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Synthesis and Evaluation of Polyamines As Antimalarial Agents Synthesis and Evaluation of Polyamines as Antimalarial Agents A Thesis submitted in part fulfilment of the requirements of the degree of Doctor of Philosophy Lindsay Anne Slater Department of Chemistry University of Glasgow Glasgow G12 8QQ March 1998 ProQuest Number: 13815441 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 com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 13815441 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 GLASGOW UNIVERSITY LIBRARY (H O t GLASGOW UNIVERSITY UB3ARY mmm malaria (moqeorio) n. an infectious disease characterized by recur­ ring attacks of chills and fever, caused by the bite of an anopheles mosquito infected with any of four protozoans of the genus Plasma - dium (P . vivax, P. falciparum, P. malariae, or P. ovale), [€18; from Ita lia n mala aria bad air, from the belief that the disease was caused by the unwholesome air in swampy districts] —ma'Iarial, m a’larian, or ma’Iarious adj. Acknowledgements 1 would like to thank David Robins for his help and advice throughout the last few years and especially for his guidance when presenting this thesis (grammar!). My thanks also go out to my co-supervisor Stephen Phillips for his patience when explaining biology, to Fiona McMonagle who carried out the majority of the malaria testing and to Dale Walters et a l at Auchincruive for their swift anti-fungal results. The people at Glasgow who have helped are numerous and include all technical support staff: NMR, IR, mass spectrometry, elemental analysis. Throughout the years many people have passed through the chemistry department and my deepest thanks goes to anyone I have had the pleasure of knowing, and for making these years so enjoyable. The Alchemists. Finally to all those people who have kept me sane when away from chemistry, you know who you are, but especially to everyone at Strathallan. Why Fall Man Small Skies Call That's All Anon This is dedicated to my family who have always supported me, but most of all to Danny who has put up with so much, especially when I was writing this thesis, thanks! Thanks to the Wellcome Trust for putting their faith and money into this project and for the extra training they provided throughout the PhD. Summary Plasmodium species is transmitted between humans by the female anopheles mosquito. It kills 1.5-2.7 million people every year and 40% of humanity lives in an endemic area. Throughout time numerous attempts have been made to control the disease through natural remedies such as quinine (A) and artemisinin (B), synthetic drugs e.g. chloroquine (C), and also by the use of bed nets and insect repellents. Polyamines such as putrescine (D), spermidine (E) and spermine (F) are naturally occurring and are widespread in nature. They have been shown to be important in fundamental processes such as cell proliferation and differentiation. The study of these compounds has led to the development of polyamine analogues to treat a wide range of diseases from cancer and parasitic diseases through to their use as anti-fungal agents. We started work in this area when a simple putrescine analogue (G) was shown to have promising antimalarial activity and became the "lead" compound for this project. Initially we synthesized a number of analogues of (G) varying the carbon chain and the substitution patterns on the nitrogens. We did not see any improvement in activity until a A/,/V-bisbenzyl compound was prepared; however in vivo results were disappointing. We decided to investigate analogues of higher polyamines as these had shown better activity than putrescine analogues by workers in the cancer field. Surprisingly the spermidine analogues that were prepared showed little antimalarial activity, although separate tests showed them to have excellent anti-fungal properties. The spermine analogues synthesized were more promising with the bisbenzyl analogue (H) the most active in vitro so far. It was known that the genome of P. falciparum is rich in adenine and thymine base pairs compared to the human host so we decided to study some AT specific binding agents to see if this improved the activity. We decided to incorporate the A/,A/-dimethylaminoethyl (I) and propioamidino (J) moieties into spermine analogues to see if antimalarial activity increased. These functional groups had been used previously in AT binding agents. No test data is available on these compounds. A number of compounds were prepared and we observed increased activity as we added hydrophobic benzyl groups and also as we increased the number of nitrogens present to four, as in spermine analogues. This is in agreement with the hypothesis that DNA binding is related to the activity of the compounds which itself is controlled by the increased number of nitrogens in the compound. A number of compounds are still awaiting testing. We have prepared a range of polyamines, both known and novel, and examined their antimalarial activity. Antimalarial testing was carried out by Prof. Stephen Phillips and Fiona McMonagle in the Division of infection and Immunity and antifungal tests by Dr Dale Walters and Caroline Macintosh at the Scottish Agricultural College, Auchincruive. Contents 1. Malaria 1.1 Public Enemy No1..................................................................1 1.2 Malaria - A Potted History................................................. 1 1.3 Transmission of Malaria......................................................3 1.4 Prevalence of Malaria .......................................................... 5 1.5 Life Cycle of the Malaria Parasite in the Human Host ................................................................ 6 1.5.1 The Liver: The Hiding Place of the Parasite ....................6 1.5.2 The Red Blood Cell: Erythrocytic Stage ...........................6 1.5.3 The Mosquito: Sexual Life of a Parasite ...........................7 1.6 Do you have Malaria? ......................................................... 7 1.7 Coping with Malaria........................................................... 10 1.7.1 Chemotherapy - Preventative and Curative .................. 10 1.7.2 Drug Resistance................................................................ 15 1.7.3 Vaccines - Present and Future Prospects ...................... 16 1.7.4 Transgenic Mosquitos.......................................................17 1.7.5 Prevention of the Bite .........................................................17 1.8 Summary ..................................................................................... 18 2. Polyamines 2.1 Introduction..............................................................................19 2.2 Polyamines: Formation and Degradation ....................21 2.2.1 Biosynthesis....................................................................... 21 2.2.2 Catabolism...........................................................................24 2.2.3 Polyamine Transport Apparatus....................................... 25 2.3 Polyamine Inhibitors............................................................25 2.3.1 Ornithine Decarboxylase (ODC) Inhibitors .................... 25 2.3.2 S-Adenosylmethionine Inhibition ......................................28 2.3.3 Inhibitors of the Spermidine/Spermine A^-Acetyltransferases (SSAT).......................................... 29 2.3.4 Arginine Decarboxylase (ADC) Inhibitors ....................... 29 2.4 Polyamines as Potential Anti-fungal Agents........................................................................................30 2.5 Evaluation of Polyamines as Anti-cancer Agents........................................................................................31 2.5.1 Introduction..........................................................................31 2.5.2 Cancer Chemotherapy ....................................................... 31 2.5.3 Transport of Therapeutic Moieties via Polyamines 37 2.6 Polyamines to Fight Parasitic Diseases...................... 38 2.7 DNA Binding Properties of Polyamine A nalogues ................................................................................41 2.8 Summary ..................................................................................... 43 Synthesis and Evaluation of Putrescine Analogues 3.1 Introduction and Rationale................................................44 3.2 Evaluation of Antimalarial Activity................................ 45 3.2.1 In vitro Testing against P. falciparum Asexual Erythrocytic Stages............................................................ 46 3.2.2 In vivo Testing against P. chaubaudi................................. 47 3.3 Synthesis of Lead Compound (77)............................... 47 3.4 Alkyl Analogues of (77)..................................................... 48 3.4.1 Synthesis of Compounds (83), (84), (85), (89), (90) and (92) ................................................................................48 3.4.2 Biological Evaluation..........................................................50 3.5 Aromatic Analogues of (77)............................................
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