Support for the Anticipated Binding Mode of a Cytotoxic Dinuclear Copper Complex to Two Neighboring Phosphate Esters of the DNA Backbone

The cytotoxic dinuclear complex [(Htom^6-Me){Cu^II(OAc)}₂](OAc) (H₂tom^6-Me = 2,7-bis(di(6-methylpyridine-2-yl-methyl)aminomethyl)-1,8-naphthalenediol) binds to DNA, interferes with DNA synthesis in PCR at lower concentrations than cisplatin, and kills human cancer cells more efficiently than human stem cells of the same proliferation rate. It is supposed that the OAc^- ligands dissociate in aqueous buffer, providing [(Htom^6-Me){Cu^II(OH₂)}₂]³⁺, while the fragment [(Htom^6-Me)Cu^II₂]³⁺ binds to two neighboring phosphate diesters of the DNA backbone. Here, we report the hydrolysis of [(Htom^6-Me){Cu^II(OAc)}₂](OAc) in phosphate buffer providing the anticipated [(Htom^6-Me){Cu^II(OH₂)}₂]³⁺. Moreover, the same reaction in H₂O/CH₃OH yields the complex [(Htom^6-Me){Cu^II(H₂PO₄)}₂]⁺. The molecular structures of [(Htom^6-Me){Cu^II(OH₂)}₂]³⁺ and [(Htom^6-Me){Cu^II(H₂PO₄)}₂]⁺ show different coordination modes around the Cu^II ions demonstrating a significant flexibility of the fragment [(Htom^6-Me)Cu^II₂]³⁺ for binding to exogenous ligands despite its rigid naphthalene backbone. The coupling is weakly antiferromagnetic in [(Htom^6-Me){Cu^II(H₂PO₄)}₂]⁺, while that in tricationic [(Htom^6-Me){Cu^II(OH₂)}₂]³⁺ is weakly ferromagnetic and can be attributed to the orthogonal orientation of the basal planes. UV-vis-NIR spectra of [(Htom^6-Me){Cu^II(H₂PO₄)}₂]⁺ but also of [(Htom^6-Me){Cu^II(OAc)}₂](OAc) in aqueous solution resemble that of [(Htom^6-Me){Cu^II(OH₂)}₂]³⁺ demonstrating our earlier assumption that [(Htom^6-Me){Cu^II(OH₂)}₂]³⁺ is the active species in buffer solutions for interaction with DNA. Moreover, the exchange of the OAc^- ligands by H₂PO₄^- ligands models the anticipated binding of [(Htom^6-Me){Cu^II(OH₂)}₂]³⁺ to the phosphates of DNA.