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Download (2MB) Reid, Caroline Mary (2006) Synthesis and evaluation of tetraazamacrocycles as antiparasitic agents. PhD thesis. http://theses.gla.ac.uk/6257/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Synthesis and Evaluation of Tetraazamacrocycles as Antiparasitic Agents Caroline Mary Reid MSci Thesis submitted in part fulfilment of the requirements for the Degree of Doctor of Philosophy Supervisor: Prof. D. J. Robins Department of Chemistry Physical Sciences Faculty UNIVERSITY of GLASGOW November 2006 Caroline M. Reid, 2006 2 Abstract Human African Trypanosomiasis (HAT), commonly known as Sleeping Sickness, is endemic in over 36 countries in sub-Saharan Africa. It is caused by the parasitic subspecies Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense , which is transmitted to humans by the tsetse fly . The World Health Organisation estimates that 0.5 million people are currently infected with the disease, with a further 60 million at risk. HAT is lethal if left untreated and there is no vaccine available. There are only four accessible drugs, which are all inadequate and highly toxic. Thus there is a vital need for novel anti-parasitic agents. Compounds interfering with polyamine biosynthesis or function have shown potential use as anti-cancer, anti-HIV, anti-fungal and antiparasitic agents. The overall aim of this work was to synthesise novel macrocyclic polyamines containing different substituents to increase the toxicity against T. brucei . Twenty racemic substituted tetraazamacrocycles B have been synthesised using an iron template method in good yields (54-100%) from triethylenetetraamine and aromatic glyoxal derivatives A. The R-groups were aromatic or heteroaromatic and were selected to give compounds with varying electronic demand and a broad range of log P values. Two derivatives contain parasite-specific recognition motifs were also prepared. The compounds were tested against T. brucei and several of the analogues displayed high activity. O H R Cl H NH O NH NH2 H H N R NH HN R FeCl3 N Cl A i)NaBH Fe Fe Cl 4 ii) H O+ NH NH MeOH N Cl 3 2 NH N N - NH HN H H iii) OH B Some of these azamacrocycles were also tested for activity against the malarial parasite Plasmodium falciparum, and for oligopeptidase B (OPB) inhibition, with a number of compounds exhibiting promising results. 3 Acknowledgements This thesis is dedicated to my big sisters Sarah and Louise Reid. “Sisters, sisters, there were never such devoted sisters ” Firstly I would like to thank my supervisor Prof. Robins for all his encouragement and guidance throughout this project, and also to Dr Andy Sutherland for his help and advice especially when the chemistry became trying! The support received from other members of staff in the Chemistry Department has been second to none, and in particular I would like to mention Jim Gall, Dr David Rycroft and Dr David Adams (NMR spectroscopy), Jim Tweedy (mass spectroscopy), Arlene Douglas (IR spectroscopy) and Stuart Mackay (IT). Josie, you brighten up the C wing! I thoroughly enjoyed being involved with and carrying out the biological evaluation of my compounds. A special mention goes to Dr Mike Barrett and members of his group Mhairi Stewart, Charles Ebikeme and Matt Gould for assistance throughout the trypanosome testing. Thanks also to Prof. Sylke Muller and Eva-Maria Patzewitz (malaria), Prof. Ian Gilbert (trypanosome) and Nick Bland (OBP). I would also like to express my love and gratitude to my friends and work colleagues: Kathryn, Carolyn, Jenny, Rosie, Andy, Kate, Louise, Dave, Ally, Iain and Cameron, as well as the current and previous members of the Robins, Hartley and Sutherland research groups. It’s been a ball! To all the members of my church housegroup: your prayers and friendship are priceless. Mum, thanks for all your love and cards! I always knew your were worrying with me every step of the way. To my Stephen – I hope there will always be chemistry between us… “I can do everything through Him who gives me strength.” Philippians 4:13 4 Preface This thesis represents the original work of Caroline Mary Reid unless explicitly stated otherwise in the text. The research was carried out at the University of Glasgow in the Henderson and Loudon Laboratories under the supervision of Prof. David J. Robins and Dr Andrew Sutherland during the period of October 2003 to September 2006. 