Transcript Microsoft PowerPoint 2007

Structure Determination of OrnithineLinked 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
Structure and Reactivity of Cisplatin
• Anticancer drug
(FDA approved)
carrier
labile
ligands
ligands • Chemical probe for
structured RNA
Cisplatin, cis-[Pt(NH3)2Cl2] • Resistance, kidney damage,
[cis-diamminedichloridoplatinum(II)]
lung damage …
• Purine N7 position; G > A
• Alter the carrier ligands to
change the adduct profile
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.
Amino Acid-Linked Platinum Complexes
AA=Amino Acids
• Widely available
• Backbone amino and
carboxylate moieties
• Side-chain diversity
Lysplatin
DNA studies
rRNA studies
• Coordination preferences differ
• Exhibited high reactivity
from those of cisplatin when
during the screening of a
reacted with rRNA
mixture of 17 L-amino acidlinked platinum complexes • Reactivity at ApG and GpA sites
was observed
• DNA adduct profile differs
• Potential to be used as an
from that of cisplatin
anticancer drug or chemical probe
• Cytotoxic to Hela cells
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.
Amino Acid-Linked Platinum Complexes
Glyplatin
AA = glycine
AA = ornithine
• Simple model
• Absence of side-chain effects
• Low computational cost
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
Argplatin
AA = arginine
• Positively charged side chain
• Additional coordination sites
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.
IRMPD Experimental Setup
Infrared Multiple Photon Dissociation (IRMPD) Action Spectroscopy
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.
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
Polfer, N. C.; Oomens J., Mass Spectrom. Rev. 2009, 28, 468– 494.
Hybrid Theoretical Approaches
Relative Intensity
•IRMPD spectrum of Glyplatin is best reproduced by
B3LYP/mDZP/def2-TZVP
•Selected based on structural information
[(Gly-H)PtCl2]- IRMPD
900
600
300
x5
0
1000
1500
3000
3500
-1
Frequency (cm )
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, 10980-10987.
Ornplatin Structure Determination
0.9
0.6
[(Orn-H)PtCl2]-
[(Orn-H)PtCl2]-
0.3
IRMPD Yield
0.0
0.6
800
1000
[(Orn)PtCl
2+Na]
+
1200
1400
1600
1800
Frequency(cm-1)
[(Orn)PtCl2+Na]+
0.3
0.0
0.2
+
[(Orn)PtCl]
[(Orn)PtCl]+
0.1
0.0
0.4
800
1000O)]+ 1200
[(Orn)PtCl(H
2
1400
1600
1800
[(Orn)PtCl(H2O)]+
0.2
0.0
800
1000
1200
1400
Frequency(cm-1)
1600
1800
Structure Determination of [(Orn)PtCl2+Na]+
B3LYP/mDZP/def2-TZVP
Awaiting data in the H-stretching region
300
180
[(Orn)PtCl2+Na]+, NbNs SF:0.97/0.95
120
Relative Intensity
150
60
0
1200
0
[(Orn)PtCl2+Na]+, NbOb_NHO SF: 0.97/0.95
-1
60
Frequency (cm )
30
600
0
300
0.0 kJ/mol
0
[(Orn)PtCl2+Na]+, NbOb_NHN SF:0.97/0.95
42.5 kJ/mol
180
120
150
60
0
0
1000
1500
3000
Frequency (cm-1)
3500
66.3 kJ/mol
Structure Determination of [(Orn)PtCl2+Na]+
B3LYP/mDZP/def2-TZVP
Awaiting data in the H-stretching region
300
180
[(Orn)PtCl2+Na]+, NbNs_NaOO SF:0.97/0.95
120
Relative Intensity
150
0
1200
60
62.9 kJ/mol
0
[(Orn)PtCl2+Na]+, NbOb_NHNaO SF:-10.97/0.95
60
Frequency (cm )
600
30
0
600
0
90
[(Orn)PtCl2+Na]+, NsOb_NHNaO SF:0.97/0.95
84.8 kJ/mol
60
300
30
0
0
1000
1500
3000
Frequency (cm-1)
3500
105.1 kJ/mol
Featured Structures for Ornplatin
0.0 kJ/mol
[(Orn)PtCl2+Na]+
[(Orn)PtCl]+
0.0 kJ/mol
[(Orn-H)PtCl2]-
5.6 kJ/mol
5.1 kJ/mol
[(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.
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
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