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“Synthesis and Biological Evaluation of the Antioxidant Properties of New Università degli Studi di Palermo Westälische Wilhelms-Universität Mϋnster Dottorato in Ph.D in Scienze Molecolari e Biomolecolari Pharmaceutical and Medicinal Chemistry Dipartimento STEBICEF Department of S.S.D. -- CHIM/08 Pharmaceutical and Medicinal Chemistry “Synthesis and biological evaluation of the antioxidant properties of new analogues of natural products with piperidine based structure and evaluation of the affinity and activity towards σ-receptors and ĸ-receptors” PhD STUDENT COORDINATOR DANIELE AIELLO PROF. PATRIZIA DIANA TUTOR TUTOR PROF. PATRIZIA DIANA PROF. DR. BERNHARD WÜNSCH PROF. DR. MATTHIAS LEHR CICLO XXX 2019 Pharmaceutical and Medicinal Chemistry Pharmazeutische und Medizinische Chemie Synthesis and biological evaluation of the antioxidant properties of new analogues of natural products with piperidine based structure and evaluation of the affinity and activity towards σ-receptors and ĸ-receptors Inaugural-Dissertation To obtain the Doctoral degree in “Scienze Molecolari e Biomolecolari” from the Faculty of Pharmacy from Università degli Studi di Palermo and zur Erlangung des Doktorgrades der Naturwissenschaften im Fachbereich Chemie und Pharmazie der Mathematisch-Naturwissenschaftlichen Fakultät der Westfälischen Wilhelms-Universität Münster vorgelegt von Daniele Aiello Aus Palermo, Italy 2019 For the University of Palermo Rector: Prof. Fabrizio Micari First supervisor (expert): Prof. Patrizia Diana For the Westfälischen Wilhelms-Universität Dekan: Prof. Dr. Uwe Karst Erster Gutachter: Prof. Dr. Bernhard Wünsch Zweiter Gutachter: Prof. Dr. Matthias Lehr Tag der mündlichen Prüfung: Tag der Promotion: I have completed this work at the Institut für Pharmazeutische und Medizinische Chemie, Westfälischen Wilhelms-Universität Münster and at the department of Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università degli Studi di Palermo under the supervision of Herrn Prof. Dr. Bernhard Wünsch I would like to extend my sincere gratitude for accepting me and let me be part of your research group. Without your patience, constant motivation and support this work would not have been achievable. Your wisdom, knowledge in the field of organic and medicinal chemistry and enthusiasm showed me how a good scientist and more importantly a wise leader must be. Your willingness to share knowledge, kindness and optimism inspired me, both professionally and personally. For all of this, I will be forever grateful to you. Prof. Patrizia Diana I would like to extend my earnest gratitude to Prof. Diana for accepting me in her research group. Her support, understanding, commitment and patience contribute immensely to my personal development as a researcher. I thank her for providing me with an interesting research topic, tremendous academic support and intellectual freedom in my work. Without her guidance this work would not have been achievable. Acknowledgments: I would like to thank: ● Prof. Dr. Matthias Lehr for being my mentors and for fruitful discussions in my progress reports. ● Prof. Girolamo Cirrincione for accepting me in his research group, for the advices and for the support. ● Dr. Anna Carbone, for her patience, support and guide on my road to be a good researcher. For the chats, small talks and for your help in everyday problems both in the lab and outside. For this and for a lot more, especially for enduring me during my bad days, I will always be grateful. ● Prof. Paola Barraja, Prof. Alessandra Montalbano and Dr. Virginia Spanò for your constant support, advices, the small talks and jokes in good days and for enduring me during the bad days. ● Dr. Barbara Parrino, Dr. Stella Cascioferro for the help and support. ● Prof. Luisa Tesoriese for the biological testing and for your support, advices and your kindness. ● Dr. Anna Junker for our talks, your advices, support and constant motivation. ● Dr. Dirk Schepmann and Bastian Frehland for the biological testing and for your kindness. ● Dr. Jens Köhler, Claudia Thier and Thomas Meiners for your support with NMR measuraments. ● Dr. Jörg Fabian and Thomas Meiners for the mass spectra recording. I also thank Frederik for the help with the LC-MS. ● Kirstin Lehmkuhl for your constant support with the HPLC measurements, orders of chemicals and your friendship during my stay in Mϋnster. ● Dott. Vincenzo Delia, Giuseppe Impeduglia and Paolo Bonomo, for your help in everyday problems in the lab, with the orders and with tech. problems. ● Dr. Peter Dziemba, Laura Prause and Sarah Berling for your organization of the institute and for your constant help with bureaucratic problems. ● Ulrich Heczko and Alfred Gerber for their help with chemicals and lab supplies. ● Thomas Gottschlich, Michael Janning, Vanessa Gulczynski, Annemarie