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Rationally designed Tocotrienol analogues in order to enhance their antiproliferative activity
Cancer is the second most common cause of death in the US, accounting for one of every four deaths. Vitamin E is a generic term for tocopherols and tocotrienols. Vitamin E members have potent antiangiogenic and antiproliferative activities. Unfortunately, their activity is weakened due to their short elimination half life in vivo as a result of CYP450 oxidation to the corresponding caboxyethyl-hydroxychromans. Recent findings suggest that the antiproliferative γ-tocotrienol may act upstream of the PI3K/PDK-1/AKT mitogenic signaling pathway at the level of the EGF-receptor. Results demonstrated that the antiproliferative effects of γ-tocotrienol on the neoplastic +SA mammary epithelial cells are mediated through the reduction of ErbB3 tyrosine phosphorylation and subsequent activation of the PI3K/PDK-1/AKT mitogenic signaling pathway. Molecular modeling provides a good method to make rationally designed tocotrienol analogues with better affinity to α-tocopherol transfer protein (α-TT) and epidermal growth factor (ErbB3) receptors. However, chemists can't totally depend on molecular modeling without biological assay results. Flexible docking and Molcad surface creation were performed using SYBYL 8.0 program package. Docking process demonstrated good binding scores of carbamate analogues of tocotrienols to both α-TT and ErbB3 over tocotrienols. The ultimate objective was to safely develop semisynthetically modified tocotrienols with enhanced therapeutic effects. Reaction of isocyanate derivatives with the phenolic hydroxyl group produced a series of tocotrienol carbamates that demonstrated a good yield with enhanced anticancer activity. Computer- assisted drug design is an efficient technology for the design of semisynthetic tocotrienol analogues with enhanced antiproliferative activity.
Acknowledgements: Financial support is provided from First Tech. Company, Australia.
Referances:1. Sylvester, P. et al. (2007) Curr Res in Cancer 1:55–75.
2. You, C., Sontag, T. (2005)J Nutr 135:227–232.