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Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors.

Abstract：

: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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Congdon MD,Childress ES,Patwardhan NN,Gumkowski J,Morris EA,Kharel Y,Lynch KR,Santos WL

doi

10.1016/j.bmcl.2015.03.041

subject

Has Abstract

pub_date

2015-11-01 00:00:00

pages

4956-4960

issue

21

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(15)00247-4

journal_volume

25

pub_type

杂志文章

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