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Structure-Activity Relationship Analysis of the Subtype-Selective Sirt5 Inhibitor Balsalazide

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Structure-Activity Relationship Analysis of the Subtype-Selective Sirt5 Inhibitor Balsalazide Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Structure-activity relationship analysis of the subtype-selective Sirt5 inhibitor balsalazide Carina Glas aus Konstanz 2020 Erklärung Diese Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Franz Bracher betreut. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, den 14.12.2020 ____________________ Carina Glas Dissertation eingereicht am: 14.12.2020 1. Gutachter: Prof. Dr. Franz Bracher 2. Gutachter: Prof. Dr. Manfred Jung Mündliche Prüfung am: 26.01.2021 Danksagung Mein herzlichster Dank gilt meinem Doktorvater Herrn Prof. Dr. Franz Bracher für die Möglichkeit, dieses vielseitige Thema in seinem Arbeitskreis bearbeiten zu dürfen. Vielen Dank für die gewährte Freiheit und die allzeit verfügbare Hilfe sowie die stetige Unterstützung während meines Studiums und der Promotion. Ich möchte mich bei den Mitgliedern meiner Prüfungskommission bedanken: Herrn Prof. Dr. Manfred Jung für die freundliche Übernahme des Koferats sowie Herrn Prof. Dr. Stefan Zahler, Herrn Prof. Dr. Christian Ochsenfeld, Herrn Prof. Dr. Paintner und Herrn Prof. Dr. Winter. Ein großer Dank gilt meinen Kooperationspartnern und deren Mitarbeitern: Prof. Dr. Christian Ochsenfeld, Prof. Dr. Manfred Jung, Prof. Dr. Wolfgang Sippl und Prof. Dr. Bernhard Küster. Insbesondere Johannes Dietschreit, Nathalie Wössner und Severin Lechner möchte ich für die großartige Zusammenarbeit danken. Den Analytikabteilungen danke ich für die zuverlässige Bearbeitung meiner Proben, egal, ob NMR (Claudia Glas und Dr. Lars Allmendinger), Masse (insb. Dr. Werner Spahl) oder Elementaranalyse. Martina Stadler danke ich für die Durchführung der MTT- und Agar- Diffusions-Tests und Anna Niedrig für die Messung der HPLC Reinheiten. Vielen Dank an meine Studenten und Hiwis, durch deren Mitwirken diverse Publikationen und diese Doktorarbeit realisiert werden konnten. Insbesondere Moritz Kornmayer, Sarah Baierl, Doreen Reuter, Ricky Wirawan und Lars Urban sind hierbei namentlich zu nennen. Ein großes Dankeschön geht an die Gruppe von Dr. Oliver Thorn-Seshold für die herzliche Aufnahme in ihre Reihen für zahlreiche lustige und lehrreiche Events. Allen aktuellen und ehemaligen Mitgliedern des AK Bracher danke ich für die angenehme Arbeitsatmosphäre. Mein besonderer Dank geht dabei an Desi, Bini, Ramona, Susi, Julia, Charlotte und Anna – wenn aus Kollegen Freunde werden. Vielen Dank für die schöne Zeit. Weiterhin möchte ich mich bei meinen offiziellen und inoffiziellen Mentoren für die Unterstützung und Förderung bedanken. Besonders hervorheben möchte ich Dr. Oliver Thorn-Seshold, Dr. Julia Thorn-Seshold, Prof. Dr. Lena Daumann und Dr. Kerstin Riedel. Vielen Dank meinen Korrekturlesern Dr. Desirée Heerdegen und Andrea Glas, die sich nicht durch die Seitenzahl haben abschrecken lassen. Bei meinen Freunden, meiner Familie und der Familie Sickler möchte ich mich für die tagtägliche Unterstützung und Motivation bedanken. Mein größter Dank gilt hier Nikolai Sickler, der immer hinter mir steht und mich motiviert. Danke, dass es dich gibt und ich immer auf dich zählen kann. Danke! “Curiosity is the most powerful thing you own.” JAMES CAMERON Table of Contents 1. INTRODUCTION ......................................................................................................................................... 1 1.1. EPIGENETICS .......................................................................................................................................... 1 1.2. METABOLISM MEETS EPIGENETICS.......................................................................................................... 3 1.3. BIOREVERSIBLE ε-N-ACYLATION OF LYSINE SIDE CHAIN AMINO GROUPS ................................................ 3 1.4. SIRT5 ...................................................................................................................................................... 6 2. OBJECTIVE ................................................................................................................................................. 8 3. SYNTHESIS AND FIRST BIOLOGICAL EVALUATION ...................................................................... 12 3.1. BALSALAZIDE AND ANALOGUES WITH DELETED OR MINIMALLY ALTERED FUNCTIONAL GROUPS ............ 12 3.1.1. Synthesis ..................................................................................................................................... 13 3.1.1.1. Balsalazide and analogues with a modified salicylic acid part of the molecule ................................ 