Crown ether-metalloporphyrins as ditopic receptors and pyropheophorbide-a conjugates for the photodynamic therapy of tumors [Elektronische Ressource] / vorgelegt von Helmreich Matthias

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Crown Ether-Metalloporphyrins as Ditopic Receptors and Pyropheophorbide-a Conjugates for the Photodynamic Therapy of Tumors Den Naturwissenschaftlichen Fakultäten der Friedrich-Alexander-Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades 2005 vorgelegt von Matthias Helmreich aus Bamberg Als Dissertation genehmigt von den Naturwissenschaftlichen Fakultäten der Universität Erlangen-Nürnberg Tag der mündlichen Prüfung: 14.10.2005 Vorsitzender der Promotionskommission: Prof. Dr. D.-P. Häder Erstberichterstatter: Prof. Dr. A. Hirsch Zweitberichterstatter: Prof. Dr. J. Gladysz Drittberichterstatterin: Prof. Dr. B. Röder Mein besonderer Dank gilt meinem Doktorvater Prof. Dr. Andreas Hirsch für die gewährte Unterstützung, sowie das rege Interesse am Fortgang der Arbeit. Außerdem möchte ich mich herzlichst bei meinem Co-Doktorvater und Betreuer Dr. Norbert Jux für die Bereitstellung des interessanten Themengebietes, die Bereitschaft zu fachlichen Diskussionen, sowie die umfassende Betreuung während der gesamten Promotionszeit bedanken. Die vorliegende Arbeit entstand in der Zeit vom April 2002 bis Juni 2005 am Institut für Organische Chemie der Friedrich-Alexander-Universität Erlangen-NürnbergTable of Contents 1 Introduction............................................................................1 1.
Publié le : dimanche 1 janvier 2006
Lecture(s) : 48
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Source : WWW.OPUS.UB.UNI-ERLANGEN.DE/OPUS/VOLLTEXTE/2006/415/PDF/MATTHIASHELMREICHDISSERTATION.PDF
Nombre de pages : 200
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Crown Ether-Metalloporphyrins as Ditopic Receptors

and

Pyropheophorbide-a Conjugates for the Photodynamic
Therapy of Tumors






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



2005



vorgelegt von
Matthias Helmreich

aus Bamberg Als Dissertation genehmigt von den Naturwissenschaftlichen Fakultäten der
Universität Erlangen-Nürnberg























Tag der mündlichen Prüfung: 14.10.2005


Vorsitzender der Promotionskommission: Prof. Dr. D.-P. Häder
Erstberichterstatter: Prof. Dr. A. Hirsch
Zweitberichterstatter: Prof. Dr. J. Gladysz
Drittberichterstatterin: Prof. Dr. B. Röder


Mein besonderer Dank gilt meinem Doktorvater Prof. Dr. Andreas Hirsch für die
gewährte Unterstützung, sowie das rege Interesse am Fortgang der Arbeit.
Außerdem möchte ich mich herzlichst bei meinem Co-Doktorvater und Betreuer Dr.
Norbert Jux für die Bereitstellung des interessanten Themengebietes, die
Bereitschaft zu fachlichen Diskussionen, sowie die umfassende Betreuung während
der gesamten Promotionszeit bedanken.























Die vorliegende Arbeit entstand in der Zeit vom April 2002 bis Juni 2005 am Institut
für Organische Chemie der Friedrich-Alexander-Universität Erlangen-NürnbergTable of Contents

