Mass Spectrometric and Computational Investigation of the Protonated Carnosine-Carboplatin Complex Fragmentation.

Platinum(II)-based anticancer drugs are square-planar d(8) complexes that, activated by hydrolysis, cause cancer cell death by binding to nuclear DNA and distorting its structure. For that reason, interactions of platinum anticancer drugs with DNA have been extensively investigated, aiming at disentangling the mechanism of action and toxicity. Less attention, however, has been devoted to the formation of adducts between platinum drugs with biological ligands other than DNA. These adducts can cause the loss and deactivation of the drug before it arrives at the ultimate target and are also thought to contribute to the drug's toxicity. Here are reported the outcomes of electrospray ionization mass spectrometry experiments and density functional theory (DFT) computations carried out to investigate the fragmentation pathways of the protonated carnosine-carboplatin complex, Carnosine + CarbPt + H. DFT calculations at the B3LYP/LANL2DZ level employed to probe fragmentation mechanisms account for all experimental data. Because of the relative rigidity of the structure of the most stable 1A conformer, stabilized by three strong hydrogen bonds, the first step of all of the examined fragmentation pathways is the interconversion of the 1A conformer into the less stable structure 1B. Formation of the Carnosine + H fragment from the precursor ion, Carnosine + CarbPt + H, is calculated to be the lowest-energy process. At slightly higher energies, the loss of two amino groups is observed to produce the Carnosine + (CarbPt - NH3) + H and Carnosine + (CarbPt - 2NH3) + H ions. At significantly higher energies, the loss of CO2 occurs, yielding the final Carnosine + (CarbPt - NH3) - CO2 + H and Carnosine + (CarbPt - 2NH3) - CO2 + H products. Formation of the CarbPt + H fragment from Carnosine + CarbPt + H, even if not hampered by a high activation barrier, is calculated to be very unfavorable from a thermodynamic point of view.