Design and Synthesis of Selective Butyrylcholinesterase (BChE)

312 Pages·2016·21.11 MB·English

Design and Synthesis of Selective
Butyrylcholinesterase (BChE) Inhibitors for the
Development of Radiotracers to Investigate the
Role of BChE in Alzheimer’s Disease

Dissertation
zur Erlangung des naturwissenschaftlichen Doktorgrades der
Julius-Maximilians-Universität Würzburg

vorgelegt von
Edgar Sawatzky
aus Darmstadt

Würzburg 2016

Eingereicht bei der Fakultät für Chemie und Pharmazie am
_______________________________

Gutachter der schriftlichen Arbeit
1. Gutachter:______________________________
2. Gutachter:______________________________

Prüfer des öffentlichen Promotionskolloquiums
1. Prüfer:______________________________
2. Prüfer:______________________________
3. Prüfer:______________________________

Datum des öffentlichen Promotionskolloquiums
_____________________________

Doktorurkunde ausgehändigt am
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The presented work has been carried out under supervision of Professor Michael Decker
in Pharmaceutical and Medicinal Chemistry at the Institute of Pharmacy and Food
Chemistry of the Julius Maximilian University Würzburg between January 2013 and
February 2016.
The great tragedy of Science:
The slaying of a beautiful hypothesis
by an ugly fact.

Thomas Henry Huxley (1825-1895)

Publications

Sawatzky, E.; Al-Momani, E.; Kobayashi, R.; Higuchi, T.; Samnick, S.; Decker, M. A Novel Way to
Radiolabel Human Butyrylcholinesterase for Positron Emission Tomography through Irreversible Transfer of
the Radiolabelled Moiety. ChemMedChem 2016, 11, 1540-1550. (cf. Appendix 1)

Sawatzky, E.; Wehle, S.; Kling, B.; Wendrich, J.; Bringmann, G.; Sotriffer, C. A.; Heilmann, J.; Decker, M.
Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational
Investigation into Their Inhibition Mode. J. Med. Chem. 2016, 59, 2067-2082. (cf. Appendix 2)

Dolles, D.; Nimczick, M.; Scheiner, M.; Ramler, J.; Stadtmüller, P.; Sawatzky, E.; Drakopoulos, A.; Sotriffer,
C.; Wittmann, H.-J.; Strasser, A.; Decker, M. Aminobenzimidazoles and Structural Isomers as Templates for
Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands to Combat Neurodegenerative Disorders.
ChemMedChem 2016, 11,1270-1283.

Darras, F. H.; Kling, B.; Sawatzky, E.; Heilmann, J.; Decker, M. Cyclic Acyl Guanidines Bearing Carbamate
Moieties Allow Potent and Dirigible Cholinesterase Inhibition of either Acetyl- or Butyrylcholinesterase.
Bioorg. Med. Chem. 2014, 22, 5020-5034.

Sawatzky, E.; Bukowczan, J.; Decker, M. Investigation into Selective Debenzylation and Ring Cleavage of
Quinazoline Based Heterocycles. Tetrahedron Lett. 2014, 55, 2973-2976. (cf. Appendix 3)

Sawatzky, E.; Drakopoulos, A.; Rölz, M.; Sotriffer, C. A.; Engels, B.; Decker, M. Experimental and Theoretical
Investigations into the Stability of Cyclic Aminals. Beilstein J. Org Chem., Accepted. (cf. Appendix 4)
Copyrights

Parts of this work have been published previously and are reproduced, adapted and/or modified with permission
from:

Sawatzky, E.; Al-Momani, E.; Kobayashi, R.; Higuchi, T.; Samnick, S.; Decker, M. A Novel Way to Radiolabel
Human Butyrylcholinesterase for Positron Emission Tomography through Irreversible Transfer of the
Radiolabelled Moiety. ChemMedChem 2016, 11, 1540-1550. Copyright (2016) John Wiley and Sons.
http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201600223/abstract

Sawatzky, E.; Wehle, S.; Kling, B.; Wendrich, J.; Bringmann, G.; Sotriffer, C. A.; Heilmann, J.; Decker, M.
Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational
Investigation into Their Inhibition Mode. J. Med. Chem. 2016, 59, 2067-2082. Copyright (2016) American
Chemical Society.
http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01674

Sawatzky, E.; Bukowczan, J.; Decker, M. Investigation into Selective Debenzylation and Ring Cleavage of
Quinazoline Based Heterocycles. Tetrahedron Lett. 2014, 55, 2973-2976. Copyright (2014) Elsevier.
http://www.sciencedirect.com/science/article/pii/S0040403914005413