1 Introduction............................................................................1
1.1 Porphyrin Systems and their Applications............................................... 1
1.2 Ditopic Receptors: Crown Ether-Porphyrins............................................ 3
1.3 Photodynamic Therapy ........................................................................... 8
1.3.1 The History of Photodynamic Therapy .................................................... 8
1.3.2 Mechanisms of the Photodynamic Therapy .......................................... 11
1.3.3 Photosensitizers in P 14
1.3.4 Photodynamic Therapy as a Therapy for other Diseases than
Cancer .................................................................................................. 17
1.4 Modular Carrier Systems ...................................................................... 20
1.5 Finding a Good Name for Porphyrin- and Chlorophyll-Compounds ...... 22
1.6 C -Fullerene as a building block .......................................................... 22 60
2 Aims..................................................................................... 25
3 Results and Discussion ..................................................... 27
3.1 Molecular Recognition – Crown Ether-Porphyrins and their
Coordination Properties ........................................................................ 27
3.1.1 Synthesis of the Parent Crown Ether-Porphyrin 26 and its Metal
Complexes ............................................................................................ 27
3.1.2 Kinetic Experiments – The Stabilizing Effect of the Crown.................... 30
3.1.3 Ditopic Receptors.................................................................................. 33
3.1.4 Synthesis of a Water Soluble System ................................................... 50
3.1.5 A Concept for the Synthesis of Oligomeric Porphyrin Crown Ether
Arrays – Construction of a Library of Building Blocks............................ 52
3.1.6 Rare Earth Metal Porphyrins................................................................. 56
3.2 The Photodynamic Therapy of Tumors – Construction of Multi-
Pyropheophorbide-a-Fullerene Assemblies .......................................... 59
3.2.1 Isolation of Pyropheophorbide-a 19 ...................................................... 59
3.2.2 Synthesis of Fullerene-Pyropheophorbide-a Conjugates Carrying
two Chromophoric Units........................................................................ 61
3.2.3 Increasing the Number of Chromophores – Introduction of a
Dendritic Unit......................................................................................... 66
3.2.4 Hexa-Substituted C -Systems as Multiplying Units.............................. 72 60
3.2.5 Synthesis of a Decapyropheophorbide-a-Antibody-Conjugate.............. 81
3.2.6 Increasing the Solubility in Polar Solvents - Pyropheophorbide-a
Derivatives with Polar Side Chains ....................................................... 88
3.2.7 Photophysical Investigations................................................................. 91
3.2.8 Biological Investigations: In Vitro Experiments with Photosensitizer-
Carrier-Systems; Uptake and Phototoxic Activity on Human
Lymphoid Cells...................................................................................... 97
4 Summary / Zusammenfassung........................................ 104
5 Experimental Part.............................................................. 115
5.1 Chemicals and Instrumentation........................................................... 115
5.2 Synthetic Procedures .......................................................................... 117
6 Crystal Structures..............................................................175
7 Publications........................................................................183
8 References..................................185

Index of Abbreviations

Ac acetyl
AFM atomic force microscopy
ALA 5-aminolevulinic acid
AMD age-related macular degeneration
BOC t-butyloxycarbonyl
Chl a chlorophyll-a
Chl b ll-b
DAPI 4´,6-diamidino-2-phenylindol dihydrochloride
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC N,N‘-dicyclohexylcarbodiimide
DMA 9,10-dimethylanthracene
DMAP 4-dimethylaminopyridine
DMF N,N‘-dimethylformamide
DMSO dimethylsulphoxide
ε extinction coefficient
EI-MS electron-impact mass spectrometry
eq equivalent
ESI electron spray ionisation
ET electron-transfer
FAB-MS fast atom bombardment mass spectrometry
FC flash column chromatography
FDA U.S. Food and Drug Administration
fs femto seconds
GPC gel permeation chromatography
HOBT 1-hydroxybenzotriazol
Hp hematoporphyrin
HpD hematoporphyrin derivative
HPLC high performance liquid chromatography
IR infra-red
ISC Intersystem crossing
LAH lithium aluminum hydride
LDL low density lipoproteins
MAb monoclonal antibody
MALDI-TOF matrix assisted laser desorption ionization – time of flight


