Fluorinated cyclitols as useful biological probes of phosphatidylinositol metabolism

A number of deoxyfluoro cyclitols have been synthesized and evaluated as probes of the phosphatidylinositol pathway (PtdIns pathway), most notably 5-deoxy-5-fluoro-myo-inositol, which is incorporated into the pathway at about 25% the level of myo-inositol itself. Unfortunately, none of the cyclitols have proved effective in limiting cell proliferation, as the cells are able to 'synthesize around' the fraudulent cyclitols using natural myo-inositol as substrate. Inhibitors for 3-phosphatidylinositol kinase, which has importance in a number of pathological conditions, including cancer, have been intensively investigated. 3-Deoxy-3-fluoro-myo-inositol is incorporated into the PtdIns pathway; however, only related phosphatidyl derivatives, for example, a methyl ether derivative of the 3-deoxy inositol, showed significant antiproliferative activity. Synthesis of the deoxyfluoro analogues most often has been accomplished by DAST fluoro-de-hydroxylation of the appropriate cyclitol, generally leading to products of inversion.