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Synthesis and Structure-Activity Relationships of Inhibitors of Bacterial Hyaluronidase: an Approach to Obtain Compounds with Drug-Like Properties

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Synthesis and Structure-Activity Relationships of Inhibitors of Bacterial Hyaluronidase: an Approach to Obtain Compounds with Drug-Like Properties Synthesis and structure-activity relationships of inhibitors of bacterial hyaluronidase: An approach to obtain compounds with drug-like properties Dissertation Zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Fakultät für Pharmazie und Chemie der Universität Regensburg vorgelegt von Carolin Meyer aus Bad Soden-Salmünster 2014 Die vorliegende Arbeit entstand in der Zeit von November 2010 bis März 2014 unter der Leitung von Herrn Prof. Dr. A. Buschauer am Institut für Pharmazie der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie – der Universität Regensburg. Das Promotionsgesuch wurde eingereicht im März 2014. Tag der mündlichen Prüfung: 17.04.2014 Prüfungsausschuss: Prof. Dr. A. Slenczka (Vorsitzender) Prof. Dr. A. Buschauer (Erstgutachter) Prof. Dr. G. Bernhardt (Zweitgutachter) Prof. Dr. F.-M. Matysik (Prüfer) Für meinen Vater Stefan Meyer (* 1945 – † 2002) I Danksagungen An dieser Stelle möchte ich mich bedanken bei: Herrn Prof. Dr. Armin Buschauer für die Möglichkeit an diesem interessanten Projekt zu arbeiten, seine wissenschaftlichen Anregungen und seine konstruktive Kritik bei der Durchsicht dieser Arbeit, Herrn Prof. Dr. Günther Bernhardt für seine stete Hilfsbereitschaft, fachliche Unterstützung bei der Lösung experimenteller Probleme und seine konstruktive Kritik bei der Durchsicht dieser Arbeit, Herrn Prof. Dr. Franz Bracher (Ludwigs-Maximilian-Universität München) und seinem Mitarbeiter Dr. Nikolaus Hilz für die erfolgreiche Zusammenarbeit und Bereitstellung der 6,7-Dichloro-1H-indole als Testsubstanzen, Herrn Dr. Marc Kunze für die Bereitstellung der beiden Schlangengifte, Herrn Dr. Michael Thormann und Frau Laure Bourbon (Origenis GmbH Martinsried) für die Durchführung der Tests zur Plasmaproteinbindung, Frau Dr. Janina Hamberger für die gute Zusammenarbeit und die Testung von Substanzen an Spn Hyl, Frau Lydia Schneider für die große Hilfe bei der Testung der Substanzen, Frau Dita Fritsch für die Hilfe bei der Charakterisierung der Schlangengifte und die Testung von Substanzen an Spn Hyl, Frau Uta Hasselmann, Frau Karin Reindl und Herrn Peter Richthammer für die Unterstützung bei technischen und organisatorischen Problemen, allen Mitarbeitern der analytischen Abteilung der Universität Regensburg für die Aufnahme und Hilfestellung bei der Interpretation der NMR- und Massenspektren, den Mitstreitern auf dem Gebiet der Hyaluronidasen, Dr. Janina Hamberger, Dr. Martin Rothenhöfer und Dr. Christian Textor für die gute Zusammenarbeit und zahlreichen Diskussionen, II allen aktuellen und ehemaligen Mitgliedern des Lehrstuhls für die gute Kollegialität, Arbeitsatmosphäre und die schönen Zeiten auch außerhalb des Labors, meinen Laborkollegen Dr. Roland Geyer, Dr. Melanie Kaske, Kilian Kuhn und Xueke She (Coco) für die schöne Zeit im Labor, den aktuellen und ehemaligen Mitarbeitern für die unvergessliche Zeit in Regensburg sowie auf der Hütte und beim Skifahren in Ochsengarten, insbesondere: Steffi, Paul, Johannes (Felix), Roland, Stefan, Niki und Meli, Uta für die schönen Mittagspausen, ihr offenes Ohr und ihre zahlreichen Ratschläge in jeglichen Belangen, Coco für gemeinsame Abende, an denen sie mir beigebracht hat chinesisch zu kochen, meinen Freunden Pia, Petra und Stefan für ihre tollen Besuche bei mir in Regensburg sowie Christina, Patricia, Michi und Theresa für die schöne Zeit beim TC Rot Blau und außerhalb. Ganz besonderer Dank gilt meiner Familie, allen voran meinen Eltern Anne und Jochen, auf deren Hilfe und Unterstützung ich mich immer verlassen kann, meinen Geschwistern Sascha (mit Helga und Simon), Vanessa (mit Sebastian und Maxi), Christopher und Constantin und vor allem Christian für ihre Geduld, ihr Verständnis und ihren Rückhalt. III Poster presentations: Meyer, C. S.; Textor, C. S.; Bernhardt, G.; Buschauer, A.; „ Analogs of Diflunisal as Inhibitors of Bacterial Hyaluronidase “, 22 nd International Symposium on Medicinal Chemistry; Berlin, September 2 – 6, 2012 Meyer, C. S.; Textor, C. S.; Bernhardt, G.; Buschauer, A.; „Analogs of Diflunisal as Inhibitors of Bacterial Hyaluronidase“, 6 th Summer School Medicinal Chemistry, University of Regensburg, Germany, September 26 – 28, 2012 Meyer, C. S.; Textor, C. S.; Bernhardt, G.; Bracher, F.; Buschauer, A.; „Indole Derivatives as Inhibitors of Bacterial Hyaluronidase“ ; Frontiers in Medicinal Chemistry; Munich, March 17 - 20, 2013 IV Contents V Contents 1 Introduction.................................................................................................. 1 1.1 Hyaluronic acid ........................................................................................................ 