Synthesis and biological evaluation of sphingosine kinase 2 inhibitors with anti-inflammatory activity

VETTORAZZI, MARCELA; VILA, LAURA ; LIMA, SANTIAGO ; ACOSTA, LINA ; YEPES, FELIPE ; PALMA, ALIRIO ; COBO, JUSTO ; TENGLER, JAN ; MALIK, IVAN ; ALVAREZ, SERGIO ; MARQUÉS, PATRICE ; CABEDO, NURIA ; SANZ, M. JESUS ; JAMPILEK, JOSEF ; SPIEGEL, SARAH ; ENRIZ, RICARDO D.

ARCHIV DER PHARMAZIE.

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2018 vol. 352

0365-6233

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.