Synthesis of selective non-Ca(2+)-mobilizing inhibitors of D-myo-inositol 1,4,5-trisphosphate 5-phosphatase.

Syntheses of novel phosphorothioate-based non-Ca(2+)-releasing inhibitors of myo-inositol 1,4,5-trisphosphate 5-phosphatase are described. 1L-myo-Inositol 1,4,5-trisphosphorothioate, myo-inositol 1,3,5-trisphosphorothioate, and 1L-chiro-inositol 1,4,6-trisphosphorothioate have been synthesized from 1L-2,3,6-tri-O-benzyl-1-O-(cis-prop-1-enyl)-myo-inositol, 2,4,6-tris-O-(p-methoxybenzyl)-myo-inositol orthoformate and 1L-2,3,5-tri-O-benzyl-chiro-inositol, respectively. 1L-2,3,5-Tri-O-benzyl-chiro-inositol was also used to prepare 1L-chiro-inositol 1,4,6-trisphosphate. The phosphorothioates did not mobilize intracellular Ca2+ but were highly potent inhibitors of Ins(1,4,5)P3 5-phosphatase, and myo-inositol 1,3,5-trisphosphorothioate and 1L-chiro-inositol 1,4,6-trisphosphorothioate were selective for this enzyme.