Binding Motifs of Carboplatin and Oxaliplatin with Guanine: A Combined MS/MS, IRMPD, and Theoretical Study
Résumé
Complexes generated in the gas phase involving the purine nucleobase guanine bound to second and third generation platinum drugs, namely carboplatin (CarboPt) and oxaliplatin (OxaliPt), were investigated by combining tandem mass spectrometry, collision induced dissociation (CID), infrared multiple photon dissociation spectroscopy (IRMPD) and density functional theory (DFT) calculations.
As first step, a spectroscopic characterization of the protonated platinum drugs was accomplished. Protonation of both CarboPt and OxaliPt in the gas phase occurs on one of the two carbonyl groups of the cyclobutanedicarboxylate and oxalate ligand, respectively. Such protonation has been postulated by several theoretical studies as a key preliminary step in the hydrolysis of Pt drugs under acidic conditions.
Subsequently, the protonated drugs react with guanine in solution to generate a complex of general formula [Pt drug + H + guanine]+, which was then mass-selected. CID experiments provided evidence for the presence of strong binding between guanine and platinum-based drugs within the complexes. The structure of the two complexes has also been examined by comparing the experimental IRMPD spectra recorded in two spectral regions with DFT-computed IR spectra. For each system, the IRMPD spectra agree with the vibrational spectra calculated for the global minimum structures, which present a monodentate complexation of Pt onto the N7 position of canonical guanine. This binding scheme is therefore akin to that observed for cisplatin, while other coordination sites yield substantially less stable species. Interestingly, in the case of oxaliplatin, the IRMPD spectra are consistent with the presence of two isomeric forms very close in energy.
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