P-55 フォスファチジルイノシトール-3、4、5-トリスフォスフェートおよびその新規類縁体の合成(ポスター発表の部)

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Polyphosphoinositides are important in the cellular signal transduction. The PI-3 kinase, recently discovered, phosphorylates 1 to 4. It is said that 4 is a candidate second messenger in cellular signal transduction, but its role is not clear, yet. To investigate its roles, we designed and synthesized its novel derivatives, such as 1-O-alkyl- and 1-O-acyl-inosiol-3,4,5-trisophosphate in homochiral form as shown in Scheme 3. The key intermediate 7 was prepared according to the reported procedure. The 7 was alkylated with alkyl halide or acylated with acid anhydride. Removal of MPM groups and phosphorylation gave fully protected derivatives 9. All protecting groups were removed by hydrogenolysis to give 1-O-alkyl and 1-O-acyl derivatives. On the other hand, condensation of 7 with 1,2-di-O-stearoyl-glyceromethyl-N,N-diisopropylphosphoramiditc 11 and oxidation gave phosphoinositide 12 (Scheme 4). The MPM groups were removed and the resulting triol phosphorylated to give 13. Removal of all protecting groups of 13 is in progress. To see whether or not 1-O-alkyl and 1-O-acyl derivatives serve as the analogues of 4, we examined the effects on the activities of three enzymes, PIns-3 kinase, PIns-4 kinase and PIns-3,4,5-P_3, 5-phosphatase. The derivatives with long lipophilic side chains inhibited these enzymes. These novel derivatives may be applicable for the further studies of the role of 4 in cellular signal transduction. In order to synthesize various other derivatives, we have established the efficient asymmetric synthetic route of myo-inositol from D-(-)-diethyltartrate 14. Acetalization to diethyl-2,3-isopropylidenc tartrate, successive DIBAH reduction and Wittig-Horner reaction in one pot and DIBAH reduction gave 15 according. Sharpless's asymmetric epoxidation of 15 afforded the diepoxy alcohol 16, which was iodinated and the resulting mixture was reduced with Zn to give 17. Protection and ozonolysis of 17 gave known dialdehyde 18 which could be transformed to myo-inositol ring by intramolecular pinacol coupling (Scheme 5). Coupling of asymmetric dialdchyde 20 gave two inositol derivatives 21 and 22 in 2:1. These synthetic routes were not only applicable for the synthesis of 1-O-alkyl and 1-O-acyl derivatives, but also of some inositol-polyphosphates such as inositol-1,2,4,5-tetrakisphosphate etc..
天然有機化合物討論会の論文
1995-09-01

P-55 フォスファチジルイノシトール-3、4、5-トリスフォスフェートおよびその新規類縁体の合成(ポスター発表の部)

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