Emanuel Debele Thesis (PDF 2MB)

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  • Queensland University of Technology

    SYNTHESIS AND EVALUATION OF RESVERATROL-

    BASED NITROXIDES AS POTENTIAL TREATMENTS FOR

    HYPERTENSION

    Submitted by

    Emmanuel Amoko DEBELE

    Bachelor of Science (Honours, Chemistry)

    Submitted in partial fulfillment of the requirements of the degree of Masters of

    Applied science

    Faculty of Science and Engineering

    Queensland University of Technology

    March 2013

  • Keywords

    Aryl Iodination, Cancer, Cardiovascular Diseases, DOCA-Salt, Free Radical, Hypertension,

    Iodination, Neurodegenerative diseases, Isoindoline, Oxidative Stress, Reactive Oxygen

    Species, Resveratrol, Resveratrol-Nitroxide, Nitroxide.

  • Abstract

    The synthesis and evaluation of novel resveratrol-based nitroxides have been

    explored for the potential treatment of hypertension. New methodology for the direct

    aryl iodination of isoindoline and isoindoline nitroxide using periodic acid and

    potassium iodide in concentrated sulphuric acid was developed. Diiodinated

    tetramethyl and tetraethyl isoindolines and a tetramethyl isoindoline nitroxide were

    prepared in excellent yields (70 82%). A diiodinated tetraethyl isoindoline

    nitroxide was generated from the corresponding nitroxide in modest yield (37%)

    alongside iodinated nitrones. The mono-iodinated species were also generated in

    modest yields (34 48%). Incorporation of the nitroxide unit into the structure of

    resveratrol was achieved using palladium-catalysed Heck coupling. Use of the

    previously prepared iodo products 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloyl 18

    and 5,6-diiodo-1,1,3,3-tetramethylisoindolin-2-yloyl 22 gave resveratrol nitroxides

    12 and 13 in yields of 50% (optimized) and 1.6% respectively. Preliminary

    evaluation of the resveratrol analogue 12 as a treatment for hypertension was

    undertaken in the DOCA-salt rat model. A reduction in systolic blood pressure as

    well as alleviation of ventricular hypertrophy was observed. A larger study involving

    the DOCA salt rats is currently in progress.

  • Publication from this work

    Kathryn E. Fairfull-Smith, Emmanuel A. Debele, Jesse P. Allen, Michael C.

    Pfrunder and John C. McMurtrie, Direct Iodination of Isoindolines and Isoindoline

    Nitroxides as Precursors to Functionalized Nitroxides, Eur. J. Org. Chem., 2013,

    DOI: 10.1002/ejoc.201300313.

    Conference posters

    Emmanuel A. Debele and Kathryn E. Fairfull-Smith, The Facile Iodination of

    Isoindoline: Precursors to Functionalised Nitroxides, International Conference on

    Organic Synthesis (ICOS 19), Melbourne, Australia, 2012.

    Emmanuel A. Debele and Kathryn E. Fairfull-Smith, The Facile Iodination of

    Isoindoline: Precursors to Functionalised Nitroxides. Nanotechnology and Molecular

    HDR Symposium, QUT, Brisbane, Australia, 2013.

  • Contents Abstract .................................................................................................................................... 3

    List of Figures .......................................................................................................................... 7

    List of Tables ........................................................................................................................... 9

    List of Reaction Schemes ....................................................................................................... 10

    Abbreviations ......................................................................................................................... 12

    Statement of Original Authorship .......................................................................................... 13

    Acknowledgements ................................................................................................................ 14

    Introduction ............................................................................................................................ 16

    1.0 Antioxidants, Reactive Oxygen Species and Diseases .......................................... 16

    1.1. Resveratrol .................................................................................................................. 24

    1.1.1. RESVERATROL AND HEART DISEASE ........................................................ 26

    1.1.2. RESVERATROL AND CANCER ...................................................................... 28

    1.1.3. RESVERATROL AND NEURODEGENERATIVE DISEASES ...................... 31

    1.2. NITROXIDES ............................................................................................................. 34

    1.2.1. OVERVIEW ........................................................................................................ 34

