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Synthesis and biological evaluation of sphingosine kinase 2 inhibitors with anti‐inflammatory activity
Author(s) -
Vettorazzi Marcela,
Vila Laura,
Lima Santiago,
Acosta Lina,
Yépes Felipe,
Palma Alirio,
Cobo Justo,
Tengler Jan,
Malik Ivan,
Alvarez Sergio,
Marqués Patrice,
Cabedo Nuria,
Sanz María J.,
Jampilek Josef,
Spiegel Sarah,
Enriz Ricardo D.
Publication year - 2019
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201800298
Subject(s) - chemistry , sphingosine , sphingosine kinase , pharmacology , inflammation , biochemistry , stereochemistry , biology , immunology , sphingosine 1 phosphate , receptor
The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7‐bromo‐2‐(2‐phenylethyl)‐2,3,4,5‐tetrahydro‐1,4‐epoxynaphtho[1,2‐ b ]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti‐inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil–endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.