52(P13) 新規ジエノン型プロスタグランジンの合成と神経突起伸展促進作用(ポスター発表の部)

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A and J-type prostaglandins (PGs) are important biosignaling compounds that are closely concerned with cell proliferation and differentiation. Such PGs suppress tumor cell growth by arresting the cell cycle at the G1 phase via regulation of specific gene expression. Further, dehydrated 15-deoxy-Δ^<12,14>-PGJ_2 promotes adipocyte differentiation by activating a nuclear receptor PPARγ. However, little is known about the biological action and physiological role of the enone type PGs except these activities. In this context, we here examined the effects of natural J series PGs and artificial Δ^7-PGA_1 methyl ester and related compounds in PC12 neuronal cells, and found that the dienone type PGs markedly promoted neurite outgrowth/regeneration in the presence of nerve growth factor (NGF). The simple enone PGs such as PGJ_2 and PGA_2 were less active or inactive, indicating that the dienone structure is essential for the activity. Δ^7-PGA_1 methyl ester and its congeners (termed NEPPs, Neurite outgrowth/regeneration promoting prostaglandins) were more potent than natural Δ^<12>-PGJ_2 and 15-deoxy-Δ^<12,14>-PGJ_2. Although Δ^7-PGA_1 methyl ester and its stereoisomers exerted the neurite outgrowth/regeneration promoting activity in PC12 cells in the presence of NGF at a concentration range of 0.1-0.5μM, they undesirably induced cell damage at higher concentrations (>2-5μM). To remove such toxic effects from NEPPs, we modified the structure of Δ^7-PGA_1 based on the hitherto structure/antiproliferative activity data to succeed in synthesizing 13,14-dihydro-15-epi-Δ^7-PGA_1 methyl ester (NEPP10) which has an equipotent neurite outgrowth/regeneration promoting activity to Δ^7-PGA_1 methyl ester and low cytotoxicity. Because of the absence of the C(13)-C(14) double bond, NEPP10 is metabolically stable in sera different from Δ^7-PGA_1. In addition, it can readily be supplied by chiral chemical synthesis. Thus, NEPP10 is expected to be applied as a promising agent to the chemotherapy for neuronal diseases accompanying neurite degeneration.
天然有機化合物討論会の論文
1999-09-01

52(P13) 新規ジエノン型プロスタグランジンの合成と神経突起伸展促進作用(ポスター発表の部)

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