Synthesis and Biological Activity of PTEN-Resistant Analogues of Phosphatidylinositol 3,4,5-Trisphosphate

Abstract

The activation of phosphatidylinositol 3-kinase (PI 3-K) and subsequent production of PtdIns(3,4,5)P₃ launches a signal transduction cascade that impinges on a plethora of downstream effects on cell physiology. Control of PI 3-K and PtdIns(3,4,5)P₃ levels is an important therapeutic target in treatments for allergy, inflammation, cardiovascular, and malignant human diseases. We designed metabolically stabilized, that is, phosphatase resistant, analogues of PtdIns(3,4,5)P₃ as probes for long-lived potential agonists or potential antagonists for cellular events mediated by PtdIns(3,4,5)P₃. In particular, two types of analogues were prepared containing phosphomimetics that would be selectively resistant to the lipid 3-phosphatase PTEN. The total asymmetric synthesis of the 3-phosphorothioate−PtdIns(3,4,5)P₃ and 3-methylenephosphonate−PtdIns(3,4,5)P₃ analogues is described. These two analogues showed differential binding to PtdIns(3,4,5)P₃ binding modules, and both were potential long-lived activators that mimicked insulin action in sodium transport in A6 cells.