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Functionalized Prodrugs of a Bacterial RNAP-Inhibitor & Bio-Reversibly

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Functionalized Prodrugs of a Bacterial RNAP-Inhibitor & Bio-Reversibly Functionalized Prodrugs of a bacterial RNAP-Inhibitor & Bio-reversibly masked purinergic 2nd Messenger derivatives associated with Ca 2+ Signaling Dissertation to obtain the Scientific Doctoral Degree by Alexandra Ruthenbeck presented to the Department of Chemistry of the Faculty of Sciences at the University of Hamburg Hamburg 2018 First Reviewer: Prof. Dr. Chris Meier Second Reviewer: Prof. Dr. Dr. h.c. mult. Wittko Francke Date of the disputation: 11.01.2019 Date of print approval: 14.01.2019 The present work was compiled in the group of Prof. Dr. Chris Meier at the Institute of Organic Chemistry in the Department of Chemistry at the University of Hamburg from No- vember 2014 until October 2018. There is only one way to find out … … always running for the thrill of it, always pushing up the hill searching for the thrill of it, on and on never looking down, just in awe of what’s in front. (from ‘Walking on a Dream’ by Nick Littlemore, Jonathan T. Sloan, Luke J. Steele) Table of Contents Table of Contents List of Publications ----------------------------------------------------------------------------------------- I List of Abbreviations -------------------------------------------------------------------------------------- II 1. Zusammenfassung ------------------------------------------------------------------------------- 1 1.1. Funktionalisierte Prodrugs eines Inhibitors der bakteriellen RNAP ----- 1 1.2. Bio-reversibel maskierte purinerge sekundäre Botenstoffderivate ----- 3 2. Abstract --------------------------------------------------------------------------------------------- 6 2.1. Functionalized Prodrugs of a bacterial RNAP-Inhibitor --------------------- 6 2.2. Bio-reversibly masked purinergic 2 nd Messenger derivatives --------------- associated with Ca 2+ Signaling ---------------------------------------------------- 8 3. Introduction and Background----------------------------------------------------------------- 12 4. Aim of the Work --------------------------------------------------------------------------------- 28 5. Results and Discussion-------------------------------------------------------------------------- 30 5.1. Catecholate-type masks ---------------------------------------------------------- 31 5.1.1. Synthesis of dibenzyloxyphenyl carboxylic acids and alcohols ---------- 32 5.1.2. Synthesis of the chloromethyl carbonate and the carboxylate------------- building blocks ---------------------------------------------------------------------- 33 5.2. Pyrone- and pyridone type masks ---------------------------------------------- 34 5.2.1. Synthesis of the benzyl protected pyridone --------------------------------- 35 5.2.2. Oxidation and linker modification of the 2-hydroxymethylene ------------ group ---------------------------------------------------------------------------------- 37 5.3. Syntheses of the siderophore-type prodrugs -------------------------------- 39 5.3.1. Synthesis of benzyl-protected siderophore-type ester prodrugs ------- 39 Table of Contents 5.3.2. Synthesis of benzyl-protected siderophore-type acyloxymethyl ---------- and carboxyloxymethyl ester prodrugs --------------------------------------- 43 5.3.3. Synthesis of unprotected siderophore-type prodrugs --------------------- 45 5.3.3.1. Development of the reaction protocol for debenzylation ---------------- 46 5.3.3.2. Development of the purification protocol------------------------------------ 49 5.4. Evaluation of siderophore-type prodrugs ------------------------------------ 52 5.4.1. Study of the iron(III) coordination capacity ---------------------------------- 53 5.4.2. Investigation of the activation by bacterial esterases ------------------------ and the antibacterial activity of siderophore-type prodrugs 41 – 44 -- 57 6. Introduction and Background ---------------------------------------------------------------- 63 7. Aim of the Work --------------------------------------------------------------------------------- 87 8. Results and Discussion ------------------------------------------------------------------------- 89 8.1. Approaches towards masked NAADP-derivatives starting ------------------ from NAADP ------------------------------------------------------------------------- 89 8.1.1. Studies on the synthesis of NAADP-AM --------------------------------------- 89 8.1.2. Studies on the reaction between NADP and diazo-mask -------------------- derivatives --------------------------------------------------------------------------- 93 8.1.3. Development of a total synthesis route towards membrane- -------------- permeant, bio-reversibly protected derivatives of NAADP -------------- 95 8.1.3.1. Retrosynthetic