Stabilized N-oxyamide anionic glycoglycerolipids targeting protein kinase B (AKT)

Protein kinase are enzymes involved in the regulation of many crucial cellular processes like proliferation, differentiation and apoptosis. Among them, the serine/threonine protein kinase B, 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 making Akt a critical player in cell survival and, consequently, inhibitors that target Akt are potentially relevant for cancer therapy. The structure of the phosphatidylinositol 3,4,5 triphosphate [PtdIn(3,4,5)P3 or PIP3], the natural ligand of Akt PH domain, is composed by an inositol, with a phosphate group in position 3 and a glycerol moiety in position 1 carrying long acyl chains. Recently, two classes of anionic glycoglycerolipids based on 2-O-b-D-glucosylglycerol mimicking PIP3 bearing a carboxilate or sulfonate group on the sugar moiety were syntesized. The antiproliferative activity of the compounds was observed in the human ovarian carcinoma IGROV-1 cell line showing an interesting difference in their IC50 values depending on the experimental procedure used. In fact, we found that their growth inhibitory effect was favored in a serum-free medium, thus implying that serum affects the stability. Conversion into N-oxyamide is an eligible modification to improve metabolic stability of carboxylic derivatives. Therefore, in this study N-oxyamide-linked anionic glycoglycerolipids analogues of the previously tested Akt inhibitors were prepared and tested for their antiproliferative activity in the human ovarian carcinoma IGROV-1 cell line.