5 Abbreviations Å Ångstrom AcOH acetic acid abs. absolute N’-AcSpd N1-acetyl spermidine N’-AcSpm N1-acetyl spermine ALDH aldehyde dehydrogenase Ar aryl ATP adenosine triphosphate aq aqueous B.C. before Christ Bn benzyl Boc tert -butoxycarbonyl br broad Bu butyl CBSS Carter’s Balanced Salt Solution CI chemical ionisation CNS central nervous system cyclen 1,4,7,10-tetraazacyclododecane [2,2,2,2] conc concentrated d days (or doublet in NMR spectral data) dd doublet of doublets DAPI 4’-6-diamidino-2-phenylindole dba bisdibenzylideneacetone dcSAM decarboxylated S-adenosylmethionine DFMO DL-α-difluoromethylornithine DIBAL-H diisobutylaluminium hydride DIC differential interference contrast DIPEA N,N-diisopropylethylamine DMAP 4-(dimethylamino)-pyridine DMF N,N -dimethylformamide DMSO dimethylsulfoxide DNA deoxyribose nucleic acid dt doublet of triplets EATRO East African Trypanosomiasis Research Organisation EI electron impact ionisation est. estimate Et ethyl EtOH ethanol eq equivalents FAB fast atom bombardment FDA Food and Drug Administration FITC fluorescein-5-isothiocyanate Fmoc 9-fluorenylmethoxycarbonyl g gram h hours HAT Human African Trypanosomiasis HDM2 Human Double Minute gene 2 HEK Human Embryonic Kidney HIV Human Immunodeficiency Virus HPLC high performance liquid chromatography HRMS high resolution mass spectrometry 6 Hz Hertz IC 50 concentration of a drug to inhibit 50% of enzyme activity ICR Institute for Cancer Research IR infra red J NMR spectra coupling constant kDa kilodalton kg kilogram Km binding constant of P2 transporter L litre (or ligand in TETA complex with FeCl 3) µL microlitre LEC lowest effective concentration LiHMDS lithium hexamethyldisilazane lit. literature LRMS low resolution mass spectrometry m multiplet M molar (or metal in TETA complex with FeCl 3) µm micromole µM micromolar λmax maximum ultraviolet-visible absorbance νmax maximum velocity of adenosine uptake MDM2 Mouse Double Minute gene 2 Me methyl Mel B melarsoprol MeOH methanol mg milligram MGBG methyl glyoxal bis(guanylhydrazine) MHz mega Hertz mmol millimole mM millimolar mL millilitre MOM methoxymethyl mp melting point Ms methanesulfonyl MSF Médecins Sans Frontièrs MTA 1,5’-methylthioadenosine ng nanogram nm nanomole NMR nuclear magnetic resonance NMRI Naval Medical Research Institute OPB oligopeptidase B ODC ornithine decarboxylase P partition coefficient p53 p53 protein p53 p53 gene Ph phenyl PO polyamine oxidase ppm parts per million q quartet QSAR Qualitative Structure-Activity Relationships QY catalyst Rf retention factor RHOD rhodamine RNA ribose nucleic acid RPE retinal pigment epithelial 7 ROS reactive oxygen species rt room temperature s singlet SAM decarboxylated S-adenosylmethionine SAMDC S-adenosylmethionine decarboxylase SDS-PAGE sodium dodecyl sulfate poly-acrylamide gel electrophoresis SpdSyn spermidine synthase SpmSyn spermine synthase STIB Swiss Tropical Institute, Basel t temperature (or triplet in NMR spectral data) TBDMSCl tert -butyldimethylsilyl chloride TEBACl triethylbenzylammonium chloride TETA triethylene tetraamine THF tetrahydrofuran TLC thin layer chromatography TMSI trimethylsilyl iodide tosyl para -toluenesulfonyl Tr trityl TR trypanothione reductase Ts para -toluenesulfonyl VSG variant surface glycoprotein UNC University of North Carolina UV ultraviolet WHO World Health Organisation XPhos 2-dicyclohyxylphosphino-2’-4’-6’-triisopropylbiphenyl 8 Table of Contents 1 Human African Trypanosomiasis.............................................. 11 1.1 Human African Trypanosomiasis (HAT)....................................................11 1.1.1 HAT Transmission...............................................................................11 1.1.2 HAT History.........................................................................................12 1.1.3 Current Situation of HAT.....................................................................12 1.2 The Trypanosome.....................................................................................13 1.3 Trypanosome Life Cycle ...........................................................................14 1.4 Disease and Diagnosis .............................................................................15 1.5 Prevention and Control .............................................................................16 1.6 Treatment .................................................................................................17 1.6.1 Suramin...............................................................................................17 1.6.2 Pentamidine ........................................................................................18
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