Synthesis and evaluation of a new anionic glycoglycerolipids targeting protein kinase B (AKT)

Protein kinases are enzymes involved in the regulation of many crucial cellular processes. Among them, 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 (PI3P) 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. Thus, inhibitors that target PI3Ks and its downstream effectors, including Akt are potentially relevant for cancer therapy. New sulfoquinovosylacylglycerols (SQAG) analogues are currently investigated as potential Akt inhibitors, their structure being easily reconducted to PI3P. Here, the synthesis of new anionic glycoglycerolipids 2 derived from the sulfoglycolipids as PI3P analogues targeting the PKB PH domain will be reported. In particular, a series of analogues of natural SQAG in which glucose is β-linked to the 2 position of an acylglycerol and a carboxyl replaces the sulfonate group, together with some simpler related β-glucuronides, will be shown. Their PKB inhibitory activity and the biological activity of selected compounds will be presented.