, Hsiao-Ching Chuang, Shu-Chuan Weng, Po-Hsien Huang, Hao-Yu Hsieh, Samuel K Kulp, Ching-Shih Chen

Index: J. Med. Chem. 52 , 5642-8, (2009)

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Abstract

This study is aimed at the pharmacological exploitation of alpha-tocopheryl succinate (1) to develop potent antiadhesion agents. Considering the structural cooperativity between the phytyl chain and the carboxylic terminus in determining the antiadhesion activity, our structural optimization led to compound 5 ([2-(4,8-dimethyl-non-1-enyl)-2,5,7,8-tetramethyl-chroman-6-yloxy]-acetic acid), which exhibited an-order-of-magnitude higher potency than 1 in blocking the adhesion of 4T1 metastatic breast cancer cells to extracellular matrix proteins (IC(50), 0.6 microM versus 10 microM). Evidence indicates that the ability of compound 5 to block cell adhesion and migration was attributable to its effect on disrupting focal adhesion and actin cytoskeletal integrity by facilitating the degradation of focal adhesion kinase. Interactions between tumor cells and the ECM in the tumor microenvironment have been increasingly recognized as critical modulators of the metastatic potential of tumor cells. Consequently, the ability of compound 5 to block such interactions provides a unique pharmacological tool to shed light onto mechanisms that govern cell adhesion and tumor metastasis.