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

Abstract

Despite its success as an anticancer drug, cisplatin suffers from resistance and produces side effects. To overcome these limitations, amino-acidlinked cisplatin analogues have been investigated. Lysine-linked cisplatin, Lysplatin, (Lys)PtCl 2 , exhibited outstanding reactivity toward DNA and RNA that differs from that of cisplatin. To gain insight into its differing reactivity, the structure of Lysplatin is examined here using infrared multiple photon dissociation (IRMPD) action spectroscopy. To probe the influence of the local chemical environment on structure, the deprotonated and sodium-cationized Lysplatin complexes are examined. Electronic structure calculations are performed to explore possible modes of binding of Lys to Pt, their relative stabilities, and to predict their infrared spectra. Comparisons of the measured IRMPD and predicted IR spectra elucidate the structures contributing to the experimental spectra. Coexistence of two modes of binding of Lys to Pt is found where Lys binds via the backbone and side-chain amino nitrogen atoms, NN s , or to the backbone amino and carboxylate oxygen atoms, NO − . Glycine-linked cisplatin and arginine-linked cisplatin complexes have previously been found to bind only via the NO − binding mode. Present results suggest that the NN s binding conformers may be key to the outstanding reactivity of Lysplatin toward DNA and RNA.

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 .…”

“…To unequivocally assign the structure of complex 3 to a specific isomer, IR multiple-photon dissociation (IRMPD) spectroscopy was exploited. 27 , 29 − 31 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 .…”