20 統一的合成法によるスフィンゴ脂質挙動解明に効果的なツール分子の開発(口頭発表の部)

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Sphingolipids such as sphingomyelin, ceramide, sphingosine, and sphingosine 1-phosphate are known as secondary lipid messengers in mammalian cells and cell membranes, and a great deal of attention has been devoted to studies of the biological processes regulated by sphingolipids. Among them, sphingomyelin has been known as a major component to form raft domain, which has been proposed as the particular organism in a mammalian cell membrane to efficiently transmit various biological signals. Then, efficient synthetic method for these sphingolipids and providing various kinds of their analogues are strongly desired. Now, we established the widely applicable synthetic method for these attractive compounds, and successfully synthesized various kinds of sphingolipids and their analogues including fluorescence and photoaffinity labeled derivatives by utilizing an olefin cross metathesis reaction. This method was very effective to construct their backbone skeleton possessing various functional groups at the terminal. Meanwhile, our method is also very successful to provide the substrate analogues, which possess CH_2, S, NH groups instead of an oxygen atom of the phospholic acid ester in the native sphingolipids, respectively. By utilizing this method, we synthesized many kinds of sphingolipids such as sphingosine, ceramide, sphingomyelin, fluorescence labeled sphingosine 1-phosphate analogues 15, 16, and sphingomyelin analogues 17, 18, 19. Next, we actually utilized our synthesized tool molecules to investigate the behavior of sphongosine 1-phosphate (S1-P) in cell. S1-P is known as an extracellular mediator participating in cell differentiation, cell growth and so on. Directing toward elucidation of the sphingosine 1-phosphate behavior in cell, we examined the effectiveness of fluorescence labeled sphingosine 1-phosphate 14, 15, and 16 in Chinese Hamster Ovary (CHO) cell, respectively. As a result, fortunately, all analogues were recognized as a ligand by sphingosine 1-phosphate receptor. Each analogue, however, played different behavior in cell. Analogue 14 was metabolized to corresponding sphingosine by cellular phosphatases, while analogues 15 and 16 were not metabolized. Furthermore, the analogue 15 activated MAPK and showed no activation after addition of PTx in cell. On the other hand, the analogue 16 did not show this behavior. Thus, they have strongly been expected as effective tool molecules toward elucidation of sphingosine 1-phosphate behavior in cell.
天然有機化合物討論会の論文
2006-09-15

20 統一的合成法によるスフィンゴ脂質挙動解明に効果的なツール分子の開発(口頭発表の部)

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