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Development of Novel Protein Kinase Inhibitors As Potential Therapeutics for Breast Cancer Dissertation

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Development of Novel Protein Kinase Inhibitors As Potential Therapeutics for Breast Cancer Dissertation Development of Novel Protein Kinase Inhibitors as Potential Therapeutics for Breast Cancer Dissertation zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer. nat.) vorgelegt der Naturwissenschaftlichen Fakultät I (Biowissenschaften) der Martin-Luther-Universität Halle-Wittenberg von Dipl. Pharm. Kazem Ahmed Mahmoud geb. am 06.01.1981 in Sohag, Ägypten Gutachter: 1. PD Dr. Andreas Hilgeroth, Halle (Saale) 2. Prof. Dr. Wolfgang Sippl, Halle (Saale) 3. Prof. Dr. Christoph Ritter, Greifswald Halle (Saale), den 03.07.2013 (Tag der Verteidigung) Selbstständigkeitserklärung Hiermit erkläre ich gemäß § 5 (2) b der Promotionsordnung der Naturwissenschaftlichen Fakultät I – Biowissenschaften der Martin-Luther-Universität Halle-Wittenberg, dass ich die vorliegende Arbeit selbstständig und ohne Benutzung anderer als der angegebenen Hilfsmittel und Quellen angefertigt habe. Alle Stellen, die wörtlich oder sinngemäß aus Veröffentlichungen entnommen sind, habe ich als solche kenntlich gemacht. Ich erkläre ferner, dass diese Arbeit in gleicher oder ähnlicher Form bisher keiner anderen Prüfbehörde zur Erlangung des Doktorgrades vorgelegt wurde. Halle, April 2013 __________________________________ Kazem Ahmed Mahmoud Acknowledgment The present work was carried out at the Department of Pharmaceutical Chemistry and Clinical Pharmacy, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany, in the period from April 2010 to October 2012 under the supervision of PD Dr. Andreas Hilgeroth (the leader of Drug Development and Analysis research group). First and foremost, I would like to express my deep thanks and gratitude to my supervisor PD Dr. Andreas Hilgeroth, who allowed me to perform this research in his group, as well as the hiring of the interesting topic, his guidance during this work and the scope for creativity. Furthermore, I thank Mrs. Manuela Woigk for the production of ESI-MS spectra, Mrs. Heike Rudolph for recording the IR spectra and Dr. Dieter Ströhl, Department of Chemistry, and his staff for carrying out the NMR spectra. I also thank Dr. Frank Totzke from the ProQinase GmbH in Freiburg for the protein kinase assay achievement. I acknowledge all the staff of the National Cancer Institute (NCI) in the United States for the execution of the 60-cell-line screenings. My thanks also should go to Prof. Dr. Wolfgang Sippl for carrying out the docking studies in this work. A special thanks to Dr. Marc Hemmer for his deep proofreading of the manuscript and continues help. Felix Neubauer, I appreciate his kindly help in translations. My thanks to all members of our research group for creating a nice atmosphere in the lab. I also thank all other members of the Institute of Pharmacy who have contributed in making this work. The most special thanks belong to my father, my mother, my sister and my brothers in Egypt for their understanding about my leaving during all these years. Great thanks are owed to my wonderful family, my wife Mardia and my children Ahmed and Rabab. Mardia has been my inspiration and motivation for continuing to improve my knowledge and move my career forward. I appreciate your sustainable support and encouragement, thank you my love. Contents: List of Abbreviations …………………………………………………………………………….. IV List of Tables ……………………………..………………………………………………………. VI List of Figures ……………………………………………………………………………………. VII Glossary ………………………………………………………………………………..…………. X 1. INTRODUCTION ………………………………………………………………………… 1 1.1. Breast Cancer……………………………………………………………………............... 1 1.1.1. Female Breast Cancer……………………………………………………………… 1 1.1.1.1. Background………………………………………………………………… 1 1.1.1.2. Anatomy…………………………………………………………………… 2 1.1.1.3. Pathophysiology…………………………………………………………… 3 1.1.1.4. Etiology……………………………………………………………………. 3 1.1.1.5. Signs and Symptoms………………………………………………………. 4 1.1.1.6. Diagnosis………………………………………………………………….. 4 1.1.1.7. Medication Summary……………………………………………………… 5 1.1.2. Male Breast Cancer………………………………………………………………... 6 1.1.3. Therapeutic Targets in Breast Cancer……………………………………………... 6 1.1.3.1. Protein Tyrosine Kinases……………………………………………........... 6 1.1.3.1.1. Breast tumor kinase/protein tyrosine kinase 6……………………... 7 1.1.3.1.2. Brk signaling substrates, protein interactions and biology………… 9 1.1.3.2. Epidermal Growth Factor Receptor (EGFR) family………………………. 12 1.1.3.2.1. Human Epidermal Growth Factor Receptor (HER)-2……………... 13 1.1.3.2.2. HER2 dimerization………………………………………………… 14 1.1.3.2.3. MAPK signaling…………………………………………………… 15 1.1.3.2.4. PI3K signaling……………………………………………………... 15 1.1.4. Inhibitors of Breast Cancer-Relevant Kinases…………………………………….. 