α-Tocopheryl Succinate as a Scaffold to Develop Potent Inhibitors of Breast Cancer Cell Adhesion

This study is aimed at the pharmacological exploitation of α-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 comp...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-09, Vol.52 (18), p.5642-5648
Main Authors: Wang, Dasheng, Chuang, Hsiao-Ching, Weng, Shu-Chuan, Huang, Po-Hsien, Hsieh, Hao-Yu, Kulp, Samuel K., Chen, Ching-Shih
Format: Article
Language:English
Subjects:
alpha-Tocopherol - chemistry
alpha-Tocopherol - pharmacology
Animals
Antineoplastic agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Breast Neoplasms - pathology
Cell Adhesion - drug effects
Cell Line, Tumor
Cell Movement - drug effects
Drug Discovery
Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors
Focal Adhesion Protein-Tyrosine Kinases - metabolism
General aspects
Humans
Inhibitory Concentration 50
Medical sciences
Mice
Neoplasm Metastasis
Pharmacology. Drug treatments
Pseudopodia - drug effects
Pseudopodia - metabolism
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Summary:This study is aimed at the pharmacological exploitation of α-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 (IC50, 0.6 μM versus 10 μM). 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9002457