From Preassociation to Chelation: A Survey of Cisplatin Interaction with Methionine at Molecular Level by IR Ion Spectroscopy and Computations

Abstract

Methionine (Met) plays an important role in the metabolism of cisplatin anticancer drug. Yet, methionine platination in aqueous solution presents a highly complex pattern of interconnected paths and intermediates. This study reports on the reaction of methionine with the active aqua form of cisplatin, cis -[PtCl(NH 3 ) 2 (H 2 O)] + , isolating the encounter complex of the reactant pair, { cis -[PtCl(NH 3 ) 2 (H 2 O)] + ·Met}, by electrospray ionization. In the unsolvated state, charged intermediates are characterized for their structure and photofragmentation behavior by IR ion spectroscopy combined with quantum-chemical calculations, obtaining an outline of the cisplatin–methionine reaction at a molecular level. To summarize the major findings: (i) the { cis -[PtCl(NH 3 ) 2 (H 2 O)] + ·Met} encounter complex, lying on the reaction coordinate of the Eigen-Wilkins preassociation mechanism for ligand substitution, is delivered in the gas phase and characterized by IR ion spectroscopy; (ii) upon vibrational excitation, ligand exchange occurs within { cis -[PtCl(NH 3 ) 2 (H 2 O)] + ·Met}, releasing water and cis -[PtCl(NH 3 ) 2 (Met)] + , along the calculated energy profile; (iii) activated cis -[PtCl(NH 3 ) 2 (Met)] + ions undergo NH 3 departure, forming a chelate complex, [PtCl(NH 3 )(Met)] + , whose structure is congruent with overwhelming S-Met ligation as the primary coordination step. The latter process involving ammonia loss marks a difference with the prevailing chloride replacement in protic solvent, pointing to the effect of a low-polarity environment.

Amino Acids as Chelating Ligands for Platinum: Enhanced Stability in an Aqueous Environment Promoted by Biocompatible Molecules

“…Isomer 3_3 simulates the coordination of the histidine carboxylic group to platinum, but the structure is significantly higher in energy, with a relative Gibbs free energy of 73.9 kJ/mol. To unequivocally assign the structure of complex 3 to a specific isomer, IR multiple-photon dissociation (IRMPD) spectroscopy was exploited. ,− Mass selected ions were submitted to IR photons of variable energy. Figure S17 shows the IRMPD spectrum together with the calculated spectra of isomers 3_1–3 .…”

“…D.01 . To plot the calculated spectra, harmonic frequencies were scaled by 0.97 based on their good agreement with the IRMPD spectra. , Calculated linear IR spectra were convoluted with a Gaussian profile of 20 cm –1 (fwhm).…”

Ligation Motifs in Zinc-Bound Sulfonamide Drugs Assayed by IR Ion Spectroscopy

“…Optimization of the as-obtained geometries was accomplished at the B3LYP/6-311+G(d,p) level. Selected lowest-lying isomers were subsequently reoptimized at the B3LYP level using the 6-311+G(2df,pd) basis set for all O, N, C and H atoms and the 6-311+G(3df) basis set for the S atom [ 29 , 32 ]. Gaussian 09 rev.…”

“…IRMPD spectroscopy has been demonstrated to afford a valuable characterization of biologically active molecules and molecular complexes since its expansion as a structural diagnostic tool of mass-selected charged species [ 17 , 18 , 19 , 20 , 21 ]. In a considerable number of studies, including contributions from these authors, it has been applied to identify binding motifs and preferred geometries of transition metal complexes coordinating biomolecular ligands and targets [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Zinc complexes of biomolecules have also been assayed [ 33 , 34 , 35 , 36 , 37 , 38 ].…”

Structural Determination of Lysine-Linked Cisplatin Complexes via IRMPD Action Spectroscopy: NNs and NO– Binding Modes of Lysine to Platinum Coexist

“…It is believed that the chlorido ligands of cisplatin are labile and prominently determine the rate of adduct formation; the ammonia molecules are carrier ligands predominantly determining the coordination sites of cisplatin to DNA or RNA strands ,, and to amino acids. − In an attempt to alter the reactivity and ideally improve the performance of cisplatin, amino acids are examined as replacements for the ammonia ligands in cisplatin. All amino acids provide backbone amino and carboxylic acid functionalities that may potentially bind to the Pt metal center.…”