CONICET | Buscador de Institutos y Recursos Humanos

The sphingosine kinase 1 (SPhK1), is an oncogenic lipid kinase that produces the formation of sphingosine-1-phosphate, a bioactive sphingolipid metabolite, emerging as a promising new therapeutic target with great potential in the treatment of anti-inflammatory, cancer, or another proliferative diseases. We are interested in finding new and more potent inhibitors than those of the known inhibitors, and herein we present a library of structures with a central pyrimidinic scaffold.The rational design of these new chemical entities could be performed from the knowledge of X-ray structures of this enzyme with different inhibitors, and taking advance from the second generation of SPhK1 thiazole inhibitors like 1V2,[1] with a improved activity by merging residues of known SKI-II inhibitor[2] with those of natural ligand in their bound to the enzyme.As depicted from figure, new chemical entities were designed bearing pyrimidine instead of thiazol as the heterocyclic core, and attaching the polar tail via a linker to C2 and the apolar heads to C4 in a similar fragment classification to that made from 1V2. Virtual screening was carried out using our recent model based on QTAIM calculations that analyses the molecular interactions that stabilize the different Ligand-Receptor complexes and give rise to binding affinity values that can be converted into inhibition activity.[3] Our molecular modeling study predicts promising inhibitory effect on SphK1 for these compounds. Therefore, the synthesis of a library of the designed derivatives with the fragments indicated in figure was carried out from 2,4-dicloropyrimidine. Our experimental assays have given excellent inhibitory activities for some derivatives of this series with values ranging from 1 to 10 M. It should be noted that some of these compounds possess inhibitory effect comparable to the well-known inhibitor SKI-II.