Fragmentation pathways analysis for the gas phase dissociation of protonated carnosine-oxaliplatin complexes

Abstract

Collision-induced dissociation (CID) experiments on the protonated carnosine-oxaliplatin complex, [Carnosine + OxPt + H](+) using several collision energies were shown to yield nine different fragment ions. Energy-resolved CID experiments on [Carnosine + OxPt + H](+) showed that the generation of the product ion [Carnosine - H + Pt(dach)](+) (where dach is 1,2-diaminocyclohexane) is the lowest energy process. At slightly higher collision energies, the loss of neutral carnosine from [Carnosine + OxPt + H](+) to produce [OxPt + H](+) was observed, followed by the loss of oxaliplatin from the same precursor ion to produce [Carnosine + H](+). At significantly higher energies, the ion [OxPt - CO2 + H](+) was shown to be formed, while the last two investigated ions [Carnosine + OxPt - CO2 + H](+) and [Carnosine - NH3 - H + Pt(dach)](+) did not attain any significant relative abundance. Density functional calculations at the B3LYP/LANL2DZ level were employed to probe the fragmentation mechanisms that account for all experimental data. The lowest free energy barriers for the generation of each of the ions [Carnosine - H + Pt(dach)](+), [OxPt + H](+), [Carnosine + H](+), [Carnosine + OxPt - CO2 + H](+) and [Carnosine - NH3 - H + Pt(dach)](+) from [Carnosine + OxPt + H](+) according to the fragmentation mechanisms offered here were calculated to be 31.9, 38.8, 49.3, 75.2, and 85.6 kcal mol(-1), respectively.

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

“…The mass selection and subsequent CID of the entire isotopic envelope of the ion [Carnosine + CarbPt + H] + resulted in the MS spectrum shown in Figure . As was previously reported in the fragmentation of other platinum drug complexes to carnosine, , here there is also no difference in the fragmentation pathway of the [Carnosine + CarbPt + H] + complex among the different platinum isotopes. The generated product ion clusters centered around m / z 581, 564, 537, 520, 454, 437, 420, and 372 have been assigned as [Carnosine + CarbPt – NH 3 + H] + , [Carnosine + CarbPt – 2NH 3 + H] + , [Carnosine + CarbPt – NH 3 – CO 2 + H] + , [Carnosine + CarbPt – 2NH 3 – CO 2 + H] + , [Carnosine – H + Pt­(NH 3 ) 2 ] + , [Carnosine – H + Pt­(NH 3 )] + , [Carnosine – H + Pt] + , and [Carb + H] + , respectively.…”

“…The mass selection and subsequent CID of the entire isotopic envelope of the ion [Carnosine + CarbPt + H] + resulted in the MS 2 spectrum shown in Figure 3. As was previously reported in the fragmentation of other platinum drug complexes to carnosine, 58,38 here there is also no difference in the fragmentation pathway of the [Carnosine + All of the reported pathways start with the structural rearrangement of the most stable conformer, labeled 1A, of the precursor ion [Carnosine + CarbPt + H] + observed as the ion cluster around m/z 598, into conformer 1B, being 14.0 kcal mol −1 higher in energy. The structures of these two minima and transition state TS (1A→1B) allowing their interconversion are shown in Figure 4.…”

“…All molecular geometries have been optimized without any geometrical constraint in the framework of the density functional theory (DFT) that is based upon a strategy of modeling electron correlation via the proper functionals of the electron density. The B3LYP Becke’s three-parameter exchange-correlation hybrid functional with nonlocal correlation corrections, provided by Lee, Yang, and Parr, has been used in the calculations. − The LANL2DZ basis sets of Hay and Wadt have been employed for all atoms. − The successful use of the B3LYP/LANL2DZ computational protocol for the investigation of both the electronic properties and reaction pathways of transition-metal-containing compounds, including anticancer drugs, is well established. − The same protocol has been proven, recently, to give reliable results in the investigation of the fragmentation pathways of the oxaliplatin–carnosine complex . Frequency calculations at the same level of theory have also been performed to identify all stationary points as minima (zero imaginary frequencies) or transition states (one imaginary frequency).…”

“…46−57 The same protocol has been proven, recently, to give reliable results in the investigation of the fragmentation pathways of the oxaliplatin−carnosine complex. 58 Frequency calculations at the same level of theory have also been performed to identify all stationary points as minima (zero imaginary frequencies) or transition states (one imaginary frequency). The vibrational mode associated with the imaginary frequency of each intercepted transition state has been shown to correspond to the correct movement of the involved atoms.…”

Collision-induced dissociation products of the protonated dipeptide carnosine: structural elucidation, fragmentation pathways and potential energy surface analysis

“…Both instruments described here were previously successfully employed by us using the exact setup described to elucidate structures of metal and non-metal containing biological ligands. [37][38][39] While some of our previous studies were conducted under single collision conditions [40][41][42] the experiments reported here were all performed under multiple collision conditions.…”