Mills Stephen J, Backers Katrien, Erneux Christophe, Potter Barry V L
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, UK BA2 7AY.
Org Biomol Chem. 2003 Oct 21;1(20):3546-56. doi: 10.1039/b302986g.
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).
我们在此报告D-和L-肌醇1,2,4,6-四磷酸酯3a和3b以及外消旋体3ab的合成。外消旋肌醇1,2,4,6-四磷酸酯3ab由DL-1,2,4,6-四-O-烯丙基-肌醇9ab合成。苄基化和脱烯丙基反应得到四醇11ab，其在双(苄氧基)二异丙基氨基膦和1H-四氮唑存在下进行磷酰化反应，然后氧化得到完全保护的1,2,4,6-四磷酸酯13ab。13ab进行氢解反应，并通过离子交换色谱法纯化产物，得到外消旋肌醇1,2,4,6-四磷酸酯3ab，其在通透化肝细胞中200微摩尔浓度下对钙离子释放未表现出明显的激动或拮抗作用。手性衍生物D-3a和L-肌醇1,2,4,6-四磷酸酯3b由5-O-苄基-1,4,6-三-O-对甲氧基苄基-肌醇19ab合成，该化合物用R-(-)-O-乙酰扁桃酸拆分得到两个非对映异构体21和22，将它们分离并脱酰基得到相应的对映体。进一步转化得到相应的手性1,2,4,6-四醇，其进行磷酰化、氧化、脱保护和纯化，方法与外消旋混合物相同。与另一种合成区域异构体D-和L-肌醇1,2,4,5-四磷酸酯的对映体相比，评估了对映体四磷酸酯3a和3b对代谢酶肌醇1,4,5-三磷酸5-磷酸酶和3-激酶的抑制作用。D-和L-肌醇1,2,4,6-四磷酸酯均抑制5-磷酸酶，IC50值分别为3.8微摩尔和14微摩尔。然而，两种对映体均未被3-激酶很好地识别，IC50值大于100微摩尔。1,2,4,5-四磷酸酯的对映体对这两种酶表现出相同的相对活性模式，但对5-磷酸酶的活性更强(分别为0.47微摩尔和3微摩尔)。
