Thermodynamic and kinetic studies on biotransformation reactions of medical relevant mono- and polynuclear Pt(II) complexes [Elektronische Ressource] = Thermodynamische und kinetische Untersuchung von Biotransformationsreaktionen medizinisch relevanter ein- und mehrkerniger Pt(II)-Komplexe / vorgelegt von Nadine Kirsten Summa

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Informations

• Publié par: friedrich-alexander-universitat_erlangen-nurnberg
• Publié le: 01 janvier 2007
• Nombre de lectures: 18
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Thermodynamic and kinetic studies on biotransformation
reactions of medical relevant mono – and polynuclear Pt(II)
complexes

Thermodynamische und kinetische Untersuchung von
Biotransformationsreaktionen medizinisch relevanter ein-
und mehrkerniger Pt(II) Komplexe

Den Naturwissenschaftlichen Fakultäten der Friedrich-Alexander-Universität Erlangen-
Nürnberg zur Erlangung des Doktorgrades

vorgelegt von
Nadine Kirsten Summa
aus Fürth
Als Dissertation genehmigt von den naturwissenschaftlichen Fakultäten der Friedrich-
Alexander-Universität Erlangen-Nürnberg.














Tag der mündlichen Prüfung: 17.11. 2006
Vorsitzender der Promotionskomission: Prof. Dr. E. Bänsch
Erstberichterstatter: Prof. Dr. Dr. h.c. mult. Rudi van Eldik
Zweitberichterstatter: Prof. Dr. N. Burzlaff



Was keiner wagt, das sollt Ihr wagen,
Was keiner sagt, das sagt heraus,
Was keiner denkt, das wagt zu denken,
Was keiner anfängt, das führt aus.

Johann Wolfgang von Goethe (1749-1832)






Die vorliegende Arbeit entstand in der Zeit von Oktober 2002 bis Oktober 2006 am
Institut für Anorganische und Analytische Chemie der Friedrich-Alexander-Universität
Erlangen-Nürnberg Acknowledgements
I wish to thank Prof. Dr. Dr. h.c. mult Rudi van Eldik for the supervision of this work,
the fruitful discussions and his essential support in many ways. In particular I am
grateful for helping me to realize my own ideas and projects and finally to present the
results internationally.
I am also grateful towards Prof. Živadin D. Bugar či ć for his support and interest in my
work. I also appreciate the friendly way in which he and his group introduced me to
Serbia.
I would like to acknowledge the computational work of Dr. Ralph Puchta, who
contributes to this work not only as an excellent computational chemist, but also being
enthusiastic about chemistry, very motivating and very constructive.
Equally acknowledged is the NMR work performed by Dr. Achim Zahl and Joachim
Maigut, in particular the extreme shimming procedure for Pt(II) complexes.
The work would not have been possible without the help of Dr. Carlos Dücker-Benfer
in many ways, especially fixing the Cary. Furthermore I would like to thank Dr. Ivana
Ivanovic-Burmacovic, Dr. Anton Neubrand, Susanne Hofmann, Christina Wronna (for
the smileys), Ursula Niegratschka and all other coworkers of this institute for their help.
Many thanks are given to the whole group, for being more than just collegues and the
great working atmosphere. My special thanks go to Ariane Brausam, Hans Hanauer,
David Sarauli, Peter Illner and Hakan Ertürk for giving me a reason to come to the
institute in days, when research didn’ go well.
Thanks to all my friends for making me stay the course.
Finally I am grateful to my family for the consistent support throughout my studies. A
special acknowledgment goes to Kai Lampka, who not only shared the same challenge,
but gave me strength and motivation and I could rely on him anytime.
Publications and Conference Contributions
Publications
1. Karsten Jorgersen, Margret Czew, Nadine Summa, Kenton Renkema, Patrick
Achord and Alan Goldman, On the Mechanism of (PCP)Ir-catalyzed
Acceptorless Dehydrogenation of Alkanes: a Combined Computational and
Experimental Study, J. Am. Chem. Soc. 2002, 124, 11404-16.
2. Wolfgang Schiessl, Andreas Hofmann, Carlos Dücker-Benfer, Nadine Summa,
Michael Galle and Rudi van Eldik, Magic Show 2003: Im Auftrag der Chemie
unterwegs, GIT Labor Fachz. 2003, 47, (6), 614-616.
3. Wolfgang Schiessl, Nadine Summa, Christian Weber, Sonja Gubo, Carlos
Dücker-Benfer, Ralph Puchta, Nico van Eikema Hommes, and Rudi van Eldik,
Experimental and theoretical approaches to the protonation of thiourea: a
convenient nucleophile in coordination chemistry revisited, Z. Anorg. Allg.
Chem. 2005, 631, (13-14), 2812-2819.
4. Nadine Summa, Wolfgang Schiessl, Ralph Puchta, Nico van Eikema-Hommes
and Rudi van Eldik, Thermodynamic and Kinetic Studies on Reactions of Pt(II)
Complexes with Biologically Relevant Nucleophiles, Inorg. Chem. 2006, 45, (7),
2948-2959.
5. Wolfgang Schiessl, Carlos Dücker-Benfer, Nadine Summa, Ariane Brausam,
Peter Pfeifer and Rudi van Eldik, Chemie Edutainment – Zaubervorlesung mit
Salvador Dalí, Chemie in unserer Zeit 2006, 40, 184-193.
6. Nadine Summa, Joachim Maigut, Ralph Puchta and Rudi van Eldik, Possible
biotransformation reactions of polynuclear Pt(II) complexes, Inorg. Chem. 2006,
submitted.
7. Nadine Summa, Tanja Soldatovic, Lutz Dahlenburg, Živadin D. Bugar či ć and
Rudi van Eldik, The impact of different chelating leaving groups on the kinetics in
mononuclear Pt(II)(dach)(X-Y) complexes, 2006, JBIC, accepted.
6 8. Jovana Rosic, Biljana Petrovic, Nadine Summa, Rudi van Eldik and Živadin D.
+Bugar či ć, Kinetics and mechanism of substitution reactions of [Pt(bpma)Cl] ,
[]Pt(gly-met-S,N,N)Cl] complexes and their aqua analogues with L-methionine,
glutathione and 5’GMP, 2006, manuscript in preparation