17 1.1.4.1. BRK/PTK6 Inhibitors……………………………………………………… 17 1.1.4.2. HER2 Inhibitors……………………………………………………............ 18 2. OBJECTIVES………………………………………………………………….……………… 22 3. RESULTS & DISCUSSION………………………………………………………………….. 26 3.1. Chemistry…………………………………………………………………………………. 26 3.1.1. Synthesis of the 4-substituted α-carbolines………………………………………... 26 3.1.1.1. Reaction of the 4-chloro-α-carboline with aromatic amines………………. 28 3.1.1.2. Reduction of compound 19 into the amino form 29………………………. 30 3.1.2. Substitutions on the 6-position of the α-carbolin derivatives……………………… 32 3.1.2.1. Synthesis of the 6-sulfonamide-4-chloro-α-carbolines (Sulfonation)……... 33 3.1.2.1.1. Reaction of the 6-sulfonamide 4-chloro-α-carboline with aromatic amines……………………………………………………………………... 34 3.1.2.2. Friedel-Crafts-Acylation Reaction (Acetylation)……...………………….. 36 3.1.2.2.1. Reaction of the 6-acetyl 4-chloro-α-carboline with aromatic amines...…………………………………………………………………… 36 3.1.2.2.2. Aldol Condensation of the 6-acetyl 4-chloro-α-carboline with DMF/DMA……………………………………………………………….. 37 3.1.2.3. Synthesis of the 6-bromo-4-chloro-α-carboline (Bromination)…………… 42 I 3.1.2.3.1. Reaction of the 6-bromo-4-chloro-α-carboline with aromatic amines…………………………………………………………………….. 43 3.1.2.3.2. Reaction of the 6,8-dibromo-4-chloro-α-carboline with aromatic amines…………………………………………………………………….. 44 3.1.2.3.3. Cyanation of the 6-bromo-4-(m-hydroxyphenylamino)-α-carboline derivative 69……………………………………………………………… 45 3.1.2.4. Synthesis of the 6-nitro 4-chloro-α-carboline (Nitration)…………………. 46 3.1.2.4.1. Reaction of the 6-nitro 4-chloro-α-carboline with aromatic amines……………………………………………………………………... 48 3.1.2.4.1.1. Reduction of some 6-nitro-4-phenylamino-α-carboline derivatives…………………………………………………………… 49 3.1.2.4.2. Reaction of the 6,8-dinitro 4-chloro-α-carboline with aromatic amines……………………………………………………………………... 49 3.1.2.4.2.1. Reduction of some 6,8-dinitro-4-phenylamino-α-carboline derivatives…………………………………………………………… 50 3.2. Biology……………………………………………………………………………………. 51 3.2.1. Protein Kinase Assay………………………………………………………………. 51 3.2.1.1. Results of the 4-phenylamino-α-carboline derivatives…………………….. 53 3.2.1.2. Results of the 6-sulfonamide-4-phenylamino-α-carboline derivatives……. 55 3.2.1.3. Results of the 6-acetyl-4-phenylamino-α-carboline derivatives…………… 56 3.2.1.4. Results of the 6-heterocylce-4-phenylamino-α-carboline derivatives........... 56 3.2.1.5. Results of the 6-bromo-4-phenylamino-α-carboline derivatives………….. 58 3.2.1.6. Results of the 6,8-dibromo-4-phenylamino-α-carboline derivatives……... 59 3.2.1.7. Results of the 6-nitro- and 6-amino-4-phenylamino-α-carboline derivatives………………………………………………………………………. 60 3.2.1.8. Results of the 6,8-dinitro-4-phenylamino-α-carboline derivatives……….. 61 3.2.2. Results of the NCI 60-cell-line-screenings………………………………………… 62 3.2.2.1. Results of one-dose screenings…………………………………………….. 66 3.2.2.2. Results of five-dose screenings……………………………………………. 67 3.2.3. Structure Activity Relationship (SAR)……………………………………………. 74 3.2.4. Docking Studies…………………………………………………………………… 76 3.2.4.1. Computational Methods…………………………………………………… 76 3.2.4.1.1. Protein structure preparation………………………………………. 76 3.2.4.1.2. Molecular Docking………………………………………………… 78 3.2.4.2. Results……………………………………………………………………... 78 3.2.4.2.1. Examination of Brk and HER2 structural similarity………………. 78 3.2.4.2.2. Results' Discussion………………………………………………… 79 3.2.4.3. Figures…………………………………………………….……….............. 80 4. SUMMARY & OUTLOOK…………………………………………………………………… 82 4.1. Summary………………………………………………………………………………….. 82 4.2. Zusammenfassung………………………………………………………………………… 91 4.3. Outlook…………………………………………………………………………………… 100 5. EXPERIMENTAL SECTION…………………………………………………………………. 101 5.1. Synthetic part……………………………………………………………………………… 101 5.1.1. Materials and Methods…………………………………………………………….. 101 5.1.2. Synthetic procedures……………………………………………………………….. 105 II 5.2. Biological part…………………………………………………………………….............. 185 5.2.1. Protein Kinase Assay………………………………………………………………. 185 5.2.2. 60-cell-line-screenings……………………………………………………………... 187 6. APPENDIX……………………………………………………………………….............…… 189 7. CURRICULUM VITAE.............................................................................................................. 222 8. BIBLIOGRAPHY....................................................................................................................... 224 III Abbreviations: μM Micromolar AcOH Acetic acid aq Aqueous ATP Adenosine triphosphate br broad (NMR) Brk Breast tumor kinase Brk/PTK6 Breast tumor kinase/protein tyrosine kinase 6 conc. Concentrated dd Double doublet DMF N,N-dimethyl formamide DMF/DMA N,N-dimethyl formamide dimethyl acetal DMSO Dimethyl sulfoxide DTP Developmental Therapeutics Programme EGF Epidermal growth factor eq Equivalent ER Estrogen receptor ErbB2 Erythroblastic leukemia viral oncogene homolog 2 ERK5 Extracellular signal-regulated kinase 5
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