Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents

VETTORAZZI, MARCELA; DÍAZ, IVÁN; ANGELINA, EMILIO; SALIDO, SOFÍA; GUTIERREZ, LUCAS; ALVAREZ, SERGIO E.; COBO, JUSTO; ENRIZ, RICARDO D.

BIOORGANIC CHEMISTRY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2024 vol. 144

0045-2068

We report here the virtual screening design, synthesis and activity of eight new inhibitors of SphK1. For thisstudy we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. Thisexploratory analysis proposed nine compounds from which eight displayed significant inhibitory effect againstsphingosine kinase 1 (SphK1) demonstrating a high level of efficacy for this approach. Four of these compoundsalso displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have showna wide inhibitory action against many of the cancer cell line tested, with GIbelow 5 µM, being (5) the mostpromising with TGI below 10 µM for the half of cell lines. Our results suggest that the three most promisingcompounds reported here are the pyrimidine-quinolone hybrids (1) and (6) linked by p-aminophenylsulfanyl ando-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive studyabout the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecularmodeling analysis was carried out by using combined techniques: docking calculations, MD simulations andQTAIM analysis. In this study we also included PF543, as reference compound, in order to better understand themolecular behavior of these ligands at the binding site of SphK1.These results provide useful information for thedesign of new inhibitors of SphK1 possessing these structural scaffolds.