Development of a new class of potent and selective non-steroidal inhibitors of {17β-hydroxysteroid [17-beta-hydroxysteroid] dehydrogenase type 1 [Elektronische Ressource] : bis(hydroxyphenyl)substituted azoles, thiophenes, benzenes and aza-benzenes / von Emmanuel Bey

Emmanuel Bey

Informations

• Publié par: universitat_des_saarlandes
• Publié le: 01 janvier 2008
• Nombre de lectures: 28
• Langue: English
• Poids de l'ouvrage: 11 Mo

Extrait

Development of a New Class
of Potent and Selective Non-Steroidal Inhibitors of
17 -Hydroxysteroid Dehydrogenase Type 1

Bis(hydroxyphenyl)substituted
Azoles, Thiophenes, Benzenes and Aza-Benzenes


Dissertation


zur Erlangung des Grades
des Doktors der Naturwissenschaften
der Naturwissenschaftlich-Technischen Fakultät III
Chemie, Pharmazie, Bio- und Werkstoffwissenschaften
der Universität des Saarlandes

von
Diplom-Chemiker
Emmanuel Bey
Saarbrücken
2008
b - I -



































Tag des Kolloquiums: 29 Januar 2009

Dekan: Prof. Dr. U. Müller

Berichterstatter: Prof. Dr. R.W. Hartmann
Prof. Dr. U. Kazmaier - II -
Diese Arbeit entstand unter der Anleitung von Prof. Dr. R.W. Hartmann in der
Fachrichtung 8.2 Pharmazeutische und Medizinische Chemie der Naturwissenschaftlich-
Technischen Fakultät III der Universität des Saarlandes von Juli 2004 bis November 2007. - III -
Acknowledgements

I would like to express my sincere gratitude to my supervisor Prof. Dr. Rolf W.
Hartmann, for introducing me in the field of medicinal chemistry, and for giving me the
opportunity to prepare my thesis as a member of his research group. His support and advice
have been a great help during these years.
I would like to thank my official referee Prof. Dr. Uli Kazmaier for the reviewing of
this dissertation.
I am deeply grateful to Dr. Sandrine Marchais-Oberwinkler, my second supervisor, for
guiding me on performing the lab work as well as the writing of scientific papers and for
her invaluable support and encouragement during these years.
I will also acknowledge Dr. Martin Frotscher for his valuable suggestions and for all the
stimulating discussions in the biochemistry field.
I wish to express my sincere thanks to Anke Steinbach for her warm friendship, for
encouragements during my stay in the lab and for her critical appraisal of the manuscript of
this thesis.
I am grateful to all my HSD co-workers, especially Patricia Kruchten, Ruth Werth,
Claudia Henn, Alexander Oster and Alessandro Spadaro, for the fruitful collaboration.
I wish warmly thank to Kerstin Esch, Anja Palusczak, Beate Geiger, Jannine Ludwig
for performing the in vitro tests, Dr. Christiane Scherer for performing the CaCo-2
experiments, Dr. Joseph Zapp for the NMR measurements, Dr. Stefan Boettcher and Dr.
Marc Angotti for running the mass experiments.
I would also like to thank Matthias Negri for his help and support in the molecular
modeling field.
I would like to thank Thomas, Marcel, Mariano, Karsten and Cornelia who have been
excellent partners during the organic practical course.
I also wish to thank the laboratory staff, especially Corina Przybyla, Frau Tehrani and
Lothar Jager for their sympathy and their pleasant service.
I wish to thank all my undergraduate research participants: Alexander Oster, Tobias
Klein, Petra Schmitz, Christian Steuer, Daniela Hodapp, Anika Demuth, Lisa Wirtz, Sarah
Thies and Sabine Göpfert for their help and contribution in the development of the project.
Finally, I would like to thank my family, especially my parents for their support. - IV -
Papers included in this thesis


The present thesis is divided into four publications which are referred to in the text by their
Roman numerals:
I. Design, Synthesis and Biological Evaluation of
Bis(hydroxyphenyl)azoles as Potent and Selective Non-Steroidal
Inhibitors of 17 -Hydroxysteroid Dehydrogenase Type 1 (17 -
HSD1) for the Treatment of Estrogen-Dependent Diseases
Emmanuel Bey, Sandrine Marchais-Oberwinkler, Patricia Kruchten, Martin
Frotscher, Ruth Werth, Alexander Oster, Oztekin Algül, Alexander Neugebauer
and Rolf W. Hartmann
Bioorganic Medicinal Chemistry, 16, 6423-6435 (2008).


II. The Role of the Heterocycle in Bis(hydroxyphenyl)triazoles for
Inhibition of 17 -Hydroxysteroid Dehydrogenase (17 -HSD) Type
1 and Type 2
Yaseen A. Al-Soud, Emmanuel Bey, Alexander Oster, Sandrine Marchais-
Oberwinkler, Ruth Werth, Patricia Kruchten, Martin Frotscher and Rolf W.
Hartmann
Molecular and Cellular Endocrinology, (2008), doi:10.1016/j.mce.2008.09.012.


