Synthesis of 3-Position-Modified Analogues of myo-Inositol 1,4,5-Trisphosphate, Tools for Investigation of the Polyphosphoinositide Pathway of Cellular Signaling.
Synthesis of 3-Position-Modified Analogues of myo-Inositol 1,4,5-Trisphosphate, Tools for Investigation of the Polyphosphoinositide Pathway of Cellular Signaling.
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肌醇 1,4,5-三磷酸 3 位修饰类似物的合成，用于研究细胞信号传导多磷酸肌醇途径的工具。
DOI：
10.1021/jo970926y
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
B. Potter
中科院分区：
文献类型：
--
作者：
C. Liu;B. Potter
本文介绍了以肌醇为原料合成外消旋形式的3-O-（羧甲基）-和3-O-烷基化肌醇1，4，5-三磷酸酯的方法。对于DL-3-O-（羧甲基）-肌醇-1，4，5-三磷酸盐，一种肌醇-1，3，4，5-四磷酸盐的类似物，DL-3-O-烯丙基-2，6-二-O-苄基-1-O-（对甲氧基苄基）-4，5-O-异亚丙基-肌醇（14）是从肌醇经七步反应制得的。将14用酸处理后得到的三醇DL-3-O-烯丙基-2，6-二-O-苄基-肌醇（26）进行亚磷酸化，产物氧化得到完全保护的三磷酸酯27。27的3-O-烯丙基醚在氰乙基保护的磷酸三酯存在下的有效氧化裂解是通过用NaIO（4）/RuCl（3）水合物处理27得到完全保护的3-O-（羧甲基）三磷酸酯28来实现的。解封闭后，得到DL-3-O-（羧甲基）三磷酸盐6。对于DL-3-O-烷基化肌醇1，4，5-三磷酸类似物，完全保护的14被异构化为顺式丙-1-烯基衍生物15。除去丙烯基，得到DL-2，6-二-O-苄基-1-O-（对甲氧基苄基）-4，5-异亚丙基-肌醇（16）。分别用甲基碘、乙基碘或正丙基碘处理16的阴离子，合成了3-O-甲基醚17、3-O-乙基醚18和3-O-正丙基醚19衍生物。除去异亚丙基和对甲氧基苄基，得到3-O-烷基化三醇20、21或22，将其亚磷酸化，并将产物氧化，得到相应的完全保护的3-O-烷基化三磷酸盐23-25。脱保护得到3-O-甲基-（3）、3-O-乙基-（4）或3-O-正丙基-肌醇1，4，5-三磷酸盐（5）。这些化合物将为研究肌醇1，4，5-三磷酸与其受体和代谢酶的相互作用提供有用的药理学工具。
Methods for the synthesis of 3-O-(carboxymethyl)- and 3-O-alkylated myo-inositol 1,4,5-trisphosphates in racemic form from myo-inositol have been devised. For DL-3-O-(carboxymethyl)-myo-inositol 1,4,5-trisphosphate, an analogue of myo-inositol 1,3,4,5-tetrakisphosphate, DL-3-O-allyl-2,6-di-O-benzyl-1-O-(p-methoxybenzyl)-4,5-O-isopropylidene-myo-inositol (14) was prepared from myo-inositol in seven steps. The triol DL-3-O-allyl-2,6-di-O-benzyl-myo-inositol (26), which was obtained after treatment of 14 with acid, was phosphitylated and the product oxidized to give the fully protected trisphosphate 27. The efficient oxidative cleavage of the 3-O-allyl ether of 27 in the presence of the cyanoethyl-protected phosphate triesters was achieved by treatment of 27 with NaIO(4)/RuCl(3).hydrate to afford the fully protected 3-O-(carboxymethyl) trisphosphate 28. After deblocking, DL-3-O-(carboxymethyl) trisphosphate 6 was obtained. For DL-3-O-alkylated myo-inositol 1,4,5-trisphosphate analogues, the fully protected 14 was isomerized to the cis-prop-1-enyl derivative 15. The propenyl group was removed to give DL-2,6-di-O-benzyl-1-O-(p-methoxybenzyl)-4,5-isopropylidene-myo-inositol (16). The 3-O-methyl ether 17, 3-O-ethyl ether 18, and 3-O-n-propyl ether 19 derivatives were synthesized by treatment of the anion of 16 with methyl iodide, ethyl iodide, or n-propyl iodide, respectively. Removal of the isopropylidene and p-methoxybenzyl groups afforded 3-O-alkylated triols 20, 21, or 22, which were phosphitylated and the products oxidized to give the respective fully protected 3-O-alkylated trisphosphates 23-25. Deprotection furnished 3-O-methyl- (3), 3-O-ethyl- (4), or 3-O-n-propyl-myo-inositol 1,4,5-trisphosphate (5). These compounds will be useful pharmacological tools to explore the interaction of myo-inositol 1,4,5-trisphosphate with its receptor and metabolic enzymes.