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Synthesis of Six-Membered Rings and Inhibitors of Protein Kinases

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Synthesis of Six-Membered Rings and Inhibitors of Protein Kinases View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Helsingin yliopiston digitaalinen arkisto Division of Pharmaceutical Chemistry Faculty of Pharmacy University of Helsinki Finland Synthesis of Six-Membered Rings and Inhibitors of Protein Kinases Alexandros Kiriazis ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Pharmacy of the University of Helsinki, for public examination in lecture room 1041, Viikki Biocenter 2 (Viikinkari 5), on 14 September 2012, at 12 noon. Helsinki 2012 1 Supervised by Professor Jari Yli-Kauhaluoma, PhD Division of Pharmaceutical Chemistry Faculty of Pharmacy University of Helsinki Helsinki, Finland Reviewed by Professor Tarek Ghaddar, PhD Department of Chemistry American University of Beirut Beirut, Lebanon Professor Angel Messeguer, PhD Department of Chemical and Biomolecular Nanotechnology The Institute for Advanced Chemistry of Catalonia Consejo Superior de Investigaciones Científicas (CSIC) Barcelona, Spain Opponent Professor Peter Goekjian, PhD Lab. Chimie Organique 2-Glycosciences Université de Lyon, France © Alexandros Kiriazis 2012 ISBN 978-952-10-8192-7 (paperback) ISBN 978-952-10-8193-4 (PDF) ISSN 1799-7372 http://ethesis.helsinki.fi Helsinki University Print Helsinki 2012 2 Abstract The six-membered rings have a priviledged presence in both natural products and synthetic compounds such as drug molecules. Multiple methods to prepare them in the laboratory have been developed. The Diels-Alder reaction provides several pathways toward the construction of substituted six-membered rings with a high degree of regio-, diastereo- and enantioselectivity. It can be considered to be the most important and powerful carbon- carbon bond-forming reaction of all, in synthetic organic chemistry. A practical synthetic method for the preparation of hexahydrocinnolines was developed here, as part of continuing research on polymer-supported pericyclic reactions in preparation of biologically interesting compounds. Some cinnoline derivatives from the literature were reported to show interesting biological properties, such as antimicrobial activity and inhibition of cancer cell lines. Hexahydro-1,2,4-triazolocinnoline-1,3-diones and related compounds were synthesized via aza Diels-Alder reaction on solid-phase. Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families. By adding phosphate groups to substrate proteins, kinase driven phosphorylation plays a significant role in a wide range of cellular processes. More than 500 protein kinase genes are present in the the human genome, constituting about 2% of all human genes. They regulate many cellular processes such as growth, differentiation, and proliferation. Protein kinases are seen as potential therapeutic targets since their mutation and dysregulation is causal in multiple human diseases, including metabolic, immunological disorders, and cancer. The consistent structure of the catalytic site among protein kinases sets limits for the development of protein kinase inhibitors. Some protein kinases, however, have regulatory domains as part of their structure, such as protein kinase C (PKC), whose regulatory (C1) domain is unique and is found only in a small number of kinases. This offers a selectivity advantage, thus making the C1-domain an attractive drug target. In fact, the utilization of the the X-ray crystal structure of the PKCį C1b domain, with molecular modeling, led to the discovery, in this work, of novel C1 domain ligands, the tricyclic Ȗ-amino alcohols. Synthesis of these compounds was achieved by the utilization of the Diels-Alder reactions. In the process of modifying a naturally occurring deep-blue colored hydrocarbon guaiazulene, a novel aminoguaiazulene derivative was synthesized. This novel derivative undergoes ring annulation reactions with 1,2-dicarbonyl reagents to yield tricyclic į- lactams, types of benzo[cd]azulenes. Benzo[cd]azulenes derived from guaiazulene, are colorful synthetic carbocyclics with interesting chemical and biological properties. Some of the benzo[cd]azulenes synthesized in this study were recently characterized as selective Pim kinase inhibitors. Pim kinases have become intriguing targets for cancer therapy that possess unique structural features, among protein kinases, that offer a great potential in the design of selective Pim-inhibitors. Based on the promising Pim-kinase inhibition results from multiple cell-based assays, a further modification of the benzo[cd]azulenes was conducted, where some interesting findings in their chemical behavior were observed; new phenolic benzo[cd]azulene compounds were formed, with potent Pim-inhibitory activities. The benzo[cd]azulenes developed in this study were found to be useful research compounds, potential Pim-selective kinase inhibitors, and putative anti-cancer drug candidates. The new synthetic methods detailed in this study will be valuable tools in the further development of additional benzo[cd]azulenes and related systems in the future. 