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Design and evaluation of seven-coordinate manganese and iron complexes, and fullerene derivatives, as SOD mimetics [Elektronische Ressource] / vorgelegt von Gao-Feng Liu

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Design and Evaluation of Seven-coordinate Manganese and Iron Complexes, and Fullerene derivatives, as SOD mimetics Der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades vorgelegt von Gao-Feng Liu aus VR China IDesign and Evaluation of Seven-coordinate Manganese and Iron Complexes, and Fullerene derivatives, as SOD mimics Als Dissertation genehmigt von den Naturwissenschftlichen Fakultäten der Friedrich -Alexander-Universität Erlangen-Nürnberg. Tag der mündlichen Prüfung: 02.05.2008 Vorsitzender der Promotionskommission: Prof. Dr. E. Bänsch Erstberichterstatter: Prof. Dr. Dr. h. c. R. van Eldik Zweitberichterstatter: Prof. Dr. Lutz Dahlenburg IIAcknowledgements This study was carried out from February 2003 to February 2008 at the Institute of Inorganic Chemistry at the Friedrich-Alexander-University of Erlangen-Nürnberg under the supervision of Prof. Dr. Dr. h. c. mult Rudi van Eldik. I would like to express my sincere gratitude to my supervisor, Dr. Ivana Ivanovi ć-Burmazovi ć for her essential guidance, her never-ending enthusiasm, and permanent encouragement throughout my study. At the same time I am thankful to Prof. Dr. Dr. h. c. mult Rudi van Eldik for his kind and helpful discussion.
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Design and Evaluation of Seven-coordinate
Manganese and Iron Complexes, and Fullerene
derivatives, as SOD mimetics


Der Naturwissenschaftlichen Fakultät
der Friedrich-Alexander-Universität Erlangen-Nürnberg
zur
Erlangung des Doktorgrades

vorgelegt von
Gao-Feng Liu
aus
VR China


IDesign and Evaluation of Seven-coordinate Manganese and Iron Complexes, and
Fullerene derivatives, as SOD mimics

Als Dissertation genehmigt von den Naturwissenschftlichen Fakultäten der Friedrich
-Alexander-Universität Erlangen-Nürnberg.

















Tag der mündlichen Prüfung: 02.05.2008

Vorsitzender der Promotionskommission: Prof. Dr. E. Bänsch

Erstberichterstatter: Prof. Dr. Dr. h. c. R. van Eldik

Zweitberichterstatter: Prof. Dr. Lutz Dahlenburg

IIAcknowledgements

This study was carried out from February 2003 to February 2008 at the
Institute of Inorganic Chemistry at the Friedrich-Alexander-University of
Erlangen-Nürnberg under the supervision of Prof. Dr. Dr. h. c. mult Rudi van
Eldik.

I would like to express my sincere gratitude to my supervisor, Dr. Ivana
Ivanovi ć-Burmazovi ć for her essential guidance, her never-ending enthusiasm, and
permanent encouragement throughout my study. At the same time I am thankful to
Prof. Dr. Dr. h. c. mult Rudi van Eldik for his kind and helpful discussion.

Warm thanks are given to the whole group for the friendly working
atmosphere.

Thanks to the Friedrich-Alexander-University of Erlangen-Nürnberg and the
DFG within SFB 583 “Redox-active Metal Complexes” for the financial support.

Finally I am grateful to my parents and to my wife for endless support which
has been valuable during my study.


