The function of oncogenes is to code for components of intracellular signalling pathways thus subverting the normal process of regulated cell growth. The signalling pathways are rational and attractive targets at which to direct the development of new classes of anticancer drugs that reverse oncogene action. myo-lnositol occupies a unique position in that it mediates two pathways important for cell proliferation, the inositol phosphate/diacylglycerol signalling pathway and the phosphatidylinositol 3- phosphate (Ptdlns-3-k) pathway. Specifically, phosphorylation at the 3- position of the myo-inositol ring appears to be essential for growth stimulation and transformation by both pathways. The hypothesis on which our studies are based is that substitution at the 3-position of myoinositol will give compounds that block the formation of myo-inositol derived second messengers necessary for cell proliferation and transformation, while leaving other aspects of myo-inositol signalling unaffected. This approach provides a basis for the selective control of cancer cell growth without disrupting the function of normal cells. The objective of our studies is to synthesize a series of phosphatidylinositol analogues and use them to study the mechanisms of myo-inositol signalling.
The Specific Aims of the proposal are: (1) To synthesize a series of 3-substituted phosphatidylinositol analogues 2) To use the compounds to study mechanisms of the phosphatidylinositol- kinase signalling in relation to growth factor and oncogene action (3) To study the ability of the compounds above to selectively inhibit the growth of cancer cells in vitro
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