1. International Symposium on Molecular Spectroscopy
Structure Determination of Ornithine-Linked Cisplatin by Infrared Multiple Photon Dissociation Action Spectroscopy
AA= Ornithine
C. C. He, B. Kimutai, L. Hamlow, H. Roy, Y-w Nei, X. Bao, J. Gao, J. K. Martens, G. Berden, J. Oomens, P. Maitre, V. Steinmetz, P. B. Armentrout, C. P. McNary, C. S. Chow, and M. T. Rodgers*
International Symposium on Molecular Spectroscopy
06/22/2016

2. Structure and Reactivity of Cisplatin
Anticancer drug (FDA approved)
Chemical probe for structured RNA
Resistance, kidney damage, lung damage …
carrier
ligands
labile
ligands
Cisplatin, cis-[Pt(NH3)2Cl2]
[cis-diamminedichloridoplatinum(II)]
Purine N7 position; G > A
Alter the carrier ligands to change the adduct profile
Major target GN7 A minor binding target
In previous experimental studies it was shown that Cisplatin preferentially binds to the N7 position of Guanine over Adenine, due to the amine-oxygen hydrogen bond. Hence, substituting the carrier ligands can have an impact on the binding profile. And AA have been known to be great ligand carriers.
DNA or RNA chain
Lippert, B. Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug. Wiley-VCH: Weinheim, Germany, 1999; p 563.
Jamieson, E. R.; Lippard, S. J. Chem. Rev. 1999, 99, 2467.
Rijal, K.; Chow, C. S. Chem. Commun. 2009, 107.

3. Amino Acid-Linked Platinum Complexes
Widely available
Backbone amino and carboxylate moieties
Side-chain diversity
AA=Amino Acids
Lysplatin
DNA studies
rRNA studies
Coordination preferences differ from those of cisplatin when reacted with rRNA
Reactivity at ApG and GpA sites was observed
Potential to be used as an anticancer drug or chemical probe
Exhibited high reactivity during the screening of a mixture of 17 L-amino acid- linked platinum complexes
DNA adduct profile differs from that of cisplatin
Cytotoxic to Hela cells
This slide shows the oplatin complex, which differs from the cisplatin by the oxygen atom here, and binds to A over G. This binding mode has been proven on both ……
No C, M, H bind strongly to metal ions
Sandman, K. E.; Fuhrmann, P.; Lippard, S. J. J. Biol. Inorg. Chem. 1998, 3, 74.
Rijal, K.; Bao, X.; Chow, C. S. Chem. Commun. 2014, 50, 3918.

4. Amino Acid-Linked Platinum Complexes
Glyplatin
Simple model
Absence of side-chain effects
Low computational cost
AA = glycine
Ornplatin
Orn side chain is one CH2 shorter than Lys
Preference at the nucleoside level: Ado > Guo >> Cyd
More than one adduct with adenosine was observed
This slide shows the oplatin complex, which differs from the cisplatin by the oxygen atom here, and binds to A over G. This binding mode has been proven on both ……
AA = ornithine
Argplatin
Positively charged side chain
Additional coordination sites
AA = arginine
Rijal, K.; Bao, X.; Chow, C. S. Chem. Commun. 2014, 50, 3918.
Dalla Via, L.; Gia, O.; Magno, S. M.; Dolmella, A.; Marton, D.; Di Noto, V. Inorg Chim Acta 2006, 359, 4197.

5. IRMPD Experimental Setup
Infrared Multiple Photon Dissociation (IRMPD) Action Spectroscopy
This is a schematic of the instrument we have used to collect our experimental data. It is a FT-ICR MS equipped with an ESI source and interfaced to a FEL. The ions of interest are generated by an ESI source with a typical solution condition shown here. Ions generated from the source enters the skimmer cone and are accumulated for several seconds in the rf only hexapole, follow by pulse extraction and deflection off axis from the source by a dc only quadrupole bender, and then guided into the ICR cell by an rf only octopole ion guide. Ions inside the cell are trapped and mass isolated using the SWIFT technique. Then the FEL enters into the ICR cell via a ZnSe window in the back of the cell to photodissociate the mass isolated ions inside the cell via IRMPD, and produce fragmented product and unfragmented precursor ions. An IRMPD yield can be calculated by using this equation shown here, where If is the fragmented product ions and Ip is the unfragmeneted precursor ions.
or OPO/OPA laser
IRMPD yield = (SIf)/(Ip + SIf)
Oepts, D.; Van der Meer, A. F. G.; van Amersfoort, P. W. Infrared Phys. Technol. 1995, 36, 297.
Polfer, N. C.; Oomens J. Phys. Chem. Phys. 2007, 9, 3804.

6. IRMPD Mechanism Rapid intramolecular vibrational redistribution
Photon energy is redistributed
The ion relaxes to the ground vibrational mode
Reach or exceed dissociation threshold
Requires the absorption of tens to hundreds of photons
IRMPD is a process where the initial absorption of photon energy takes place at a resonant vibrational mode. The photon energy is then distributed throughout all ro-vib modes of the ions in order to absorb additional photons. This process is repeated many times until sufficient energy has been absorbed to reach the dissociation threshold.
Polfer, N. C.; Oomens J., Mass Spectrom. Rev. 2009, 28, 468– 494.

7. Hybrid Theoretical Approaches
IRMPD spectrum of Glyplatin is best reproduced by
B3LYP/mDZP/def2-TZVP
Selected based on structural information
x 5
He, C. C.; Kimutai, B.; Bao X.; Hamlow, L.; Zhu, Y.; Strobehn, S. F.; Gao, J.; Berden, G.; Oomens, J.; Chow, C. S.; Rodgers, M. T. J. Phys. Chem. A 2015, 109,

8. Ornplatin Structure Determination
[(Orn-H)PtCl2]-
[(Orn)PtCl2+Na]+
[(Orn)PtCl]+
[(Orn)PtCl(H2O)]+

9. Structure Determination of [(Orn)PtCl2+Na]+
B3LYP/mDZP/def2-TZVP
Awaiting data in the H-stretching region
0.0 kJ/mol
42.5 kJ/mol
66.3 kJ/mol

10. Structure Determination of [(Orn)PtCl2+Na]+
B3LYP/mDZP/def2-TZVP
Awaiting data in the H-stretching region
62.9 kJ/mol
84.8 kJ/mol
105.1 kJ/mol

11. Featured Structures for Ornplatin
0.0 kJ/mol
5.6 kJ/mol
[(Orn)PtCl2+Na]+
[(Orn)PtCl]+
0.0 kJ/mol
5.1 kJ/mol
[(Orn-H)PtCl2]-
[(Orn)PtCl(H2O)]+
Orn binds to Pt via the backbone and sidechain N atoms. Binding mode is conserved on all four quasi molecular forms of Ornplatin.

12. Conclusions and Future Work
The binding mode of ornithine to Pt is (Nb, Ns), and this mode is consistent among different quasi molecular ionic complexes
Parallel studies are going to be performed on Lysplatin, dimethyl-Lysplatin, and Argplatin to examine the influence of the side chain
Structures and binding modes for Ornplatin adducts to adenosine and guanosine need to be determined

13. Acknowledgements
Professor Mary T. Rodgers Professor Christine S. Chow Rodgers group members Chow group members Dr. Cliff Frieler FELIX and CLIO International User Facility Scientists and Support staff
WSU C&IT
FELIX Facility
Department of Chemistry
National Science Foundation
CLIO User Facility