Analysis of Platinum Adducts with DNA Nucleotides and Nucleosides by Capillary Electrophoresis Coupled to ESI‐MS: Indications of Guanosine 5′‐Monophosphate O6–N7 Chelation

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Abstract
DNA is the ultimate target of platinum-based anticancer therapy. Since the N7 of guanine is known to be the major binding site of cisplatin and its analogues, adduct formation with model nucleotides, especially 2′-deoxyguanosine 5′-monophosphate (dGMP), has been studied in detail. During the last few years a coupled capillary eletrophoresis/electrospray-ionization mass spectrometry (CE/ESI-MS) method has been advantageously used in order to separate and identify platinum adducts with nucleotides in submillimolar concentrations in aqueous solutions. Beside the bisadduct, [Pt(NH3)2(dNMP)2]2− (NMP=2′-deoxynucleoside 5′-monophosphate), and the well-known monochloro and monohydroxo adducts, [Pt(NH3)2Cl(dNMP)]− and [Pt(NH3)2(dNMP)OH]−, respectively, a third kind of monoadduct species with a composition of [Pt(NH3)2(dNMP)]− can be separated by CE and detected through the m/z values measured with ESI-MS. Different experimental setups indicate the existence of an O6–N7 chelate, whereas the formation of N7–αPO4 macrochelates or dinuclear species is unlikely. Additionally, offline MS experiments with 2′-deoxyguanosine (dG) and stabilization of the controversially discussed O6–N7 chelate by oxidation with hydrogen peroxide support the assumption of the existence of O6–N7 chelation.

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