Natural Product-Like Furopyranones: Synthesis and Natural Product-Like Furopyranones: Synthesis

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Transcript of Natural Product-Like Furopyranones: Synthesis and Natural Product-Like Furopyranones: Synthesis

  • Natural Product-Like Furopyranones: Synthesis and Biological Activity in Human Cancer Cells

    Inauguraldissertation

    der Philosophisch-naturwissenschaftlichen Fakultät

    der Universität Bern

    vorgelegt von

    Cyril Adrian Fuhrer von Langnau i. E. (BE)

    Leiter der Arbeit:

    Prof. Dr. Robert Häner

    Departement für Chemie und Biochemie der Universität Bern

  • Natural Product-Like Furopyranones: Synthesis and Biological Activity in Human Cancer Cells

    Inauguraldissertation

    der Philosophisch-naturwissenschaftlichen Fakultät

    der Universität Bern

    vorgelegt von

    Cyril Adrian Fuhrer von Langnau i. E. (BE)

    Leiter der Arbeit:

    Prof. Dr. Robert Häner

    Departement für Chemie und Biochemie der Universität Bern

    Von der Philosophisch-naturwissenschaftlichen Fakultät angenommen.

    Bern, 1. November 2007 Der Dekan:

    Prof. Dr. Paul Messerli

  • Für meine Eltern,

    Nadja und Philipp

  • „ Dosis sola facit venenum“

    Theophrastus Bombastus von Hohenheim

    (1493 – 1541)

  • List of Publications:

    C. Fuhrer, R. Messer, R. Häner:

    ‚Stereoselective synthesis of 3a,7a-dihydro-3H,4H-furo[3,4-c]pyran-1-ones via

    intramolecular hetero-Diels-Alder reaction’

    Tetrahedron Lett. 2004, 45, 4297-4300.

    P. Gerner, C. Fuhrer, Ch. Reinhard, H. U. Güdel:

    ‘Near-infrared to visible photon upconversion in Mn and Yb containing

    materials’

    2+ 3+

    J. Alloys Comp. 2004, 380, 39-44.

    R. Messer, C. A. Fuhrer, R. Häner:

    ‘Natural product-like libraries based on non-aromatic, polycyclic motifs’

    Curr. Opin. Chem. Biol. 2005, 9, 259-265.

    N. Guiblin, C. A. Fuhrer, R. Häner, H. Stöckli-Evans, K. Schenk, G. Chapuis:

    ‘The incommensurately modulated structure of a tricyclic natural-product-like

    compound of empirical formula C22H20O3’

    Acta Cryst. 2006, B62, 506-512.

    C. A. Fuhrer, E. Grüter, S. Ruetz, R. Häner:

    ‘Cis-Stilbene Derived Furopyranones Show Potent Antiproliferative Activity by

    Inducing G2/M Arrest’

    ChemMedChem 2007, 2, 441-444.

    R. Messer, C. A. Fuhrer, R. Häner:

    ‘Lewis acid catalysed synthesis of a tricyclic scaffold from D-(-)-ribose’

    Nucleosides, Nucleotides & Nucleic Acids 2007, in press.

  • Acknowledgements

    First of all I would like to thank Prof. Dr. Robert Häner for the opportunity to do my Ph. D. in

    his research group. I strongly appreciate his great support, the fruitful discussions and the

    possibility to collaborate with the ‘Novartis Institutes for BioMedical Research’ in Basel. I

    would like to thank him very much for his confidence and the opportunity to supervise several

    Bachelor- and Master-Students as well as educating apprentices.

    Special thanks go to Prof. Dr. Peter Gmeiner for being my co-referee and examiner and to

    Prof. Dr. Philippe Renaud who agreed to supervise the final examination.

    Many thanks go to Dr. Holger Bittermann, Dr. Volodimir Malinovskii, Luzia Moesch, Dr. Eric

    Grüter, Dr. Roland Messer and Dr. Simon Langenegger for the helpful suggestions and

    interesting discussions. Furthermore I would like to thank Sarah Maria Biner, Alina

    Nussbaumer, Sandro Manni, Florian Garo, Michael Locher and Fabian Wenger, whom I

    supervised. Special thanks go to Zoe Clerc and again to Dr. Holger Bittermann as well as to

    Dr. Volodimir Malinovskii for critical reading of this dissertation.

    Sincere thanks go to Dr. Stephan Ruetz, Dr. Bahaa Salem, Dr. Philipp Grosche, Dr. Hans-

    Jörg Roth, Dr. Jürg Zimmermann, Hélène Kiesler, Stephanie Pickett, Halil Koc, Raphael

    Gattlen, Urs Rindisbacher, Felix Thommen and their teams at the ‘Novartis Institutes for

    BioMedical Research’ in Basel for the successful collaboration, the instructive internship and

    the helpful suggestions.

    Furthermore I would like to thank the University of Bern, Prof. Dr. Helen Stoeckli-Evans and

    Dr. Antonia Neels for the x-ray crystallographic analyses, Prof. Dr. Peter Bigler and his team

    for the NMR measurements and their help concerning NMR related questions, Dr. Stefan

    Schürch and his team for MS measurements and the group of Prof. Dr. Silvio Decurtins for

    the use of their equipment. Also many thanks to the ‘Ausgabe’ team, the technical and

    electronic team and the administration of the Department of Chemistry and Biochemistry for

    various help.