Gao-Feng Liu


IIIDesign and Evaluation of Seven-coordinate Manganese and Iron Complexes, and
Fullerene derivatives, as SOD mimics

Publications

1 Gao-Feng Liu, Ralph Puchta, Frank W. Heinemann, Ivana Ivanovi ć-Burmazovi ć,
Ligand Electronic Properties in the Control of Redox Behavior and Reactivity
toward Superoxide in Seven-Coordinate Manganese Complexes, Chemical
Communication (Submitted)

2 Gao-Feng Liu, Miloš Filipovi ć, Ivana Ivanovi ć-Burmazovi ć, Florian Beuerle, Patrick
Witte, Andreas Hirsch, Highly Catalytic Metal-Free Superoxide Dismutation mimics
from Dendritic Monoadducts of C Angewandte Chemie (in print) 60,

3 Gao-Feng Liu, Miloš Filipovi ć, Frank W. Heinemann and Ivana Ivanovi ć-Burmazovi ć
Seven-Coordinate Iron and Manganese Complexes with Acyclic and Rigid Pentadentate
Chelates and their Superoxide Dismutase Activity, Inorganic Chemistry, 2007, 46,
8825-8835.

4 David Sarauli, Roland Meier, Gao-Feng Liu, Ivana Ivanovic-Burmazovic, Rudi van
Eldik, Effect of Pressure on Proton-Coupled Electron Transfer Reactions of
Seven-Coordinate Iron Complexes in Aqueous Solutions, Inorganic Chemistry, 2005,
44, 7624-7633.


Conference contributions

1 Poster “Sub-millisecond Mixing Stopped-Flow Configuration to SOD Activity”,
Inorganic Reaction Mechanism Meeting, organised by the Royal Society of
Chemistry, Athens, Greece, January 2004.

2 Poster “Cryo-stopped-flow measurements for rapid inorganic reactions”,
Inorganic Reaction Mechanism Meeting, organised by the Royal Society of
Chemistry, Athens, Greece, January, 2004.
IV
3 Oral Presentation “Seven-coordinate Iron and Manganese Complexes and
Reactivity towards Superoxide”, Conference on Coordination Chemistry of
China, organised by the Chinese Society of Chemistry, Guangzhou, China,
October, 2005.

4 Poster “Superoxide Dismutase Mimetics. From Seven-coordinate Iron and
Manganese Complexes to Fullerenes”, Inorganic Reaction Mechanism Meeting,
organised by the Royal Society of Chemistry, Krakow, Poland, January, 2006.

5 Poster “Design and Evaluation of Seven-coordinate Iron and Manganese
Complexes, Fullerenes as SOD mimics”, SFB-Symposium on Redox-Active
Metal complexes: Control of Reactivity via Molecular Architecture, Erlangen,
Germany, March, 2007.