analysis of synthesis pathways to ---------------------------- NAADP-AB derivatives ------------------------------------------------------------ 97 8.1.3.2. Synthesis of the AB-masked adenosine building blocks ---------------- 103 8.1.3.3. Approaches towards masked NAMN derivatives ------------------------- 115 8.2. Total synthesis approach towards AB-masked (d)ADPR --------------------- derivatives ------------------------------------------------------------------------- 128 Table of Contents 8.2.1. Retrosynthetic analysis of routes towards (d)ADPR-AB ----------------- 128 8.2.2. Routes towards AB-riboside and adenosine coupling partners ------- 130 8.2.2.1. Synthesis of 1-O-AB-masked ribosides as precursors ------------------------- for P III/V -modification ------------------------------------------------------------ 130 8.2.2.2. Strategies towards riboside and nucleoside P V- and P III -building ---------- blocks -------------------------------------------------------------------------------- 131 8.2.2.3. Coupling of building blocks to the protected (d)ADPR-AB ------------------- precursors -------------------------------------------------------------------------- 137 8.2.2.4. Desilylation to AB-masked (d)ADPR derivatives -------------------------- 140 8.3. Synthesis and evaluation of AB-masked cNMPs -------------------------- 145 8.3.1. Elaboration and evaluation of a synthesis approach towards -------------- AB-cNMPs -------------------------------------------------------------------------- 145 8.3.1.1. Formation of AB-cUMP as model system ----------------------------------- 145 8.3.1.2. Expansion of the reaction scope on further nucleosides ---------------- 150 8.3.2. Functional evaluation of AB-cNMPs ----------------------------------------- 152 8.3.2.1. Investigation of chemical stability and enzymatic activation --------------- by PLE ------------------------------------------------------------------------------- 152 8.3.2.2. Performance of selected AB cNMPs in cell-based settings ------------- 158 9. Experimental Part ----------------------------------------------------------------------------- 164 9.1. General ------------------------------------------------------------------------------ 164 9.2. Syntheses --------------------------------------------------------------------------- 166 9.2.1. Part I - Functionalized Prodrugs of a Bacterial RNAP-Inhibitor -------- 166 9.2.2. Part II - Bio-reversibly masked purinergic 2 nd Messenger -------------------- derivatives ------------------------------------------------------------------------- 186 Table of Contents 9.3. Compound evaluation methods ---------------------------------------------- 246 10. Bibliography -------------------------------------------------------------------------------- 250 11. Appendix ------------------------------------------------------------------------------------ 272 12. Acknowledgement ------------------------------------------------------------------------ 281 13. Declaration on Oath ---------------------------------------------------------------------- 283 List of Publications List of Publications Alexandra Ruthenbeck, Elisa Marangoni, Björn-Ph. Diercks, Aileen Krüger, Alexander Fro- ese, Nadja I. Bork, Viacheslav O. Nikolaev, Andreas H. Guse and Chris Meier, Membrane- Permeable Octanoyloxybenzyl-Masked cNMPs As Novel Tools for Non-Invasive Cell Assays, Molecules 2018 , 23(11) , 2960. Björn-Philipp Diercks, René Werner, Paula Weidemüller, Frederik Czarniak, Lola Hernan- dez, Cari Lehmann, Annette Rosche, Aileen Krüger, Ulrike Kaufmann, Martin Vaeth, Anto- nio V. Failla, Bernd Zobiak, Farid I. Kandil, Daniel Schetelig, Alexandra Ruthenbeck, Chris Meier, Dmitri Lodygin, Alexander Flügel, Dejian Ren, Insa M. A. Wolf, Stefan Feske, and Andreas H. Guse, ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation, Science Signaling 2018 , 11(561 ), eaat0358. A. Ruthenbeck, B.-Ph. Diercks, A. Krüger, V. O Nikolaev, A. H. Guse and C. Meier, Masked cNMPs as novel chemical tools for cell-based assays, poster presentation at the XXIII Inter- national Round Table on Nucleosides, Nucleotides and Nucleic Acids (IRT) 2018 , La Jolla, San Diego, CA, USA. A. Ruthenbeck, W. A. M. Elgaher, J. Haupenthal, R. W. Hartmann and C. Meier, Bacterial RNAP Inhibitors: Synthesis and Evaluation of Prodrugs of Aryl-ureidothiophene-carboxylic acids, ChemistrySelect 2017 , 2, 11899–11905. A. Ruthenbeck and C. Meier, Functionalized and lipophilic Prodrugs of novel Inhibitors of the bacterial RNAP, poster presentation at the International Congress on Antimicrobial Re- search (ICAR) 2016 , Torremolinos, Málaga, Spain I List of Abbreviations List of Abbreviations 2dADPR 2’-deoxy ADPR A Adenosine AB Acyloxybenzyl Ac Acetyl AC Adenylyl cyclase ADPR Adenosine diphosphoribose AN Adenine nucleotide AM Acetoxymethyl ATP Adenosine triphosphate AU Absorption
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