3 Acknowledgements This study was carried out at the University of Helsinki, in the Drug Discovery Technology Center (DDTC) and in the Division of Pharmaceutical Chemistry, Faculty of Pharmacy, during the years 2005–2012. Funding was provided by The Graduate School in Pharmaceutical Research (GSPR), the European Commission (Contract No LSHB-CT- 2004-503467), The National Technology Agency (Tekes), Hormos Medical Corp., Juvantia Pharma Ltd., Orion Pharma, Finnish Pharmaceutical Society and Alfred Kordelin Foundation (Gustav Komppa). I am most grateful to my supervisor, Professor Jari Yli-Kauhaluoma, for the opportunity to work under his supervision at the Division of Pharmaceutical Chemistry. His never-ending enthusiasm in research and Science, his guidance, patience and friendship that made all possible to accomplish this study. I want to thank all co-authors at the Division of Pharmaceutical Chemistry and the Division of Pharmacology and Toxicology for their collaboration and contributions. I am grateful to Dr. Ingo Aumüller for introducing me into the world of azulenes, and for all his guidance and enormous knowledge in the synthesis laboratory. I want to thank our collaborator Adjunct Professor Päivi Koskinen and her great research group at the University of Turku for all the biological results dealing with Pim-inhibition. Special thanks to Olli Aitio for NMR guidance and for original modeling of the PKC C1 domain ligands for this study. I want to thank Professor Tarek Ghaddar (American University of Beirut, Lebanon) and Professor Angel Messeguer (Consejo Superior de Investigaciones Científicas, Spain) for reviewing thesis and Jennifer Rowland for the work in improving the English language. Special thanks to all my past and present colleagues in the JYK-group Kirsi, Mikko, Antti, Gusse, Leena, Raisa, Nenad, Timo, Irene, Paula, Rali, Mohan, Martina, Erik, Kristian, Ingo B and Sami. In addition, warm thanks for all fellows at the Division of Pharmaceutical Chemistry. I am grateful to my family and friends for their generous support and understanding, and for my parents for their overwhelming financial help especially during the writing time of this thesis. Helsinki, August 2012 Alexandros Kiriazis 4 “Chemical synthesis always has some element of planning in it. But, the planning should never been too rigid. Because in fact, the specific objective the synthetic chemist uses as the excuse for his activity is often not of special importance in the general sense, rather, the important things are those that he finds out in the course of attempting his objective.” R. B. Woodward Nobel Prize laureate in chemistry (1965) 5 Contents Abstract 3 Acknowledgements 4 List of original publications 7 Abbreviations 8 1 Introduction 9 2 Review of the literature 12 2.1 Synthesis of six-membered ring of benzo[cd]azulenes 12 2.1.2 Synthesis of six-membered rings by the Diels-Alder reaction 17 2.1.2.1 Diels-Alder reactions on solution-phase 18 2.1.2.2 Diels-Alder reactions on solid-phase 22 2.2 Protein kinases 24 2.2.1 Protein kinase inhibitors 25 2.2.2 Protein kinase C 28 2.2.3 Pim kinases 34 3 Aims of the study 46 4 Experimental 47 5 Results and discussion 51 5.1 Synthesis of hexahydrocinnolines by aza Diels-Alder reaction 51 5.2 Synthesis of a tricyclic model compound targeting PKC C1b 53 5.3 Synthesis of new guaiazulene derivatives 56 5.3.1 Synthesis of 4-aminoguaiazulene and its į-lactam derivatives 56 5.3.2 Synthesis of tricyclic benzo[cd]azulenes as potential Pim-1 inhibitors 59 6 Summary and conclusions 70 References 73 6 List of original publications This thesis is based on the following publications: I Kiriazis, A., Rüffer, T., Jäntti, S., Lang, H., and Yli-Kauhaluoma, J. Stereoselective Aza Diels-Alder Reaction on Solid-Phase: A Facile Synthesis of Hexahydrocinnoline Derivatives. J. Comb. Chem. 2007, 9, 263– 266. II Kiriazis, A. Aumüller, I. and Yli-Kauhaluoma, J. Synthesis of 4-amino- guaiazulene and its į-lactam derivatives. Tetrahedron Lett. 2011, 52, 1151–1153. III Alexandros Kiriazis, Gustav Boije af Gennäs, Virpi Talman, Elina Ekokoski, Timo Ruotsalainen, Irene Kylänlahti, Tobias Rüffer, Gloria Wissel, Henri Xhaard, Heinrich Lang, Raimo K. Tuominen and Jari Yli-Kauhaluoma. Stereoselective synthesis of (3-aminodecahydro-1,4-methanonaphthalen-2- yl)methanols targeted to the C1 domain of protein kinase C. Tetrahedron 2011, 67, 8665–8670. IV Alexandros Kiriazis‡, Riitta L. Vahakoski‡, Sini Eerola, Niina
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