Modelling the binding of cytotoxic dinuclear nickel complexes to two neighboring phosphate esters of DNA using dicarboxylate ligands

Abstract

The cytotoxic complex [(Htom^6-Me){Ni^II(OAc)}₂](OAc) (H₂tom^6-Me = 2,7-bis(di(6-methylpyridine-2-yl-methyl)aminomethyl)-1,8-naphthalenediol) is supposed to bind in the aquated form [(Htom^6-Me){Ni^II(OH₂)₂}₂]³⁺ to two neighboring phosphate diesters of the DNA backbone. To further support this intended molecular mode of action, difunctional ligands in the form of the dicarboxylates succinate and glutarate are used here to mimic two neighboring phosphates of the DNA backbone. The complex [(Htom^6-Me){Ni^II(OAc)}₂](OAc) is treated with 3 equiv. HCl to protonate the acetates providing presumably [(Htom^6-Me){Ni^II(OH₂)₂}₂]³⁺, which is reacted with the dicarboxylates yielding the complexes [(Htom^6-Me){Ni^II(μ-succ)Ni^II}]⁺ and [(Htom^6-Me){Ni^II(μ-glut)Ni^II}]⁺ confirmed by single-crystal X-ray diffraction. The sterical constraints of the dicarboxylates enforces shorter Ni⋯Ni distances demonstrating the flexibility of the coordination compartments despite the rigid 1,8-naphthalenediol backbone. These steric constraints by the pull effect of the organic spacers affect the Ni^II–ligand bonds and are reflected in FTIR and UV-Vis-NIR spectroscopic but not magnetic signatures. The comparison to a related Cu^II complex indicates a severe impact of the 6-methyl groups of the pyridine donors on the relative orientation of the anticipated phosphate binding sites in these complexes. The consequences for a rational strengthening of the binding to DNA and hence increase of the cytotoxicity by possible ligand modifications are discussed.