Erdt, Karsten Suwelack and Heribert Wennemer for their constant work. ● My “students”, Chiara, Alessandra, Federica, Maria Grazia, Hendrik and Kevin for their help in the lab and their friendship. ● My colleagues of lab 337: Paul, Susi, Giovi, Cathy, Elena and Jonathan and Hendrik. For the friendship, help, that you are still giving to me, your jokes, your music and our delicious dinners. Thanks guys without you my PhD life in Mϋnster would have been much more difficult. ● The all AK Wünsch, Oriana Agoglitta, Dr. Samuel Asare, Kim Bachmann, Dr. Sören Baumeister, Elena Bechthold, Dr. Melanie Bergkemper, Sarah Berling, Frederik Börgel, Kathrin Brömmel, Dr. Paul Bunse, Charlotte Doering, Clemens Dobelmann, Dr. Sebastian Elfering, Dr. Siong Wan Foo, Bastian Frehland, Dr. Fabian Galla, Dr. Magdalena Galster, Donglin Gao, Dr. Dominik Heimann, Dr. Elisabeth Heinrichs, Christian Heselmeyer, Dr. Jonathan Hoffmann, Dr. Ralph Holl, Denise Ilari, Dr. Anna Junker, Dr. Dmitrii Kalinin, Max Kock, Dr. Jens Köhler, Dr. Lukas Kröger, Anja Langenstroer, Kirstin Lehmkuhl, Jan Lemmerhirt, Dr. Marius Löppenberg, Dr. Ines Lütnant, Benedikt Martin, Dr. Kengo Miyata, Dr. Hannes Müller, Laura Prause, Remya Rajan, Dr. Dirk Schepmann, Dr. Claudia Schmithals, Dr. Adrian Schulte, Julian Schreiber, Martha Sieg, Dr. Janine Stefanowitz, Dr. Ann-Katrin Strunz, Dr. Marina Szermerski, Dr. Louisa Temme, Dr. Stefanie Theiler, Dr. Simone Thum, Tullio Torregrossa, Karen Olejua Torres, Dr. Héctor Torres Goméz, Jan Uth, Dr. Frauke Weber und Dr. Christian Wittig. Thanks for your help, friendship and for creating an amazing atmosphere in the group. ● My “German teachers” Steffi, Susi, Paul, Cathy and Giovi and Hendrik. Thanks for your patience and you constant support. If I know something more than “ein Bier, bitte” is thank to you. ● My friends from CiM: Abhiyan, Anto, Denise and Jan, Giovanni, Guangxia, Tamara, Zahra and Mohammad. Thanks for your support, friendship and for the nice evening spent together. ● My friends from Italy: Antonietta, Andrea, Cristian, Domenico, Enza, Ilaria, Lorenzo, Paolo e Sandro for the support and the good time spent together during my Ph.D. ● My best friend from Italy Antonio, even from far away you were always able to let me feel your support. ● My friend Timo Wenning, without your support, help and friendship and your hamburgers my stay in Mϋnster would not have been the same, thanks for all. ● My sister Annamaria and especially my brother Luca, who endured my bad mood and took all over my duties during the worst periods of my PhD. ● My sincere gratitude is extended to my family, my parents, parents-in-law for their support and understanding. ● I want to thank also anyone else I forgot to mention here…. I would also like to give a special thanks to Hendrik Jonas. I could not have done it without your help and support. You made me able to be in two places at the same time. For this I will always be grateful to you and I will always be there if you will need help. Thank you so much. THANKS!!! To my family who always encourages and supports me to pursue my dreams Table of Contents 1. Introduction……………………………………………………………………………………1 1.1. Piperidine and its derivatives……………………………………………………………1 1.2. Betalains…………………………………………………………………………………...3 1.2.1. Introduction………………………………………………………………………….3 1.2.2. Biosynthesis of Betalains…………………………………………………………..4 1.2.3. Betalains: use and activity………………………………………………………….8 1.2.4. Synthesis of betalamic acid………………………………………………………..9 1.3. Opioid Receptors…………………………………………………………………………13 1.3.1. Introduction………………………………………………………………………...13 1.3.2. Structural features of opioid receptors…………………………………………..14 1.3.3. ĸ-Opioid Receptor (KOR)…………………………………………………………16 1.3.4. KOR agonists and antagonists…………………………………………………..16 1.4. σ-Receptors………………………………………………………………………………18 1.4.1. Introduction………………………………………………………………………...18 1.4.2. σ1-Receptor: structure…………………………………………………………….20 1.4.3. Expression and physiological functions of σ1-receptor………………………..22 1.4.4. σ2-Receptor……………………………………………………………………….. 24 2. Aim of the project……………………………………………………………………………25 3. Ideas and synthesis plans…………………………………………………………………27 3.1. Idea and plan for the synthesis of new betaxanthin derivatives…………………….27 3.2. Idea and plan for the synthesis of conformationally restricted KOR agonists……..28 3.3. Idea and plan for the synthesis of 1,2,3 triazole derivatives with potential antitumor activity and σ-receptors affinity…………………………………………………………30 4. Synthesis of new betaxanthin derivatives………………………………………………32 I 5. Synthesis of conformationally restricted KOR agonists…………………………….55 6. Synthesis of new 1,2,3 triazole derivatives with potential antitumor activity and σ- receptors affinity…………………………………………………………………………….62 7. Pharmacological characterization………………………………………………………..69
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