Sawatzky, E.; Drakopoulos, A.; Rölz, M.; Sotriffer, C. A.; Engels, B.; Decker, M. Experimental and Theoretical
Investigations into the Stability of Cyclic Aminals. Beilstein J. Org Chem., Accepted. Copyright (2016) is
retained by the authors according to the terms of Beilstein Journal of Organic Chemistry
https://www.beilstein-journals.org/bjoc/home/home.htm
https://www.beilstein-journals.org/bjoc/about/aboutJournal.htm
and the Creative Commons Attribution License
https://creativecommons.org/licenses/by/4.0/legalcode
Documentation of Authorship
All individual contributions for each author to the publications reprinted in this thesis as well as unpublished
manuscripts are listed below:
Sawatzky, E. (1); Al-Momani, E. (2); Kobayashi , R. (3); Higuchi, T. (4); Samnick, S. (5);
Chapter 3 Decker, M. (6) A Novel Way to Radiolabel Human Butyrylcholinesterase for Positron Emission
(Appendix 1) Tomography through Irreversible Transfer of the Radiolabeled Moiety. ChemMedChem 2016, 11,
1540-1550.
Author 1 2 3 4 5 6 Jeßberger, S. Högger, P.
Study design/concept development x x
Synthesis of intermediates and precursors x
Analytical characterization of intermediates and
x
precursors
IC determination of reference compounds on
50 x
hBChE and hAChE
Time and concentration dependent inhibition of
x
reference compounds on hBChE
Plasma stability test of reference compounds x x x
Radiosynthesis of radiotracers x x
Purification and formulation of radiotracers x x
Ex vivo Autoradiography experiments x x
Manuscript writing and correction x x
Supervision of Edgar Sawatzky x

Sawatzky, E. (1); Wehle, S. (2); Kling, B. (3); Wendrich, J. (4); Bringmann, G. (5); Sotriffer, C.
Chapter 4 A. (6); Heilmann, J. (7); Decker, M. (8) Discovery of Highly Selective and Nanomolar
(Appendix 2) Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition
Mode. J. Med. Chem. 2016, 59, 2067-2082.
Author 1 2 3 4 5 6 7 8
Study design/concept development x x
Synthesis of intermediates and test compounds x
Analytical characterization of intermediates and x
test compounds
Enzyme inhibition determination of test x
compounds on eqBChE, hBChE and hAChE
Time and concentration dependent inhibition of
x
reference compounds on hBChE and eqBChE
Computational studies/Moleculat modeling
x x
studies
Sequence comparison of AChE and BChE x x
ORAC Assay x x
Neurotoxicity and –protection of test compounds
x x
on murine HT-22 cell line
Enantiomeric resolution of the most active
x x
compound
Manuscript writing x x x x
Manuscript correction x x x x x
Supervision of Edgar Sawatzky x
Chapter 5 Sawatzky, E. (1); Decker, M. (2) Dual Addressing of Butyrylcholinesterase by Targeting the
Catalytic Active Site (CAS) and the Peripheral Anionic Site (PAS). Unpublished.
Author 1 2
Study design/concept development x x
Synthesis of intermediates and test compounds x
Analytical characterization of intermediates and x
test compounds
Enzyme inhibition determination of test x
compounds on eqBChE
Supervision of Edgar Sawatzky x

Chapter 6 Sawatzky, E. (1); Bukowczan, J. (2); Decker, M. (3) Investigation into Selective Debenzylation
(Appendix 3) and Ring Cleavage of Quinazoline Based Heterocycles. Tetrahedron Lett. 2014, 55, 2973-2976.
Author 1 2 3
Study design/concept development x x
Synthesis of intermediates and compounds x x
Analytical characterization of intermediates and x
compounds
Evaluation of reduction conditions x x
Manuscript writing x x
Manuscript correction x x
Supervision of Edgar Sawatzky x

Chapter 7 Sawatzky, E. (1); Drakopoulos, A. (2); Rölz, M. (3); Sotriffer, C. A. (4); Engels, B. (5); Decker,
(Appendix 4) M. (6) Experimental and Theoretical Investigations into the Stability of Cyclic Aminals. Beilstein
J. Org Chem., Accepted.
Author 1 2 3 4 5 6
Study design/concept development x x
Synthesis of intermediates and test compounds x x
Analytical characterization of intermediates and
x x
test compounds
Conducting calibration lines of test compounds
x
on HPLC
pH-dependent hydrolysis experiments of test
x
compounds
condensation experiments of test compounds x
MoKa calculations of test compounds x x
Quantum mechanics calculations of test
x x
compounds
Conformational search of test compounds x x
Molecular mechanics ring strain comparison of
x x x
test compounds
Manuscript writing x x x
Manuscript correction x x x x x
Supervision of Edgar Sawatzky x