3-(Hydroxymethyl)-bearing phosphatidylinositol ether lipid analogues and carbonate surrogates block PI3-K, Akt, and cancer cell growth

Phosphatidylinositol 3-kinase (PI3-K) phosphorylates the 3-position of phos phatidylinositol to give rise to three signaling phospholipids. Binding of the pleckstrin homolgy (PH) domain of Akt to membrane PI(3)P's causes the t ranslocation of Akt to the plasma membrane bringing it into contact with me mbrane-bound Akt kinase (PDK1 and 2), which phosphorylates and activates Ak t. Akt inhibits apoptosis by phosphorylating Bad, thus promoting its bindin g to and blockade of the activity of the cell survival factor Bcl-x. Herein we present the synthesis and biological activity of several novel phosphat idylinositol analogues and demonstrate the ability of the carbonate group t o function as a surrogate for the phosphate moiety. Due to a combination of their PI3-K and Akt inhibitory activities, the PI analogues 2, 3, and 5 pr oved to be good inhibitors of the growth of various cancer cell lines with IC50 values in the 1-10 mu M range. The enhanced Akt inhibitory activity of the axial hydroxymethyl-bearing analogue 5 compared to its equatorial coun terpart 6 is rationalized based upon postulated differences in the H-bondin g patterns of these compounds in complex with a homology modeling generated structure of the PR domain of Akt. This work represents the first attempt to examine the effects of 3-modified PI analogues on these two crucial cell signaling proteins, PI3-K and Akt, in an effort to better understand their cell growth inhibitory properties.