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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).

Type

Journal article

Journal

Org Biomol Chem

Publication Date

21/10/2003

Volume

1

Pages

3546 - 3556

Keywords

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