Synthesis and Ca(2+)-release activity of D- and L-myo-inositol 2,4,5-trisphosphate and D- and L-chiro-inositol 1,3,4-trisphosphate.

Partial benzoylation of the 3,4-dibenzyl ethers of D- and L-chiro-inositol provided the 1,2,5-tri-O-benzoyl-3,4-di-O-benzyl-chiro-inositols. Inversion of the free axial hydroxyl group gave a mixture of chiral 1,3,4- and 1,2,4-tri-O-benzoyl-5,6-di-O-benzyl-myo-inositols [W. Tegge and C. E. Ballou, Proc. Natl. Acad. Sci. U.S.A., 86 (1989) 94-98]. Catalytic hydrogenolysis cleaved the benzyl ether groups of the 1,3,4-tri-O-benzoyl-5,6-di-O-benzyl-myo-inositols (D- and L-) to yield the 1,3,4-tri-O-benzoyl-myo-inositols, which were phosphorylated by a dibenzyl phosphoramidite method. Removal of all blocking groups gave the pure enantiomeric myo-inositol 2,4,5-trisphosphates. Syntheses of the chiro-inositol 1,3,4-trisphosphates, which are analogs of the myo-inositol 1,4,5-trisphosphates having an axial phosphate group at position 1, or analogs of the myo-inositol 2,4,5-triphosphates having an axial hydroxyl at position 1, were also devised starting with the 1,2,5-tri-O-benzoyl-3,4-di-O-benzyl-chiro-inositols. In a calcium-release assay with saponin-permeabilized rat basophilic leukemia cells, the D isomers of both of these analogs had EC50 values of 4 microM, compared with a value of 0.17 microM for D-myo-inositol 1,4,5-trisphosphate, whereas the L isomers had EC50 values of about 100 microM.