Platinum(ii) and ruthenium(ii) coordination complexes equipped with an anchoring site for binding the protein kinase enzyme pockets: synthesis, molecular docking and biological assays

Abstract

To mimic the structural aspects of staurosporine, a potent but unspecific kinase inhibitor, several coordination compounds based on two readily available diimine ligands containing hydrogen bonding donor/acceptor sites (NH–CO fragment) have been designed and synthesized. These complexes are constructed around Ru(II) and Pt(II) metal centers. A total of 9 compounds, named Ru(1)–(5) and Pt(1)–(4), were obtained through straightforward synthetic approaches. The cytotoxicity of the compounds was evaluated on AGS gastric cancer cells (GC) through standard MTT assays. All ruthenium and platinum complexes with low toxicity, i.e. Ru(3), Ru(5), Pt(3) and Pt(4), were docked in the ATP binding pocket of two protein kinases (S6K1 and MST2). The docking scores highlighted a preferred affinity of Ru(5) for the MST2 binding pocket, whereas the platinum compounds are predicted to bind stronger to the S6K1 binding site. Inhibitory activity of the metal complexes on the MST2 and S6K1 signaling pathways was evaluated by analyzing via western blot experiments the phosphorylation state of YAP, a downstream component of the Hippo pathway and the protein expression of S6 and its phosphorylated analogue p-S6. A clear difference of behavior between the Pt(II) and the Ru(II) complexes depending on the type of kinase was observed.