Synthesis and evaluation of sphingoid analogs as inhibitors of sphingosine kinases

被引:70
作者
Kim, JW
Kim, YW
Inagaki, Y
Hwang, YA
Mitsutake, S
Ryu, YW
Lee, WK
Ha, HJ
Park, CS
Igarashi, Y [1 ]
机构
[1] Hokkaido Univ, Grad Sch Pharmaceut Sci, Dept Biomembrane & Biofunct Chem, Kita Ku, Sapporo, Hokkaido 0600812, Japan
[2] Doosan Biotech, Yongin 449795, Gyeonggi Do, South Korea
[3] Sogang Univ, Dept Chem, Program Integrated Biotechnol, Mapo Ku, Seoul 121742, South Korea
[4] Hankuk Univ Foreign Studies, Dept Chem, Mohyun 449791, South Korea
[5] Ajou Univ, Dept Mol Sci & Technol, Suwon 443749, South Korea
关键词
sphingosine analog; sphingosine kinase; inhibitor; aziridine;
D O I
10.1016/j.bmc.2005.02.053
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sphingosine 1-phosphate (SIP), a product of sphingosine kinases (SphK), mediates diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis. In an effort to search and identify specific inhibitors of human SphK, the inhibitory effects of synthetic sphingoid analogs on kinase activity were examined. Among the analogs tested, we found two, SG12 and SG14, that have specific inhibitory effects on hSphK2. N,N-Dimethylsphingosine (DNIS), a well-known SphK inhibitor, displayed inhibitory effects for both SphK1 and SphK2, as well as protein kinase C. In contrast, SG12 and SG14 exhibited selective inhibitory effects on hSphK2. Furthermore, SG14 did not affect PKC. In isolated platelets, SG14 blocked the conversion of sphingosine into sphingosine 1-phosphate significantly. This is the first report on the identification of a hSphK2-specific inhibitor, which may provide a useful toot for studying the biological functions of hSphK2. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3475 / 3485
页数:11
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