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.1
New sulfoquinovosylacylglycerols
(SQAG) analogues 12-4 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 1 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.
1. Vanhaesebroeck B. et al., Nat. Rev. Mol. Cell. Biol., 13, 195-203
(2012).
2.
Dangate M. et al., Bioorg. Med. Chem. 17, 5968–5973 (2009).
3.
Dangate M. et al., Eur. J. Org. Chem. 6019–6026 (2009).
4. Benning, C., Annu. Rev. Plant Physiol. Plant Mol. Biol. 49, 53-75 (1988).
Acknowledgements: This work has been supported
by Fondazione Cariplo, grant n° 2011-0490.
