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Mass Spectrometric and Computational Investigation of the Protonated Carnosine–Carboplatin Complex Fragmentation
journal contribution
posted on 2015-08-17, 00:00 authored by Ida Ritacco, Emilia Sicilia, Tamer Shoeib, Mohamed Korany, Nino RussoPlatinum(II)-based anticancer drugs
are square-planar d8 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.