Effects of Synthetic Sphingosine-1-Phosphate Analogs on Cytosolic Phospholipase A2α–Independent Release of Arachidonic Acid and Cell Toxicity in L929 Fibrosarcoma Cells: the Structure–Activity Relationship

Journal of Pharmacological Sciences

Hiromichi Fujino²  Takeshi Kurosawa²  Toshihiko Murayama²  Erika Yamaura²  Yuki Muramatsu¹  Atsushi Nishida¹  Masaya Shimizu²  Yuri Miyasaka¹  Yuuki Koide¹  Yuuya Houjyo¹  Hiroyuki Nakamura²  Eiko Tada² 

[1] Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Japan;Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan

关键词: sphingosine-1-phosphate;    ceramide-1-phosphate;    synthetic analog;    phospholipase A2;    cell death;   

DOI  :  10.1254/jphs.08284FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(37)Cited-By(5)Supplementary materials(1)Sphingolipid metabolites including ceramide, sphingosine, and their phosphorylated products [sphingosine-1-phosphate (S1P) and ceramide-1-phosphate] regulate cell functions including arachidonic acid (AA) metabolism and cell death. The development of analogs of S1P may be useful for regulating these mediator-induced cellular responses. We synthesized new analogs of S1P and examined their effects on the release of AA and cell death in L929 mouse fibrosarcoma cells. Among the analogs tested, several compounds including DMB-mC11S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMB-mC9S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-nonyl)phenylpropyl phosphate] released AA within 1 h and caused cell death 6 h after treatment. The release of AA was observed in C12 cells [a L929 variant lacking a type α cytosolic phospholipase A2 (cPLA2α)] and L929-cPLAα–siRNA cells (L929 cells treated with small interference RNA for cPLA2α). Treatment with pharmacological inhibitors of secretory and Ca2+-independent PLA2s decreased the DMB-mC11S–induced release of AA. The effect of the S1P analogs tested on the release of AA was comparable to that on cell death in L929 cells, and a high correlation coefficient was observed. Two analogs lacking a butoxycarbonyl moiety [DMAc-mC11S (dimethyl (2S,3R)-2-acetamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMAm-mC11S [dimethyl (2S,3R)-2-amino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate)] had inhibitory effects on the release of AA and cell toxicity induced by DMB-mC11S. Synthetic phosphorylated lipid analogs may be useful for studying PLA2 activity and its toxicity in cells. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08284FP]

【 授权许可】

Unknown