The overall objective of this study is to develop syntheses of labeled cellular phosphoinositides tagged with stable or radioactive isotopes. A strategy for synthesis is suggested which also provides a concise synthesis of the natural phosphoinositides. During Phase I, the feasibility of labeling in the inositol moiety with hydrogen isotopes will be established by the synthesis of a representative polyphosphorylated phosphoinositide. In Phase II, the synthesis will be adapted and extended to the complete series of cellular phosphoinositides and analogues tagged with selected isotope labels. The phosphoinositides are vital components of the pool of intracellular mediators in signaling, and undergo active metabolic changes in response to external stimuli and during cell cycle. The target products of this proposal are needed (I) as research reagents for studying interactions with enzymes and regulatory proteins of intracellular signaling cascades, (ii) as tracers and reference compounds for metabolic pathways of the phosphoinositides in the development of new drug modalities for aberrant intracellular signaling, and (iii) for developing medical diagnostics. PROPOSED COMMERCIAL APPLICATION: Labelled phosphoinositides and their metabolites are useful as research biochemicals and diagnostic reagents. The synthetic methodology has utility for developing analogues and congeners as potential drugs and biotechnology aids.
