Synthesis and biological activity of D- and L-chiro-inositol 2,3,4,5-tetrakisphosphate: design of a novel and potent inhibitor of Ins(3,4,5,6)P4 1-kinase/Ins(1,3,4)P3 5/6-kinase.

The synthesis of a novel and potent Ins(3,4,5,6)P4 1-kinase/Ins(1,3,4)P3 5/6 kinase inhibitor and its enantiomer is described. D-chiro-Inositol 2,3,4,5-tetrakisphosphate [D-chiro-Ins(2,3,4,5)P4, 3, Figure 1] and L-chiro-inositol 2,3,4,5-tetrakisphosphate [L-chiro-Ins(2,3,4,5)P4, ent-3] were synthesized from D-1,6-di-O-benzyl-chiro-inositol and L-1,6-di-O-benzyl-chiro-inositol, respectively. We examined inhibition of the multifunctional Ins(3,4,5,6)P4 1-kinase/Ins(1,3,4)P3 5/6-kinase from bovine aorta by 3 and ent-3. Compound 3 was a potent inhibitor with an IC(50) of 1.5 microM, and ent-3 was more than 20-fold less active. The results are compared to those for other inhibitory inositol polyphosphates with structure-activity relationship discussion. Compound 3 is a useful lead for development of further inhibitors of this important enzyme, and ent-3 should find applications in the newly emerging Ins(1,4,5,6)P4 signaling pathway.