L. A. Hamlow

Evaluation of Hybrid Theoretical Approaches for Structural Determination of a Glycine-Linked Cisplatin Derivative via Infrared Multiple Photon Dissociation (IRMPD) Action Spectroscopy

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.

Modified Quadrupole Ion Trap Mass Spectrometer for Infrared Ion Spectroscopy: Application to Protonated Thiated Uridines

AbstractModifications to a Paul-type quadrupole ion trap mass spectrometer providing optical access to the trapped ion cloud as well as hardware and software for coupling to a table-top IR optical parametric oscillator laser (OPO) are detailed. Critical experimental parameters for infrared multiple photon dissociation (IRMPD) on this instrument are characterized. IRMPD action spectra, collected in the hydrogen-stretching region with this instrument, complemented by spectra in the IR fingerprint region acquired at the FELIX facility, are employed to characterize the structures of the protonated forms of 2-thiouridine, [s2Urd+H]+, and 4-thiouridine, [s4Urd+H]+. The measured spectra are compared with predicted linear IR spectra calculated at the B3LYP/6-311+G(d,p) level of theory to determine the conformers populated in the experiments. This comparison indicates that thiation at the 2- or 4-positions shifts the protonation preference between the 2,4-H tautomer and 4-protonation in opposite directions versus canonical uridine, which displays a roughly equal preference for the 2,4-H tautomer and O4 protonation. As found for canonical uridine, protonation leads to a mixture of conformers exhibiting C2′-endo and C3′-endo sugar puckering with an anti nucleobase orientation being populated for both 2- and 4-thiated uridine. Graphical Abstractᅟ