III. Design, Synthesis, Biological Evaluation and Pharmacokinetics of
Bis(hydroxyphenyl)substituted Azoles, Thiophenes, Benzenes and
Aza-Benzenes as Potent and Selective Non-Steroidal Inhibitors of
17 -Hydroxysteroid Dehydrogenase Type 1 (17 -HSD1)
Emmanuel Bey, Sandrine Marchais-Oberwinkler, Ruth Werth, Matthias Negri,
Yaseen A. Al-Soud, Patricia Kruchten, Alexander Oster, Martin Frotscher,
Barbara Birk and Rolf W. Hartmann
Journal of Medicinal Chemistry, 51, 6725-6739 (2008).


IV. New Insights into the SAR and Binding Modes of
Bis(hydroxyphenyl)thiophenes and Benzenes: Influence of
Additional Substituents on 17 -Hydroxysteroid Dehydrogenase
Type 1 (17 -HSD1) Inhibitory Activity and Selectivity
Emmanuel Bey, Sandrine Marchais-Oberwinkler, Matthias Negri, Patricia
Kruchten, Alexander Oster, Ruth Werth, Martin Frotscher, Barbara Birk and Rolf
W. Hartmann
Journal of Medicinal Chemistry, (2008), manuscript submitted.
bbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbb - V -
Contribution report


The author wishes to clarify his contributions to the papers I–IV in the thesis.


I. Significantly contributed to the synthetical concept. Synthesized and characterized most
of the new compounds. Compounds 7 and 8 were prepared by Alexander Oster as a part
of a PhD thesis. Compounds 10 and 15 were synthesized by Dr. Oztekin Algül.
Significantly contributed to the interpretation of the results. Significantly contributed to
writing of the manuscript.


II. Contributed to the inhibitor design concept. Significantly contributed to the
interpretation of the results. Significantly contributed to writing of the manuscript.


III. Significantly contributed to the inhibitor design concept. Planned, synthesized and
characterized all new compounds except for compounds 12 to 15 (synthesized by Dr.
Yaseen A. Al-Soud) and compounds 16 and 24 (synthesized by Alexander Oster as a
part of a PhD thesis). Significantly contributed to the interpretation of the results.
Significantly contributed to writing of the manuscript.


IV. Significantly contributed to the inhibitor design concept. Planned, synthesized and
characterized all new compounds except for compounds 35, 39, 41 and 42 synthesized
by Alexander Oster as a part of a PhD thesis. Significantly contributed to the
interpretation of the results. Significantly contributed to writing of the manuscript. - VI -
Abbreviations

17β-HSD1 17β-hydroxysteroid dehydrogenase type 1
17β-HSD2 17β-hydroxysteroid dehydrogenase type 2
AcTH adrenocorticotropic hormone
AKR aldo-keto reductase
Asn asparagine
Asp aspartic acid
AUC area under the curve
CC column chromatography
CDCl deuterated chloroform 3
CD OD deuterated methanol 3
CNS central nervous system
COF cofactor binding site
DHEA dehydroepiandrosterone
DME di-methoxyethane
DMEM Dulbecco's modified eagle medium
DMF dimethylformamide
CD SOCD deuterated dimethylsulfoxyde 3 3
E1 estrone
E2 17 -estradiol
EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
EDTA ethylene diaminetetraacetate
ER estrogen receptor
ESP electrostatic potential
Eq equivalent
Et ethyl
FCS fetal calf serum
Glu glutamic acid
Gly glycine
GnRH gonatropin releasing hormone
His histidine
HOBt 1-hydroxybenzotriazole
HSD hydroxysteroid dehydrogenase
HYC hybrid inhibitor O5’-[9-(3,17 -dihydroxy-1,3,5(10)-estratrien-
16 -yl)-nonanoyl]adenosine
MEP molecular electrostatic potential
Hz hertz
Leu leucine
LH luteinizing hormone
Lys lysine
Μm micromolar
Me methyl
MES 2-(morpholino)ethanesulfonic acid
Met methionine
MHz megahertz
mRNA messenger ribonucleic acid
nM nanomolar
NADP(H) nicotinamide adenine dinucleotide phosphate
NAD(H) nicotinamide adenine dinucleotide
bbb - VII -
P apparent permeability coefficient app
PDB-ID protein data bank identification code
Ph phenyl
PK pharmacokinetic
ppm parts per million
RBA relative binding affinity
rt room temperature
SAR structure activity relationship
SDR short dehydrogenase reductase
SEM standard error of the mean
semi-QMAR semi-quantitative MEP-activity relationship
SER serine
SERM selective estrogen receptor modulator
SRE steroid response element
SUB substrate binding site
THF tetrahydrofurane
TE Tris-EDTA
Thr threonine
Tyr tyrosine
Å Ångström -