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Carbohydrates and SAAs in drug design [Elektronische Ressource] : synthesis of selective α4β7-integrin antagonists and cyclodextrin mimetics / Elsa Locardi

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Published 01 January 2002
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Institut für Organische Chemie und Biochemie
der Technischen Universität München



Carbohydrates and SAAs in Drug-Design: Synthesis of Selective α4β7-Integrin
Antagonists and Cyclodextrin Mimetics


Elsa Locardi



Vollständiger Abdruck der von der Fakultät für Chemie der Technischen Universität
München zur Erlangung des akademischen Grades eines

Doktors der Naturwissenschaften

genehmigten Dissertation.


Vorsitzender: Univ.-Prof. Dr. St. J. Glaser
Prüfer der Dissertation:
1. Univ.-Prof. Dr. H. Kessler
2. Univ.-Prof. Dr. B. Holzmann
3. apl. Prof. Dr. L. Moroder


Die Dissertation wurde am 17.10.2002 bei der Technischen Universität München
eingereicht und durch die Fakultät für Chemie am 09.12.2002 angenommen.





























ai miei genitori






There are many people who have directly and indirectly contributed to this work. First
of all I would like to thank my thesis supervisor Prof. Dr. Horst Kessler. He has been a
great source of encouragement throughout this work. I would like to especially thank
him for the amount of scientific freedom he gave me and for his brilliant ideas and
very precise and critical comments which added considerably to the quality of this
thesis.
A lot of colleagues in the working group of Professor Kessler have contributed to the
pleasure of my staying at the Institute. It would be difficult to mention all the names
but I would certainly like to mention a few:
I am especially indebted to my lab mates Dr. Claudia Biro, Dr. Jürgen Boer, Ulrich
Hersel and Dr. Matthias Stöckle for making my stay here a wonderful experience.
They have been fantastic people to work with, both in the fields of chemistry and
outside it.
I also thank the other doctoral and postdoctoral fellows at the Institute for the friendly
atmosphere and the fruitful discussions. In particular, I am very grateful to Dr. Sibylle
Gruner and Dr. Martin Sukopp for being an immense source of joy and for making me
very often laugh.
I would like to express my gratitude to Dr. Jürgen Boer who contributed to this study
not only by numerous discussions and critical remarks, but also supporting me through
all stages of it.
I would like to thank Dr. Gerd Gemecker and Dr. Rainer Haeßner for their advice on
the NMR hardware and software.
I am also grateful to Armin Modlinger for his support with many organizational
aspects of the work, in particular for getting the HRMS.


My sincerest thanks go to Maria Kranawetter for preparative HPLC purifications,
Burghard Cordes for recording MS-spectra, Evelyn Bruckmaier and Marianne
Machule for secretarial assistance.
I am also indebted to Sonia Cesana and Dr. Luciana Marinelli for the critical
inspection and reading of this work and for being great friends.
I would like to thank Prof Dr. Bernhard Holzmann for his collaboration and Anja
Schuster for measuring the biological activities of the sugar analogs.
Last, but definitely not the least I would like to thank my family for the patience they
have shown during the course of my studies. I would like to especially thank my
parents for the kind of encouragement and support they have provided me - and their
constant blessings for my success.

















Index

1 Introduction..............................................................................................................1
2 Biological Implications of α4-Integrins .................................................................. 3
2.1 α4β7 integrin as therapeutic targets ................................................................... 4
2.2 Cell adhesion molecules (CAMs)....................................................................... 6
3 Carbohydrates and Sugar Amino Acids in Drug-Design ...................................... 10
3.1 Naturally occurring sugar amino acid (SAA)................................................... 10
3.2 Carbohydrate-based peptidomimetics............................................................... 12
3.3 SAA oligomers as carbohydrate mimetics........................................................ 13
3.4 Carbohydrate and SAA as scaffolds ................................................................. 15
4 Cyclic Homo-Oligomers from Sugar Amino Acids: Synthesis, Conformational
Analysis and Significance............................................................................................. 24
4.1 Synthesis in solution and on solid phase of the oligomers containing Gum .... 24
4.2 Conformational analysis by NMR .................................................................... 27
4.3 Molecular modeling..........................................................................................30
4.4 Cyclodextrin-like complexation behavior of the cyclic hexamer..................... 34
5 Synthesis and SAR of Mannose-Based Peptidomimetics Blocking Selectively
Integrin α4β7 Binding to MAdCAM-1 ........................................................................ 39
5.1 Design and synthesis of the mannose-based peptidomimetics......................... 39
5.2 Structure Activity Relationship for the Biased Mannose-Based Library ......... 49
5.3 Structure activity relationship........................................................................... 54
6 Summary................................................................................................................57
7 Zusammenfassung..................................................................................................60
8 Experimental Section.............................................................................................63
8.1 General methods...............................................................................................63
8.2 Synthesis of the oligomers containing Gum..................................................... 63
8.3 Synthesis of individual mannose-based compounds ........................................ 71
8.4 Conformational analysis of the cyclodextrin mimetics .................................. 121
8.5 Binding studies of the cyclodextrin mimetics ................................................ 122
8.6 Biological evaluation of the mannose-based library ...................................... 122
8.7 .................................. 124
9 References............................................................................................................126
Abbreviations
Abbreviations

1D, 2D mono-dimensional, two-dimensional
-10Å angstrom, 10 m
Ac acetyl
ACN acetonitrile
ADME absorption, distribution, metabolism, excretion
Boc tert.-butoxycarbonyl
br broad
BSA bovine serum albumin
Bu n-butyl
BuLi n-butyllithium
cat. catalytic
CDA cyclohexane-1,2-diacetal
conc. concentrated
COSY correlated spectroscopy
d doublet or days
dd doublet of doublet
δ chemical shift
dist. distillated
DCC N,N´-dicyclohexylcarbodiimide
DCM dichloromethane
DIC N,N´-diisopropylcarbodiimide
DIPEA diisopropylethylamine
DME 1,2-dimethoxyethane
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
E. coli escherichia coli
EDCI N-ethyl-N,N´-(dimethylaminopropyl)-carbodiimide
EDT 1,2-ethandithiole
ELISA enzyme linked immuno sorbent assay
eq. equivalent Abbreviations
ESI electro spray ionization
Et ethyl
ECM extracellular matrix
Fmoc 9-fluorenylmethoxycarbonyl
Fmoc-ONSu (N-fluorenylmethoxycarbonyloxy)-N-succinimide
g gram
Gum Glucosyluronic acid methylamine
h hour
HATU O-(7-azabenzotriazole-1-yl)-N,N,N´,N´,-
tetramethyluronium-hexafluorophosphate
HFIP hexafluoroisopropanol
HIV human immunodeficiency virus
HOAc acetic acid
HOAt 1-hydroxy-7-azabenzotriazole
HOBt 1-hydroxybenzotriazole
HOSu N-hydroxysuccinimide
HPLC high performance liquid chromatography
Hz hertz
IC inhibitory capacity
Ig immunglobulin
K kelvin
kDa kilodalton
L liter
LDA lithiumdiisopropylamide
LHMDS lithium-bis(trimethylsilyl)amide
J scalar coupling constant
m multiplet
M molar
mAb monoclonal antibody
MD molecular dynamic
Me methyl
MeIm N-methylimidazole