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Cisplatin, (NH3)2PtCl2, has been known as a successful metal-based anticancer drug for more than half a century. Its analogue, Argplatin, arginine-linked cisplatin, (Arg)PtCl2, is being investigated because it exhibits reactivity towards DNA and RNA that differs from that of cisplatin. In order to understand the basis for its altered reactivity, the deprotonated and sodium cationized forms of Argplatin, [(Arg-H)PtCl2]− and [(Arg)PtCl2 + Na]+, are examined by infrared multiple photon dissociation (IRMPD) action spectroscopy in the IR fingerprint and hydrogen-stretching regions. Complementary electronic structure calculations are performed using density functional theory approaches to characterize the stable structures of these complexes and to predict their infrared spectra. Comparison of the theoretical IR spectra predicted for various stable conformations of these Argplatin complexes to their measured IRMPD spectra enables determination of the binding mode(s) of Arg to the Pt metal center to be identified. Arginine is found to bind to Pt in a bidentate fashion to the backbone amino nitrogen and carboxylate oxygen atoms in both the [(Arg-H)PtCl2]− and [(Arg)PtCl2 + Na]+ complexes, the NO− binding mode. The neutral side chain of Arg also interacts with the Pt center to achieve additional stabilization in the [(Arg-H)PtCl2]− complex. In contrast, Na+ binds to both chlorido ligands in the [(Arg)PtCl2 + Na]+ complex and the protonated side chain of Arg is stabilized via hydrogen-bonding interactions with the carboxylate moiety. These findings are consistent with condensed-phase results, indicating that the NO− binding mode of arginine to Pt is preserved in the electrospray ionization process even under variable pH and ionic strength.

To gain a better understanding of the binding mechanism and assist in the optimization of chemical probing and drug design applications, experimental and theoretical studies of a series of amino acid-linked cisplatin derivatives are being pursued. Glyplatin (glycine-linked cisplatin) was chosen for its structural simplicity and to enable backbone effects to be separated from side-chain effects on the structure and reactivity of ornithine- and lysine-linked cisplatin (Ornplatin and Lysplatin, respectively). Infrared multiple photon dissociation (IRMPD) action spectroscopy experiments were performed on Glyplatin to characterize its structure and guide the selection of the most effective hybrid theoretical approach for determining its structure and IR spectrum. The simplicity of the Glyplatin system allows a wide variety of density functionals, treatments of the Pt center including the use of all-electron basis sets vs valence basis sets combined with an effective core potential (ECP), and basis sets for all other atoms to be evaluated at a reasonable computational cost. The results for Glyplatin provide the foundation for calculations of more complex amino acid-linked cisplatin derivatives such as Ornplatin and Lysplatin. Present results suggest that the B3LYP/mDZP/def2-TZVP hybrid method can be effectively employed for structural and IR characterization of more complex amino acid-linked cisplatin complexes and their nucleic acid derivatives.