Structure–activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors. Issue 21 (1st November 2015)

• Record Type: Journal Article
• Authors: Congdon, Molly D.; Childress, Elizabeth S.; Patwardhan, Neeraj N.; Gumkowski, James; Morris, Emily A.; Kharel, Yugesh; Lynch, Kevin R.; Santos, Webster L.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 21(2015)
• Page Start: 4956
• Page End: 4960
• Publication Date: 2015-11-01
• Subjects: Sphingosine kinase -- SphK1 -- SphK2 -- Sphingosine-1-phosphate -- S1P; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.041
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 ofSLR080811, a SphK2-selective inhibitor. Our studies demonstrate that the internal phenyl ring is a key structural feature that is essential in theSLR080811 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.