Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors
Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors
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DOI：
10.1016/j.bmcl.2015.03.041
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发表时间：
2015-11-01
影响因子：
2.7
通讯作者：
Santos, Webster L.
中科院分区：
文献类型：
--
作者：
Congdon, Molly D.;Childress, Elizabeth S.;Santos, Webster L.
鞘氨醇-1-磷酸（S1 P）是一种普遍存在的内源性小分子，由鞘氨醇激酶的两种亚型（SphK 1和2）合成。S1 P信号通路的干预已经引起了极大的关注，因为S1 P水平的改变与几种疾病状态有关，包括癌症，纤维化和镰状细胞病。虽然密集的研究集中在开发SphK 1抑制剂，只有有限数量的SphK 2选择性药物已被报道。在此，我们报告了我们的调查的亲脂性尾部区域的SphK 2的选择性抑制剂SLR 080811的构效关系的研究。我们的研究表明，内部苯环是SLR 080811支架中必不可少的关键结构特征。此外，我们显示了SphK 2的活性和选择性对烷基尾长的依赖性，表明SphK 2中的脂质结合口袋比SphK 1更大。(C)2015爱思唯尔有限公司版权所有。
Sphingosine-1-phosphate (S1P) is a ubiquitous, endogenous small molecule that is synthesized by two isoforms of sphingosine kinase (SphK1 and 2). Intervention of the S1P signaling pathway has attracted significant attention because alteration of S1P levels is linked to several disease states including cancer, fibrosis, and sickle cell disease. While intense investigations have focused on developing SphK1 inhibitors, only a limited number of SphK2-selective agents have been reported. Herein, we report our investigations on the structure-activity relationship studies of the lipophilic tail region of SLR080811, a SphK2-selective inhibitor. Our studies demonstrate that the internal phenyl ring is a key structural feature that is essential in the SLR080811 scaffold. Further, we show the dependence of SphK2 activity and selectivity on alkyl tail length, suggesting a larger lipid binding pocket in SphK2 compared to SphK1. (C) 2015 Elsevier Ltd. All rights reserved.