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Synthesis of Lipoamino Acid-Based Glycolipids for Drug Delivery

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Synthesis of Lipoamino Acid-Based Glycolipids for Drug Delivery SYNTHESIS OF LIPOAMINO ACID - BASED GLYCOLIPIDS FOR DRUG DELIVERY by Robert Andrew Falconer A thesis submitted in partial fulfilment of the requirements for the degree of DOCTOR OF PHILOSOPHY The School of Pharmacy University of London 29/39 Brunswick Square London WCIN lAX September 2000 ProQuest Number: 10105101 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. uest. ProQuest 10105101 Published by ProQuest LLC(2016). 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 Abstract Many drug molecules are too hydrophilic to cross biological membranes and suffer from chemical and/or enzymatic degradation within the gastrointestinal tract. One approach to this problem is to conjugate such drugs to molecules that optimise their physicochemical properties. Conjugation of hpoamino acids to poorly absorbed peptides and drugs improves oral uptake due to enhanced membrane-like character and through increased protection from enzymatic degradation. The solubility of the resulting conjugates is often poor, however, in aqueous systems. This approach has been extended to incorporate a hydrophilic component, i.e. a glycosyl moiety, in an effort to improve solubility in aqueous media. In addition, the potential exists with such derivatives to exploit active transport systems, such as the sodium-dependent glucose transporter. A series of novel lipoamino acid-based glycohpids was synthesised, with functional groups suitable for both covalent and non-covalent conjugation to poorly absorbed drugs. The physicochemical properties of these compounds were varied through modifications to the sugar and lipid components and to the linkage between them (the glycosidic linkage). A series of /V-linked glycolipids was synthesised from p-glycosylamines, from glycosyl azides (using a modified Staudinger reaction) and from glycosyl isothiocyanates. A series of ^-linked glycolipids, with increased enzymatic stability, was synthesised using a set of novel Mitsunobu reaction conditions, following difficulties experienced (including low reactivity and disulphide formation) using other methods. Chemically and biologically stable C-linked glycolipids were prepared using a glycosyl radical-based reaction. In addition, novel C-linked glycohpids were successfully prepared directly from their «S-linked isosteres using a Ramberg-Backlund rearrangement. Preliminary experiments demonstrated improved oral absorption of piperacillin, a poorly absorbed p-lactam antibacterial, when administered as a novel drug-glycohpid ionic complex. In addition, the abihty to form particulate systems per se and in conjunction with conventional Hposomes was demonstrated by these glycohpids, with further potential apphcations for drug and peptide dehvery. Table of Contents Abstract 2 Table of Contents 3 Acknowledgements 7 Publications 8 Tables and Figures 11 Abbreviations 16 1 Introduction 18 2 Biology 19 2.1 Gastrointestinal Barriers to Drug Absorption 19 2.1.1 The Epithelial Barrier 19 2.1.2 The Enzymatic Barrier 20 2.2 Modes of absorption via the Oral Route 21 2.2.1 Passive Diffusion 2 2 2.2.1.1 Transcellular pathway 22 2.2.1.2 Paracellular pathway 22 2.2.2 Carrier-mediated transport 23 2.2.2.1 Substrates for the intestinal peptide transporter 24 2.2.3 Ion pair transport 25 2.2.4 Endocytosis 25 2.2.5 Efflux systems 26 2.3 Drug Delivery via the Oral route 26 2.3.1 Lipophilicity 27 2.3.1.1 Pro-Drugs: Estérification 27 2.3.1.2 Lipoderivatisation by lipoamino acids 29 2.3.2 Other factors important for effective oral absorption 30 2.3.3 Non-covalent carrier mediated lipophilicity 32 2.3.4 Ion pair transport 33 2.3.5 Exploitation of active transport systems 35 2.3.5.1 Glucose Transporters 35 2 3.5.2 The P-glycoprotein efflux system 36 Table of Contents 2.4 Summary 36 3 Chemistry 39 3.1 O-linked Glycosides 39 3.1.1 Stereo specificity 40 3.1.1.1 Neighbouring-group participation 40 3.1.1.2 Manipulation of the Anomeric Effect 41 3.1.1.2.1 The Anomeric Effect 41 3.1.2 O-glycosylation reactions 42 3.1.2.1 Koenigs-Knorr Glycosylation 42 3.1.2.2 Thioglycosides as glycosyl donors 43 3.1.2.3 Trichloroacetimidates as glycosyl donors 44 3.1.2.4 1-0-Acyl sugars as glycosyl donors 45 3.1.2.5 2-amino-2-deoxy sugars as glycosyl donors 46 3.1.3 Stable Mimics