NMR nuclear magnetic resonance
PBS phosphate buffered saline
PDT photodynamic therapy
Phe a Pheophytin-a
PIT photoimmunotherapy
ppm parts per million
ps pico seconds
Pyropheid-a pyropheophytin-a
RT room temperature
S electronic ground state 0
S first excited singlet-state 1
SEC size exclusion chromatography
T first excited triplet-state 1
TB trypan blue
TBDMS t-butyl dimethyl silyl
tBu t-butyl
TCB 1,2,4-trichlorobenzene
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
UV/Vis ultraviolet/visible
1O first excited singlet-state of dioxygen 2
3O triplet ground-state of dioxygen 2
quantum-yield of fluorescence Φ fl
triplet-state quantum yield Φ t
singlet-oxygen quantum yield Φ Δ
triplet-state lifetime τ tIntroduction
1 Introduction
1.1 Porphyrin Systems and their Applications
Why does the area of porphyrin chemistry attract so many scientists?
The answer will probably depend on the person you ask. Certainly a large number of
people interviewed will respond that porphyrin systems play a fundamental role in
many biological processes, e. g. photosynthesis (chlorophylls), oxygen transport
(hemoglobine) and oxygen storage (myoglobine), electron-transfer processes
(cytochromes), respiration, and so on.
There is no exact date for the beginning of the history of modern porphyrin research.
thIt was at the end of the 19 century when several groups started their investigations
on tetrapyrrols, mainly focused on naturally occurring pigments. In 1906, Richard
[1]WILLSTÄTTER published his first work about chlorophyll and was awarded the Nobel
Prize in chemistry in 1915 for his research on plant pigments and especially for his
work on chlorophyll.
[2]The macrocyclic structure of porphyrins was first proposed by KÜSTER in 1912. At
that time, nobody believed him, least of all Hans FISCHER, the father of modern
porphyrin chemistry. Hans FISCHER´S studies on blood and plant pigments, and his
[3, 4]synthesis of hemin were the next milestones in this area which were also awarded
the Nobel Prize in 1929.
After several decades of reduced interest, the next breakthrough was the
determination of the three-dimensional
structure of a bacterial photosynthetic
reaction center by Johann DEISENHOFER,
Robert HUBER, and Hartmut MICHEL (see
[5, 6]Figure 1-1). This was honored with
the Nobel Prize in 1988, and thanks to
their remarkable work, we now have a
more detailed understanding of
photosynthesis, although much still
remains unsolved. Photochemistry,
photophysics, and photobiology joined
the studies of photosynthesis and the
Figure 1-1: Photosynthetic reaction center.

1 Introduction

chlorophylls. It has also encouraged researchers to create model systems, which
mimic the structure and photoactivity of natural systems.
A completely different field is the geochemistry of porphyrins in the soil. Traces of
tetrapyrroles in the geosphere, while challenging the sensitivity of current
instrumentation, offer a fascinating way to investigate the fate of biological material
through geological time periods. Probably the most important feature in this area is
the possibility of using this method for geochemical oil prospecting.
Nowadays, it is almost impossible to get a real overview about the enormously wide
field of porphyrin research. Several books have been published to give an overview
about the actual state of research. The latest and also most extensive was given in
[7]the Porphyrin Handbook, which now contains 20 volumes. Other very important and
helpful tools are online databases like SCIFINDER. Nevertheless, performing an online
search by entering the concept porphyrin yields more than 40000 hits. This
enormous number gives a good impression of how intensive and attractive the
research in the field of porphyrin chemistry and related areas is.
The diversity of directions in which the chemistry and science of tetrapyrroles can
lead is quite remarkable. Basic synthesis continues to be an important subject,
[8]combined with new porphyrin-like structures (e.g. porphycenes and texaphyrins )
appearing on the scene. Also, the biosynthesis of porphyrins continues to be a major
research area. Associated with this interest is the study of the inborn errors of
[9, 10]porphyrin biosynthesis to be found amongst the porphyrias.
A large new area has emerged in the field of medicinal chemistry. Clinical interest
has developed in photodynamic therapy of cancer and other diseases. In this area
contributions come from across the entire range of disciplines. Porphyrins, chlorins,
and phthalocyanines have proved to be effective photosensitizers with excellent
[11]properties. Additionally, there is an increasing interest in photobactericides and
photoviricides based on tetrapyrroles. The phototherapy of jaundice of the newborn
provides another example of tetrapyrrole photomedicine, this time with the linear
[12]tetrapyrrole bilirubin.
A major direction is emerging in the development and use of porphyrins and
phthalocyanines as electroactive materials. Modern porphyrin chemistry tries to find
solutions for new sources of energy and faster computers. Japanese laboratories are
[13-15]particularly active here (Solar energy, Molecular wires).

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