Chemistry of Inositol Lipid Mediated Cellular Signaling

It is now slightly more than a decade since Michael Berridge and his collaborators reported in Nature “…micromolar concentrations of Ins(1,4,5) P 3 (1 D ‐ myo ‐inositol 1,4,5‐trisphosphate) release Ca 2+ from a non‐mitochondrial intracellular Ca 2+ store in pancreatic acinar cells. Our results strongly suggest that this is the same Ca 2+ store that is released by acetylcholine”. This observation ushered in an a new era in the field of signal transduction with the discovery of a small‐molecule second messenger liniking the spatially separated events of cell surface receptor activation and intracellular Ca 2+ mobilization. This event, which has spawned what is now one of the most active fields of current biology, also stimulated a renaissance in inositol and inositol phosphate chemistry. The synthesis of inositol polyphosphates presents a number of problems: the regiospecific protection of inositol and the optical resolution of the resulting precursors, the phosphorylation of the polyol, removal of all phosphate protecting groups without phosphate migration, and finally the purification of the water‐soluble target polyanion. With the solution of these problems over the last few years it is now possible to look beyond the synthesis of naturally occurring inositol polyphosphates, whose number has been steadily increasing, to the design of chemically modified inositol phosphate analogues with the prospect of developing enzyme inhibitors, rationally modified receptor ligands and antagonists, and perhaps, through pharmacological intervention in signal transduction pathways, even the therapeutical agents of the future.