Membrane-permeant analogues of the putative second messenger myo-inositol 3,4,5,6-tetrakisphosphate

For future investigations of the binding properties of D-myo-inositol 3,4,5,6- and 1,4,5,6-tetrakis-phosphate [D-Ins(3,4,5,6)P₄ and D-Ins(1,4,5,6)P₄, respectively] to their putative target proteins, a set of analogues with modifications of the 1(3)- and/or 2-hydroxy group has been prepared. The reaction sequences started from D-3,4,5,6-tetra-O-benzyl-myo-inositol or its D-1,4,5,6-enantiomer, respectively and allowed the introduction of groups with degenerative hydrogen-bonding potential like methoxy or chloride, replacing the hydroxy groups. Additionally, the corresponding DL-scylto-inositol precursor 24 was prepared by a stereochemically optimized reduction of the 2-inosose derivative 23. Classical protection/deprotection chemistry and subsequent phosphorylation employing a common phosphite approach yielded the tetrakisphosphate analogues la-e, 3. These derivatives were converted to the uncharged, bioactivalable acetoxymethyl esters 2a-e, 4. To avoid cyclization of phosphates during acetoxymethyl alkylation and to increase lipophilicity of the potentially membrane-permeant InsP₄ derivatives hydroxy groups of the monosubstituted tetrakisphosphates were covered by intracellularly hydrolysable butyrates.