Abbreviations

SODs superoxide dismutases
ROS reactive oxygen species
RNS reactive nitrogen species
SAR Structure-Activity-Relationship
His L-Histidine
Asp L-Aspartic acid
Me [15]pyridinaneN trans-2,13-dimethyl-3,6,9,12,18-pentaazabicyclo 2 5
[12.3.1]-octadeca-1(18),14,16-triene)
Hdapsox 2,6-diacetylpyridine-bis(semioxamazide) 2
HDcphp Pyridine-2,6-biscarboxylic acid-bis((N ′-2-pyridine-2-yl) 2
hydrazide)
Daphp 2,6-diacetylpyridine-bis(2-pyridylhydrazone)
Hdapmp [1-(6-acetyl-2-pyridinyl) ethylidene] hydrazone
VDesign and Evaluation of Seven-coordinate Manganese and Iron Complexes, and
Fullerene derivatives, as SOD mimics
salen N,N´-ethylenebis(salicylideniminate)
TBAP tetrakis(4-benzoic acid)porphyrin
Tempol 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl
t half life 1/2
λ wavelength (nm)
δ chemical shift(NMR)
ν stretching mode(IR)
A absorbance
PBP pentagonal-bipyramidal
DD distorted-dodecahedron
IC half maximal inhibitory concentration 50
K equilibrium constant
k catalytic rate constant cat
k observed rate constant obs
OPs oxidation potentials
NHE normal hydrogen electrode
SHE standard hydrogen electrode
CV cyclic voltammetry
NBT nitro blue tetrazolium
UV ultraviolet
DFT density functional theory
IR infrared spectroscopy
NMR nuclear magnetic resonance
MS mass spectrometry
VI
Contents
ACKNOWLEDGEMENTS......................................................................................................................................III
PUBLICATIONS................... IV
CONFERENCE CONTRIBUTIONS ........................................................................................................................ IV
ABBREVIATIONS..................V
CHAPTER 1 ...........................................................................................................................................................1
INTRODUCTION..................................................................................................................................................1
1.1 SUPEROXIDE AND SUPEROXIDE DISMUTASES (SODS) ...........................................................................1
1.1.1 Superoxide and its toxic effects to damage the cell ............................................................................1
1.1.2 Superoxide Dismutases (SODs) and their Active Metal Center Structures ..........................................3
1.2 DEVELOPMENT AND CONSIDERATIONS OF SYNZYMES AS SOD MIMICS ..............................................6
1.2.1. Manganese(III) Metalloporphyrins ..................................................................................................8
1.2.2. Manganese(III) salen Complexes .....................................................................................................9
1.2.3. Nitroxide...................10
1.2.4. Manganese(II) (pentaazamacrocyclic ligand)-Based Complexes ..................................................11
1.3 CHARACTERIZATION ARRAYS OF SOD ACTIVITY...............................................................................12
1.3.1 Indirect Assay.................................................................................................................................12
1.3.2 Direct Arrays..................................................................................................................12
1.3.3 Cyclic Voltammetry Method ...........................................................................................................13
1.4 FULLERENE AND ITS ANTIOXIDANT ABILITY ........................................................................................14
1.5 AIMS OF THIS THESIS .............................................................................................................................18
1.6 REFERENCES..........................................................................................................................................19
CHAPTER 2 .........................................................................................................................................................25
SEVEN-COORDINATE IRON AND MANGANESE COMPLEXES WITH ACYCLIC AND RIGID
PENTADENTATE CHELATES AND THEIR SUPEROXIDE DISMUTASE ACTIVITY.........................25
2.1 ABSTRACT...............25
2.2 INTRODUCTION.......26
2.3 EXPERIMENTAL SECTION29
2.4 RESULTS AND DISCUSSION ....................................................................................................................35
2.4.1 Stability of Superoxide Anion in H O-DMSO.................................................................................35 2
2.4.2 Structures .......................................................................................................................................37
2.4.3 Electrochemistry.............................................................................................................................45
2.4.4 Reaction with superoxide in DMSO ...............................................................................................48
2.4.5 superoxide in aqueous solution ...............................................................................51
2.5 CONCLUSIONS........................................................................................................................................53
2.6 REFERNCES.............54
CHAPTER 3 .........................................................................................................................................................60
LIGAND ELECTRONIC PROPERTIES IN THE CONTROL OF REDOX BEHAVIOR AND
REACTIVITY TOWARD SUPEROXIDE IN SEVEN COORDINATE MANGANESE COMPLEX........60
3.1 ABSTRACT..............................................................................................................................................60
VIIDesign and Evaluation of Seven-coordinate Manganese and Iron Complexes, and
Fullerene derivatives, as SOD mimics
3.2 INTRODUCTION ......................................................................................................................................61
3.3 EXPERIMENTAL SECTION......................................................................................................................62
3.4 RESULTS AND DISCUSSION ....................................................................................................................66
3.4.1 Structure...................66
3.4.2 Electrochemistry.............................................................................................................................70
3.4.3 Reactions with Superoxide in DMSO .............................................................................................72
3.4.4 Modelling via DFT Calculations:...................................................................................................74
3.5 CONCLUSIONS........................................................................................................................................76
3.6 REFERENCES...........76
CHAPTER 4 .........................................................................................................................................................79
STRUCTURAL FEATURES IN CONTROL OF REACTIVITY TOWARD SUPEROXIDE IN
MANGANESE AND IRON COMPLEXES.......................................................................................................79
4.1 ABSTRACT...............79
4.2 INTRODUCTION.......80
4.3 EXPERIMENTAL SECTION81
4.4 RESULTS AND DISCUSSION ....................................................................................................................85
4.4.1 Studies on the complex 7 ................................................................................................................85
4.4.2 the complex 8.........91
4.5 CONCLUSION..........................................................................................................................................96
4.6 REFERENCES...........96
CHAPTER 5 .........................................................................................................................................................99
HIGH CATALYTIC ACTIVITY OF DENDRITIC C MONOADDUCTS IN METAL-FREE 60
SUPEROXIDE DISMUTATION........................................................................................................................99
5.1 ABSTRACT...............99
5.2 INTRODUCTION.....100
5.3 EXPERIMENTAL SECTION....................................................................................................................101
5.4 RESULTS AND DISCUSSION ..................................................................................................................107
5.5 CONCLUSION........................................................................................................................................115
5.6 NOTE AND REFERENCES......................................................................................................................116
SUMMARY ........................................................................................................................................................118
ZUSAMMENFASSUNG ...................................................................................................................................122