2 1.1.1 Structure and physicochemical properties ............................................................... 2 1.1.2 Hyaluronan metabolism and physiological functions ................................................ 3 1.2 Hyaluronidases ....................................................................................................... 3 1.2.1 Occurrence and classification .................................................................................. 3 1.2.2 Hyaluronidases from eukaryotes ............................................................................. 5 1.2.3 Hyaluronidases from prokaryotes ............................................................................ 6 1.2.4 Hyaluronidase inhibitors .......................................................................................... 8 1.3 Methods for the determination of hyaluronidase activity .......................................... 9 1.3.1 Morgan-Elson assay ...............................................................................................10 1.3.2 Turbidimetric assay ................................................................................................12 1.4 Influence of the pH value on enzymatic activity ......................................................12 1.5 References .............................................................................................................14 2 Scope and Objectives ............................................................................... 23 3 Screening of commercially available drugs for hyaluronidase inhibition .................................................................................................................... 25 3.1 Introduction ............................................................................................................26 3.2 Materials and methods ...........................................................................................27 3.2.1 Materials and methods ...........................................................................................27 3.2.2 Morgan-Elson assay ...............................................................................................27 3.2.2.1 General procedures ............................................................................................27 3.2.2.2 Calculation of enzyme inhibition and IC 50 values .................................................29 3.2.3 Turbidimetric assay ................................................................................................29 3.2.3.1 General procedures ............................................................................................29 3.2.3.2 Cuvette assay .....................................................................................................30 3.2.3.3 96-well microtiter plate assay ..............................................................................30 3.2.3.4 Compound solubility ...........................................................................................31 3.2.3.5 Calculation of enzyme inhibition and IC 50 values .................................................31 3.2.3.6 Determination of turbidity in the incubation mixture the presence of plasma proteins ...............................................................................................................32 3.3 Inhibitory activity of selected non-steroidal anti-inflammatory drugs .......................32 3.3.1 Salicylates ..............................................................................................................32 3.3.2 Acetic acid derivatives ............................................................................................34 3.3.3 Propionic acid derivatives .......................................................................................36 3.3.4 N-Anthranilic acids and celecoxib ...........................................................................38 VI Contents 3.3.5 Miscellaneous compounds .....................................................................................39 3.4 Inhibitory activity of diflunisal in the presence of plasma proteins ...........................41 3.5 Peak plasma concentrations of commercial drugs ..................................................46 3.6 Summary and conclusion .......................................................................................48 3.7 References .............................................................................................................50 4 Diflunisal analogs as inhibitors of bacterial hyaluronidase .................. 53 4.1 Introduction ............................................................................................................54 4.2 Chemistry ...............................................................................................................56 4.3 Pharmacological results and discussion
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