Conference Contributions: Posters
1. Characterization of growth and properties of Cobalt thin films on Ni(111), DBG
spring conference, March 2001, Regensburg, Germany.
2. Kinetic Investigation of Pt(II) Complexes with Sulfur containing Nucleophiles,
Rennes-Erlangen Chemistry Symposium, June 2004, Erlangen, Germany.
3. Thermodynamic and Kinetic Studies on Reactions of Pt(II) Complexes with
Biologically Relevant Nucleophiles, The Younger European Chemists
Conference, August 2004,Torino, Italy.
4. Mechanistic Investigation of a series of Pt(II) Complexes with L-Methionine,
Redox-Active Metal Centers in Homogeneous and Heterogeneous Electron
Transfer Systems, Symposium, February 2005, Erlangen, Germany.
5. Kinetic Investigation of possible biotransformation reactions of Multinuclear Pt(II)
Complexes, Inorganic Reaction Mechanism Meeting (IRMM), January 2006,
Krakau, Poland.
6. Kinetic Investigation of a Series of Multinuclear Pt(II) Complexes with Biological
Relevant Nucleophiles, Gordon Research Conference (GRC), July 2006, Oxford,
UK.
7. Kinetic Investigation of a Series of Multinuclear Pt(II) Complexes with Biological
ndRelevant Nucleophiles II, 2 Erlangen Symposium on Redox-Active Metal
Complexes - Control of Reactivity via Molecular Architecture, October 2006,
Erlangen, Germany.

7 Conference Contributions: Oral Presentation
1. Kinetic Investigation of Pt(II) Complexes with Biological Relevant Nucleophiles
Inorganic Reaction Mechanism Meeting Liverpool (IRMM), January 2005,
Liverpool, UK.
2. Kinetic Investigation of a series of polynuclear Pt(II) Complexes with biological
relevant Nucleophiles, Rennes-Erlangen Chemistry Symposium, June 2006,
Rennes, France.
8 Abbreviations
Ligands
A, Py N-donating ligand: Amine, Pyridine
amp aminomethylpyridine
bpy 2,2’-bipyridine
dach 1,2-trans-R,R-diaminocyclohexane
en ethylenediamine
gly glycine
CBDCA cyclobutane-1,1-dicarboxylate

Complexes
cisplatin [cis-Pt(NH ) Cl ] 3 2 2
2+ Pt(amp) [Pt(aminomethylpyridine)(H O) ]2 2
2+Pt(bpy) [Pt(N,N’-bipyridine)(H O) ] 2 2
2+ Pt(dach) [Pt(1,2-trans-R,R-diaminocyclohexane)(H O) ]2 2
2+Pt(en) [Pt(ethylenediamine)(H O) ] 2 2
Oxaliplatin [Pt(1,2-trans-R,R-diaminocyclohexane)(O-O-oxalato)]
Carboplatin [Pt(NH ) (O,O-cyclobutane-1,1-dicarboxylate)] 3 2
AMD473 [cis-Pt(NH )(2-picoline)Cl ] 3 2
+ Pt(gly) [Pt(dach)(N,O-glycine)]
Pt(CBDCA) [Pt(dach)(O,O-cyclobutane-1,1-dicarboxylate)]
4+ BBR3464 [{trans-PtCl(NH ) } {µ-trans-Pt(NH ) -(NH (CH ) NH ) }]3 2 2 3 2 2 2 6 2 2
4+ BBR3610 [{trans-PtCl(NH ) } {µ−C H -(NH (CH ) NH ) }]3 2 2 2 4 2 2 6 2 2
6+ BBR3464-(OH ) [{trans-Pt(OH )(NH ) } {µ-trans-Pt(NH ) -(NH (CH ) NH ) }]2 2 2 3 2 2 3 2 2 2 6 2 2
6+ BBR3610-(OH ) [{trans-Pt(OH )(NH ) } {µ−C H -(NH (CH ) NH ) }]2 2 2 3 2 2 2 4 2 2 6 2 2

Other Chemicals
HOTf trifluoromethanesulfonic acid, CF SO H 3 3
-OTf trifluoromethanesulfonate, CF SO 3 3
9 2-/-5’GMP guanosine-5’-monophosphate
L-Met L-methionine
GSH γ-glutamylcysteinylglycine (glutathione)
tu thiourea
MeOH methanol
EtOH ethanol
TMS tetramethylsilane
TSP trimethylsilylpropionic acid

Other Abbreviations
DNA deoxyribonucleic acid
-1 -1R gas constant, 8.3145 J K mol
-34h Planck constant, 6.6261 x 10 J s
-23 -1k Boltzmann constant, 1.3807 x 10 J K b
k observed rate constant for pseudo-first-order reactions obs
k ,k ,k ,k rate constants 1 2 -1 -2
K equilibrium constant
-1 -1R gas constant, 8.3145 J K mol
T temperature
I ionic strength
ts transition state
-X leaving group: H O or Cl 2
X-Y chelating leaving group with different donor atoms
DFT density functional theory
NMR nuclear magnetic resonance
s, d, t, m (NMR) singlet, doublet, triplet, multiplet
#∆H activation enthalpy
#∆S activation entropy
#∆V activa