of O-glycosidic linkages 47 3.2 TV-linked glycosides 48 3.3 5-linked glycosides (Thioglycosides) 51 3.3.1 Preparation of thioglycosides 52 3.3.1.1 Acid promoted displacement at the anomeric centre 52 3.3.1.2 Base promoted displacement at the anomeric centre 53 3.3.1.3 Anomeric ^-alkylation 53 3.4 C-linked glycosides 54 3.4.1 Preparation of C-glycosides 55 3.4.1.1 Lewis acid mediated glycosylation 55 3.4.1.2 Anomeric lactones as glycosyl donors 56 3.4.1.3 Reactions of Glycosyl anions with electrophiles 58 3.4.1.4 Free radical mediated glycosylation 59 4 Results and Discussion 60 4.1 Synthesis of lipoamino acids 61 4.1.1 TV-Boc-Lipoamino acids 62 4.1.2 TV-Dde-Lipoamino acids 63 4.2 O-linked glycolipids 64 4.2.1 O-linked glycolipids via 1-0-acetyl glycosyl donors 64 4.2.1.1 Synthesis of lipoamino alcohols 65 Table of Contents 4.2.1.2 Synthesis of O-linked glycolipids via 1-O-acetyl glycosyl donors 67 4.2.2 O-glycolipids from glycosyl trichloroacetimidates 67 4.3 A^-linked glycohpids 71 4.3.1 Synthesis of P-glycosylamines 71 4.3.1.1 Synthesis of p-glycosyl azides 71 4.3.1.2 Reduction of glycosyl azides 73 4.3.2 Synthesis of A^-(amide)-linked glycohpids via glycosylamines 73 4.3.3 Synthesis of JV-linked glycohpids via a modified Staudinger reaction 74 4.3.3.1 Synthesis of A^-protected sugar building blocks 77 4.3.4 A-linked glycohpids as a potential Drug Dehvery System 78 4.3.4.1 Synthesis of non-covalent glycohpid-drug conjugates 79 4.3.4.2 Preliminary in vivo experiments 80 4.3.4.3 Microbiological assay 82 4.3.5 Glycosyl isothiocyanates as precursors for A-glycoside synthesis 84 4.3.5.1 Synthesis of glycosyl isocyanates 85 4.3.5.2 Synthesis of glycosyl isothiocyanates 87 4.3.5.3 Synthesis of glycosyl amides from isothiocyanates 8 8 4.3.5.4 Glycosyl thiocarbamates 89 4.3.5.5 Glycosyl dithiocarbonates 89 4.3.5.5.1 Synthesis of lipoamino thiols 89 4.3.5.5.2 Synthesis of glycosyl dithiocarbonates 93 4.3.5.6 Glycosyl thioureas 94 4.3.5.6.1 Synthesis of di-amine LAA derivatives 94 4.3.5.6.2 Synthesis of glycosyl thioureas 96 4.3.5.7 Influence of A-linkage on physicochemical properties 98 4.3.6 A-Glycosides of an A-Dde-protected glucosamine 99 4.3.7 Glycohpids via non-anomeric linkages 100 4.3.8 Oligosaccharide based A-linked glycohpids 105 4.3.8.1 Influence of saccharide component on physicochemical properties 107 Table of Contents 4.3.9 Particle formation properties of A^-linked glycolipids 107 4.4 »S-linked Glycolipids 11 1 4.4.1 iS-linked glycolipids via 1-O-acetyl glycosyl donors 111 4.4.2 Trichloroacetimidate approaches to <S-glycolipid formation 113 4.4.3 ^-linked glycolipids via anomeric iS-alkylation 114 4.4.4 S'-linked glycolipids via a Mitsunobu reaction 115 4.4.4.1 Synthesis of disulphides under Mitsunobu conditions 120 4.4.5 Influence of S'-linkage on physicochemical properties 121 4.5 C-linked Glycohpids 123 4.5.1 Free radical-based synthesis of C-linked glycolipids 123 4.5.2 Synthesis of C-linked glycolipids from glyconolactones 128 4.5.3 Synthesis of C-linked glycolipids from their S'-linked isosteres 130 5 Conclusion 136 6 Experimental 140 6.1 General Methods 140 6.2 Particle Formation 141 6.3 Microbiological Assay 141 6.4 Synthesised Compounds 142 7 References 205 Acknowledgements I would like to express my gratitude to my supervisor, Prof. Istvan Toth, for the opportunity to carry out this research. I thank him for his considerable expertise, advice, encouragement and enthusiasm. I would equally like to thank my co-supervisor. Prof. Sandy Florence, for his continuing support, invaluable advice, experience and expertise. I thank Dr. Istvan Jablonkai and Dr. Gyula Dekany for their knowledge, experience and expertise in the lab. I thank them both for their input into this research. I would like to thank Mr. Mike Cocksedge for performing countless FAB MS analyses on my compounds with such skill and speed. In addition, I extend thanks to Mr. Wilfred Baldeo and Dr. Mire Zloh for performing the NMR analyses and Mr. M ark Domin for providing MALDI TOF MS and ESI MS. Thanks go to Dr. Anya Hillery for performing the particle experiments, to Dr. Dick Pinney for advice regarding the microbiological experiments. In addition, I thank Dr. Nasir Hussain for helpful discussions. Finally, I would like to thank friends and colleagues in the lab for their contributions to this work, namely: Mr. John Malkinson Dr. Karen Wright Dr. Antonio Procopio Dr. Nick Flinn Dr.
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