Design and synthesis of substituted pyrido[3,2-d]-1,2,3-triazines as potential Pim-1 inhibitors

A novel series of substituted pyrido[3,2-d]-1,2,3-triazines were designed and synthesized as Pim-1 inhibitors through scaffold hopping. Most of the derivatives showed potent in vitro Pim-1 inhibitory activities and anti-proliferative effects toward prostate cancer cells. Among them, 6b, 6h and 6m showed the best Pim-1 inhibitory activity with IC50 values of 0.69, 0.60 and 0.80 mu M, respectively. Furthermore, compounds 6b, 6i, 6j and 6m showed strong inhibitory activity to human prostate cancer LNcap and PC-3 cell lines with IC50 values at low micromolar level. Structure-activity relationship analysis revealed that appropriate substitutions at C-6 positions contributed to the kinase inhibition and antiproliferative effects. Moreover, western blot assay suggested that 6j could decrease the levels of p-BAD and p-4E-BP1 in a dose-dependent manner in PC-3 cells. Docking studies showed that 3-N of the scaffold formed a hydrogen bond with Lys67, aromatic 4-aniline formed a key p-p stack with Phe49. Taken together, this study might provide the first sight for developing the pyrido[3,2-d]-1,2,3-triazine scaffold as novel Pim-1 inhibitors. (C) 2016 Published by Elsevier Ltd.