    Special thanks go to all the past and current members of the Häner and the Leumann group

    for help, support and good spirits.

    Finally, I would like to thank those who I failed to mention, but who in one way or another

    have contributed to the present thesis.

  • I Table of Contents

    Table of Contents Summary 1 1 Introduction 3 1.1 Drug Discovery 3

    1.1.1 A Brief Historical Perspective of Drug Discovery 5

    1.1.2 Medicinal Chemistry 9

    1.1.3 Tools of the Trade 11

    1.1.3.1 Combinatorial Chemistry 14

    1.1.4 Natural Products and Chemical Genetics in Drug Discovery 15

    1.1.5 A Diversity-Oriented Synthesis (DOS) Approach to Natural Product-Like

    Compounds

    17

    1.2 Approaches to the Medical Treatment of Cancer 19

    1.2.1 Some Facts about Cancer 19

    1.2.2 Genetic Faults Leading to Cancer: Proto-Oncogenes and Oncogenes 20

    1.2.3 Treatment and Resistance of Cancer 23

    1.3 Natural Product Leads for Discovering New Anticancer Agents 25

    1.3.1 Iridoids 25

    1.3.1.1 Antitumor Activity of Iridoids and Their Derivatives 28

    1.3.2 Stilbenes Including Resveratrol and Combretastatin A-4 31

    1.3.2.1 Antitumor Activity of Resveratrol, Combretastatin A-4 and Its Derivatives 32

    1.3.3 Natural Products with Anticancer Properties Containing Lactones 36

    1.4 The Diels-Alder Reaction 38

    1.4.1 Intramolecular hetero Diels-Alder Reactions 40

    1.5 Solid Support Chemistry 44

    1.6 References for Chapter 1 47

    2 Aim of the Work 51 3 Synthesis and Antiproliferative Properties of Furopyranones 53 3.1 Development of a Synthetic Route for Furopyranones 53

    3.2 Stereoselective Synthesis of 3a,7a-Dihydro-3H,4H-furo[3,4-c]pyran-1-ones

    via an Intramolecular hetero Diels-Alder Reaction

    55

    3.3 Syntheses of Furo[3,4-c]pyranones for Implementation of a Detailed

    Structure-Activity Relationship (SAR) Study

    59

    3.3.1 Synthesis of C(7)-Desphenyl Derivatives 59

  • II Table of Contents

    3.3.2 Aminolysis of the Lactone 62

    3.3.3 Synthesis of a Tricyclic Derivative 64

    3.3.4 Attempted Replacement of the γ-Lactone by a δ-Lactone 68

    3.3.5 Carboxy- and Nitro-substituted Furopyranones 69

    3.3.5.1 Nitro-substituted Furopyranones 69

    3.3.5.2 Carboxy-substituted Furopyranones 71

    3.3.6 Variation of the Substitution Pattern of the cis-Stilbene Motif 74

    3.3.6.1 Synthesis from 4,4’-Dibromobenzil 74

    3.3.6.2 Synthesis from 2,2’-Dichlorobenzil 74

    3.3.6.3 Further Furopyranones from different α-Diketones 76

    3.3.7 Hetero Diels-Alder versus Diels-Alder Reaction 77

    3.4 Antiproliferative Properties of Natural Product-Like Furopyranones 83

    3.4.1 Cis-Stilbene Derived Furopyranones and Their Antiproliferative Properties

    in A549 and KB31 Cells

    83

    3.4.2 Cis-Stilbene Derived Furopyranones and Their Antiproliferative Properties

    in K562 Cells

    87

    3.4.3 Further Cis-Stilbene Derived Furopyranones and Their Antiproliferative

    Properties in A549 and KB31 Cells

    89

    3.5 References for Chapter 3 96

    4 Preparation of Furopyranone-Libraries 98 4.1 Preparation of Furopyranones Containing a Linker Group and a Protected

    Amine Function

    99

    4.2 Elaboration of Conditions for the Solid Phase Synthesis 105

    4.2.1 Conditions for the Coupling Step 105

    4.2.2 Determination of the Loading Efficiency by UV Quantification 106

    4.2.3 Application of the Conditions to Different BAL-aminomethly-PS Solid

    Supports

    107

    4.2.4 Configurational Stability of the Final Products Under Cleavage Conditions 109

    4.3 Synthesis of Prototypes for Each Scaffold 110

    4.4 Aminolysis of the Lactone Ring 115

    4.5 References for Chapter 4 116

    5 Conclusions & Outlook 117 5.1 Antiproliferative Activity of Natural Product-Like Furopyranones 117

    5.2 Solid Support Chemistry of Furopyranones 118

    5.3 Outlook 119

  • III Table of Contents

    5.4 References for Chapter 5 121

    6 Experimental Part 122 6.1 Instrumentation 122

    6.1.1 NMR Spectroscopy 122

    6.1.2 Mass Spectrometry 123

    6.1.3 IR –Spectroscopy 123

    6.1.4 UV-VIS Spectroscopy 123

    6.1.5 Melting Point Measurement 123

    6.1.6 Analytical TLC and Preparative Column Chromatography 124

    6.1.7 High Performance Liquid Chromatography (HPLC) 124

    6.1.8 X-Ray Crystal Structure Analyses 124

    6.1.9 Autoclave 125

    6.1.10 Cellular Assays and Cell Cycle Analysis (KB31 and A549 Cells) 125

    6.2 Solvents, Che