13 3.1.1.2. Analogues with variations affecting the N-aroyl-β-alanine side chain of balsalazide ...................... 16 3.1.2. Inhibitory activity against Sirt5 ................................................................................................... 24 3.2. VARIATIONS OF THE CORE AZO GROUP (1) ........................................................................................... 27 3.2.1. Synthesis ..................................................................................................................................... 28 3.2.1.1. Analogues with open-chained variations of the azo moiety ................................................................. 28 3.2.1.2. Excursus: New general method for the preparation of N-aryl-1,2,3,4-tetrahydroisoquinolines ..... 43 3.2.1.3. Analogues with a rigidised central unit ..................................................................................................... 48 3.2.2. Inhibitory activity against Sirt5 ................................................................................................... 55 3.3. BIOISOSTERIC VARIATIONS AND MODIFICATIONS BASED ON PREVIOUS RESULTS .................................. 57 3.3.1. Synthesis ..................................................................................................................................... 58 3.3.1.1. Analogues based on previous results ....................................................................................................... 58 3.3.1.2. Bioisosteric analogues ................................................................................................................................. 62 3.3.2. Inhibitory activity against Sirt5 ................................................................................................... 69 3.4. VARIATIONS OF THE CORE AZO GROUP (2) ........................................................................................... 71 3.4.1. Synthesis ..................................................................................................................................... 71 3.4.1.1. Analogues with heteroaromatic variations of the azo moiety ............................................................... 71 3.4.2. Inhibitory activity against Sirt5 ................................................................................................... 76 4. FURTHER EXPERIMENTS AND IN-DEPTH CHARACTERISATION OF SELECTED COMPOUNDS ............................................................................................................................................... 77 4.1. ROUTINE TESTING FOR CYTOTOXICITY AND ANTIMICROBIAL EFFECTS ................................................... 78 4.1.1. MTT assay ................................................................................................................................... 78 4.1.2. Agar diffusion assay ................................................................................................................... 78 4.2. INVESTIGATION OF THE SUBTYPE SELECTIVITY OVER SIRT1, 2, AND 3 .................................................. 79 4.1. DETERMINATION OF IC50 VALUES FOR SIRT5 INHIBITORY ACTIVITY ....................................................... 82 4.2. COMPETITION EXPERIMENTS................................................................................................................. 85 4.3. COMPUTATIONAL CHEMISTRY ............................................................................................................... 86 4.3.1. Classification of the mechanism of inhibition ........................................................................... 87 4.3.1. Calculations of relative binding affinities for the Sirt5 inhibitors from molecular dynamics (MD) simulations.................................................................................................................................... 89 4.4. TARGET IDENTIFICATION VIA PULL-DOWN ASSAY AND MS ANALYSIS ..................................................... 92 5. SUMMARY ................................................................................................................................................. 96 5.1. SYNTHESIS ........................................................................................................................................... 96 5.2. BIOLOGICAL AND THEORETICAL EVALUATION ...................................................................................... 105 6. EXPERIMENTAL PART ......................................................................................................................... 109 6.1. BIOLOGY ............................................................................................................................................. 109 6.1.1.
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