    1.2.2. ANTIOXIDANT PROPERTIES OF NITROXIDES .......................................... 36

    1.4. PROJECT OUTLINE ................................................................................................. 45

    2.0. IODINATED ISOINDOLINE NITROXIDE MOIETIES .............................................. 49

    2.1 Synthesis of 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl (18). ............................... 49

    2.2 Synthesis of 5,6-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl (22). ............................ 55

    2.3. Synthesis of 5-iodo-1,1,3,3-tetraethylisoindolin-2-yloxyl (28) and 5,6-diido-1,1,3,3-

    tetraethylisoindolin-2-yloxyl (29). ................................................................................. 68

    2.4. Synthesis of 5,6-diiodo-1,1,3,3-tetraethylisoindoline (26) and 5-iodo-1,1,3,3-

    tetraethylisoindoline (27). .............................................................................................. 74

    3.0. SYNTHESIS OF RESVERATROL-NITROXIDE ANALOGUES ............................... 77

    3.1. The Heck Reaction ...................................................................................................... 77

    3.2. Synthesis of (E)-5-(2-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-yl)vinyl)-1,3-

    phenylene diol (12). ........................................................................................................... 79

    4.0. BIOLOGICAL EVALUATION OF RESVERATROL-NITROXIDE ANALGUES .... 88

    4.1. Biological Testing: Effects of Resveratrol-Nitroxide (12) on DOCA-Salt Hypertensive

    Rat Models. ........................................................................................................................ 88

    5.0. CONCLUSIONS AND FUTURE WORK ..................................................................... 96

    6.0. EXPERIMENTAL ........................................................................................................ 100

    6.1 General Methods ........................................................................................................ 100

  • 6.2. Synthesis of 3,5-dihydroxy styrene (33). .................................................................. 101

    6.3. Synthesis of 3,5-diacetoxy styrene (34). ................................................................... 102

    6.4. Synthesis of N-benzylphthalimide (14). .................................................................... 103

    6.5. Synthesis of 2-benzyl-1,1,3,3-tetramethylisoindoline (15). ...................................... 104

    6.5. Synthesis of 5-bromo-1,1,3,3-tetramethylisoindoline (16). ...................................... 105

    6.7. Synthesis of 5-iodo-1,1,3,3-tetramethylisoindoline (17). .......................................... 106

    6.8. Synthesis of 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl (18). ............................. 107

    6.12. Synthesis of 1,1,3,3-tetramethylisoindoline (19). ................................................... 111

    GENERAL EXPERIMENTAL PROCEDURE FOR DIRECT ARYL IODINATION ...... 112

    6.13. A representative procedure for the synthesis of compound (21): ............................ 112

    6.14. Synthesis of 5-iodo-1, 1, 3, 3-tetramethylisoindoline (17). ..................................... 113

    6.15. Synthesis of 1,1,3,3-tetramethylisoindolin-2-ylxoyl (20). ..................................... 113

    6.16. Synthesis of 5,6-diiodo-1,1,3,3-tetramethylisoindolin-2-yloxyl (22). ................... 114

    6.17. Synthesis of 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl (18). ........................... 115

    6.18. Synthesis of 1,1,3,3-tetraethylisoindoline (24). ...................................................... 115

    6.19. Synthesis of 1,1,3,3-tetraethylisoindolin-2-yloxyl (25).......................................... 116

    6.20. Synthesis of 5,6-diiodo-1,1,3,3-tetraethylisoindoline (27). .................................... 116

    6.21. Synthesis of 5-iodo-1,1,3,3-tetraethylisoindoline (26) and 5-iodo-1,1,3,3-

    tetraethylisoindolin-2-yloxyl (28). ................................................................................... 117

    6.22. Synthesis of 5,6-diido-1,1,3,3-tetraethylisoindolin-2-yloxyl (29). ......................... 118

    APPENDIX .......................................................................................................................... 120

    REFERENCES ..................................................................................................................... 130

  • 7

    List of Figures

    Figure 1.1:(a) No oxidative stress when ROS and antioxidants levels in the body are equal

    or antioxidants > ROS, (b) Oxidative stress results when the concentration of ROS

    o