VIIIChapter 1 Introduction

Chapter 1


Introduction


1.1 Superoxide and Superoxide Dismutases (SODs)
1.1.1 Superoxide and its toxic effects to damage the cell
Oxygen is vital to life, but as a diatomic molecule it is remarkably unreactive.
Normally when the terminal oxidases (cytochrome c oxidase) react with oxygen, four
electrons are transferred and water is formed. Occasionally oxygen can also react with
other electron transport components, herein only one electron is transferred and it
causes the overproduction of the superoxide anion in our bodies. It is a reducing agent
in the anionic form [Eq. (1)], and an oxidant in the protonated form (pK (HO ) = 4.69) a 2
[Eq. (2)]
–• -O O + e E° = - 0.16 V (1)2222 2 2 2 2
–– ––• - + O + e + H HO E° = + 0.9 V (2)2 2

·–According to the stoichiometry of O and H O dismutation reactions, in plant 2 2 2
tissues about 0.9 to 1.5% of the total oxygen uptake proceeds through the formation of
the free radical intermediates of the partial reduction of oxygen.[1] Although some of
·–the O generated by neutrophiles and other immune cells is used to kill pathogenic 2
bacteria or parasites, under the condition of bad lifestyle (smoking, over exercise, over
dieting, unbalanced diet, inadequate rest, irregular sleeping patterns and stress) or other
1Design and Evaluation of Seven-coordinate Manganese and Iron Complexes, and
Fullerene derivatives, as SOD mimics
·–external factors (UV rays, radiation, environmental pollution), O will be 2
overproduced. Although normal forms of life maintain a reducing environment in their
cells, disturbances in this normal redox state can cause toxic effects to damage all
components of the cell. The tissue toxicity from extracellular superoxide generation
seems to be based on three aspects: i) its direct reactivity with numerous types of
biological molecules (lipid, DNA, RNA, catecholamines, steroids, etc.); ii) its
dismutation to form H O , in which H-atoms were absorbed from such key biological 2 2
targets as catecholamines or the allylic CH in lipid; iii) its capacity to inactivate
iron-sulfur cluster containing enzymes (which are critical in a wide variety of
metabolic pathways), thereby liberating free iron in the cell, which can in
iron-catalyzed Fenton reaction between trace amounts of ferrous ions and H O2 2
produce the highly reactive hydroxyl radical.



Figure 1-1 the generation of reactive oxygen species (ROS) and the toxic effects to damage the cell


Moreover, superoxide also is the substrate for the generation of a variety of
reactive oxygen species (ROS), which include hydrogen peroxide, hydroxyl radicals,
hypochlorite ion and peroxynitrites. (Figure 1-1) It is known that a particularly
destructive aspect of oxidative stress is due to the overproduction of these reactive
oxygen species, which causes an imbalance between the production of reactive oxygen
and a biological system's ability to readily detoxify the reactive intermediates or easily
repair the resulting damage. For example, the hydroxyl and hydroperoxide radicals in
2