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University of Ivt-Vljtam Ih a B Ieant Leicester Synthesis of Aminosterols Structurally Related to Squalamine. University of iVT-VljTAM Ih a b Ieant Leicester Thesis submitted for the degree of Doctor of Philosophy at the University of Leicester by Andrew John Matthews Department of Chemistry University of Leicester Supervisor: Prof. Paul Cullis January 2001 UMI Number: U141457 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U141457 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Contents. Statement .......................................................................................................................................v Acknowledgements ......................................................................................................................v Abbreviations .............................................................................................................................. vi A bstract......................................................................................................................................viii Chapter 1 General Introduction ................................................................................................1 1.1 Background ............................................................................................................................2 1.2 Squalamine [15] ......................................................................................................................6 1.2.1 Structure of Squalamine .........................................................................................7 1.2.2 Antimicrobial Activity of Squalamine .................................................................. 7 1.2.3 Total Synthesis of Squalamine ............................................................................. 11 1.3 Polyamine-Sterol Conjugates Related to Squalamine ..................................................14 1.3.1 Bellini et al., 1983/1990........................................................................................ 14 1.3.2 S.L. Regen et a l, 1995.......................................................................................... 15 1.3.3 S.R. Jones et al., 1996........................................................................................... 17 1.3.4 D.Armstrong et a l, 1997......................................................................................19 1.3.5 W.A.Kinney et al., 2000.......................................................................................21 1.3.6 I.H.Gilbert et al., 2000..........................................................................................22 1.3.7 Conclusions ............................................................................................................24 1.4 Mode of Action Studies on Aminosterols ........................................................................25 1.4.1 Disruption of Cell Membranes- Ionophoric Behaviour by Regen’s Mimic....25 1.4.2 Disruption of Cell Membranes- Lytic Behaviour by Squalamine [15] ...........27 1.4.3 Disruption of Cell Membranes- T.A. Russo and D. Mylotte ............................ 29 1.4.4 Disruption of Cell Membranes- Detergent Behaviour .......................................30 1.4.5 Interference with Ion Channels/Pumps ............................................................... 30 1.4.6 Uptake via the Polyamine Transport System ......................................................31 1.4.7 DNA Binding .........................................................................................................32 1.4.8 Conclusions on the Antimicrobial Mode of Action ........................................... 32 1.4.9 Anticancer Mode of Action ................................................................................. 33 1.5 Possible Uses of Aminosterols ...........................................................................................35 1.5.1 Topical Antimicrobial Agents .............................................................................. 35 1.5.2 Cancer Therapy......................................................................................................35 1.5.3 Treatment of Proliferative Eye Disease .............................................................. 36 1.5.4 Treatment of Fybrodisplassia Ossificans Progresiva (FOP) ............................. 37 1.5.5 Treatment of Sexually Transmitted Diseases (STDs) .......................................37 1.5.6 Gene Delivery ........................................................................................................38 1.6 Proposal ................................................................................................................................ 39 Chapter 2 Synthesis of Steroids .............................................................................................40 2.1 Introduction ..........................................................................................................................41 2.2 Reaction Schemes................................................................................................................ 41 2.2.1 Synthesis of steroid A [82] .................................................................................. 41 2.2.2 Synthesis of Steroid B [85] .................................................................................. 42 2.2.3 Synthesis of Steroid C [90] .................................................................................. 44 2.2.4 Synthesis of Steroid D [93] .................................................................................. 46 2.2.5 Synthesis of steroid E [96] ..................................................................................47 2.3 Reaction Mechanisms ......................................................................................................... 48 2.3.1 Hydrogenation to give a cis- or trans-A-B Ring Junction ................................ 48 2.3.2 Oxidation of C3 hydroxyl group .......................................................................... 49 2.3.3 Mesylation of stigmasterol ....................................................................................50 2.3.4 Formation of the Cyclopropane Ring ..................................................................51 2.3.5 Ozonolysis of the side chain .................................................................................51 2.3.6 Grignard reaction ...................................................................................................53 2.3.7 Protection of the C-22 Hydroxyl Group ............................................................. 55 2.3.8 Deprotection of the Ring Alkene ......................................................................... 56 2.4 Conclusions ........................................................................................................................... 56 Chapter 3 Synthesis of Polyamines ........................................................................................ 57 3.1 Introduction .......................................................................................................................... 58 3.2 Reaction Schemes.................................................................................................................59 3.2.1 Synthesis of Protected Spermidine [101] ............................................................ 59 3.2.2 Synthesis of Protected Thermospermine [104] .................................................. 60 3.2.3 Synthesis of Protected Branched-polyamine [107] ............................................61 3.3 Reaction Mechanisms ......................................................................................................... 62 3.3.1 Michael addition to acrylonitrile .......................................................................... 62 3.3.2 BOC Protection ...................................................................................................... 63 3.3.3 Reduction of the Nitrile Group ............................................................................ 64 3.4 Conclusions ........................................................................................................................... 65 Chapter 4 Synthesis of Aminosterols .....................................................................................66 4.1 Introduction .......................................................................................................................... 67 4.2 Reaction Schemes.................................................................................................................67 4.2.1 Synthesis of Aminosterols from Steroid A .........................................................67 4.2.2 Synthesis of Aminosterols from Steroid B .........................................................70 4.2.3 Synthesis of Aminosterols from Steroid C .........................................................73 4.3 Reaction Mechanisms .........................................................................................................79
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