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

Abstract

For future investigations of the binding properties of D-myo-inositol 3,4,5,6- and 1,4,5,6-tetrakisphosphate [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-scyllo-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 1a–e, 3. These derivatives were converted to the uncharged, bioactivatable 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.