Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

We report here the synthesis of D- and L-myo-inositol 1,2,4,6-tetrakisphosphate 3a and 3b and the racemic modification 3ab. Racemic myo-inositol 1,2,4,6-tetrakisphosphate 3ab was synthesised from DL-1,2,4,6-tetra-O-allyl-myo-inositol 9ab. Benzylation and de-allylation provided the tetraol 11ab, which was phosphitylated in the presence of bis(benzyloxy)diisopropylaminophosphine and 1H-tetrazole, then oxidised to give the fully protected 1,2,4,6-tetrakisphosphate 13ab. Hydrogenolysis of 13ab and purification of product by ion exchange chromatography gave racemic myo-inositol 1,2,4,6-tetrakisphosphate 3ab, which showed no demonstrable agonism or antagonism for Ca2+ release at 200 microM in permeabilised hepatocytes. The chiral derivatives, D-3a and L-myo-inositol 1,2,4,6-tetrakisphosphate 3b were synthesised from 5-O-benzyl-1,4,6-tri-O-p-methoxybenzyl-myo-inositol 19ab, which was resolved using R-(-)-O-acetylmandelic acid providing two diastereoisomers 21 and 22 which were separated and deacylated to give the corresponding enantiomers. Further transformations gave the corresponding chiral 1,2,4,6-tetraols which were phosphitylated, oxidised, deprotected and purified as for the racemic mixture. The enantiomeric tetrakisphosphates 3a and 3b were evaluated for inhibition of the metabolic enzymes inositol 1,4,5-trisphosphate 5-phosphatase and 3-kinase in comparison with the enantiomers of another synthetic regioisomer D- and L-myo-inositol 1,2,4,5-tetrakisphosphate. Both D- and L-myo-inositol 1,2,4,6-tetrakisphosphate inhibit 5-phosphatase with an IC50 value of 3.8 microM and 14 microM, repectively. However, both enantiomers were poorly recognised by the 3-kinase enzyme, with IC50 values greater than 100 microM. The enantiomers of the 1,2,4,5-tetrakisphosphate showed the same relative pattern of activity towards the two enzymes but were more potent against 5-phosphatase (0.47 microM and 3 microM respectively).


Journal article


Org Biomol Chem

Publication Date





3546 - 3556


Animals, Brain, Crystallography, X-Ray, Enzyme Inhibitors, Humans, Inositol Phosphates, Inositol Polyphosphate 5-Phosphatases, Models, Chemical, Models, Molecular, Molecular Structure, Phosphoric Monoester Hydrolases, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Rats, Stereoisomerism