Revealing 2-Dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as Sphingosine Kinase 2 inhibitors: some hints on the structural basis for selective inhibition

Macarena Corro-Morón, Albert Granell, Varbina Ivanova, Elena Domingo, Raúl Beltrán-Debón, Xavier Barril, Maria-Jesus Sanz, M. Isabel Matheu,^* Sergio Castillón,^* Yolanda Díaz*

Bioorg. Chem. 2022, 121, 105668

Sphingosine derivatives bearing a tetrasubstituted center at C2, dimethylhydrazino or azo groups and modifications in the lipophilic tail were synthesized and evaluated in vitro as SphK inhibitors. Compounds 19a-b, featuring an alkyne moiety as a linker, showed selective SphK2 inhibition activity. Docking studies account for the interactions explaining this selectivity, and cell viability assays show that 19a is not cytotoxic to human endothelial cells at 30 μM.

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