Synthesis and Biological Evaluation of Sphingosine Kinase 2 Inhibitors with Anti-inflammatory Activity

VETTORAZZI M; VILA L; LIMA S; ACOSTA L; YEPES F; PALMA A; COBO J; TENGLER J; MALIK I; ALVAREZ SE; MARQUES E; CABEDO N; JESUS SANZ M; JAMPILEK J; SPIEGEL S; ENRIZ RD

ARCHIV DER PHARMAZIE.

WILEY-V C H VERLAG GMBH

Año: 2019

0365-6233

We report here the synthesis of inhibitors of SphK2 with novel structural scaffolds. 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.