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.
Liu
C
C
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Riley
A M
AM
Yang
X
X
Shears
S B
SB
Potter
B V
BV
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; C435196:inositol 2,3,4,5-tetrakisphosphate; C013571:inositol pentaphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C103909:inositol-tetrakisphosphate 1-kinase; C056875:myo-inositol-trisphosphate 6-kinase