New sulfoglycophoshoramidates as phosphoinositide mimetics

Protein kinases are enzymes involved in the regulation of many crucial cellular processes like proliferation, differentiation and apoptosis. Among them, the serine/threonine protein kinase B (PKB), also known as Akt, plays a key role as a component of the phosphoinositide 3-kinase (PI3K)-Akt-mTOR axis, which is implicated in aberrant tumor cell signaling. Inappropriate activation of the Akt kinase is a common event in human tumors and Akt is a critical player in cell survival. Thus, inhibitors that target PI3Ks and its downstream effectors, including PKB are potentially relevant for cancer therapy. PI3K activation generates 3-phosphorylated phosphatidylinositols [PI(3)P] that bind PKB pleckstrin homology (PH) domain promoting PKB activation through its translocation from the cytosol to the plasma membrane, conformational change and final phosphorylation. New glucose-based inositol analogues are currently investigated as potential Akt inhibitors and the structure of PI(3)P, natural ligand of PKB PH domain, can be easily reconducted to a suitably modified d-glucose scaffold as in phosphoramidate. Here, the synthesis of a set of unnatural sulphoglycophosphoramidate as PI(3)P analogues targeting the PKB PH domain will be reported. In particular, we synthesized a series of analogues of natural sulfoquinovosylacylglycerols (SQAG) in which sulfoquinovose is beta-linked to a phosphoramidate moiety with different alkyl chains.