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Using Dynamic Combinatorial Chemistry to Construct Novel Thioester and Disulfide Lipids

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Using Dynamic Combinatorial Chemistry to Construct Novel Thioester and Disulfide Lipids Using dynamic combinatorial chemistry to construct novel thioester and disulfide lipids A dissertation submitted to the University of Manchester for the degree of MSc by Research Chemistry In the Faculty of Science and Engineering 2017 Jack A. Yung School of Chemistry Table of Contents List of figures, tables and equations 5 Symbols and abbreviations 10 Abstract 12 Declaration 13 Copyright statement 13 Acknowledgements 14 The author 14 Chapter 1. Introduction 15 1.1 The cell membrane 16 1.1.1 Function and composition 16 1.2 Membrane lipids 16 1.2.1 Lipid classification 16 1.2.2 Amphiphiles 17 1.2.3 Glycolipids 17 1.2.4 Sterols 18 1.2.5 Phospholipids 19 1.3 Lipid vesicles 20 1.3.1 Supramolecular self-assembly 20 1.3.2 Interaction free energies 21 1.3.3 Framework for the theory of self-assembly 22 1.3.4 Micelles 23 1.3.5 Lipid bilayers 24 1.3.6 Vesicles 25 1.3.7 Phase-transition temperature 27 1.4 Amphiphilic building blocks 27 1.5 Thioesters 29 1.5.1 Thioester reactivity 29 1.5.2 Trans-thioesterification 30 1.5.3 Thioester exchange reactions in DCC 31 1.6 Disulfides 32 2 1.6.1 Disulfide reactivity 32 1.6.2 Thiol-disulfide interchange reactions 32 1.6.3 Disulfide exchange reactions in DCC 33 1.7 Pre-biotic lipids 34 1.7.1 Sources of pre-biotic organic compounds 34 1.7.2 The first pre-biotic membrane structure 36 1.7.3 The role of sulfur in pre-biotic chemistry 36 1.8 Artificially designed vesicles 37 1.8.1 Applications of artificially designed vesicles 37 1.8.2 Zeta-potential 37 1.8.3 Vesicle design 38 1.9 Targets 39 1.9.1 Aims 39 Chapter 2. Lipid synthesis and characterisation 43 2.1 Synthesis of 2-nitro-4-(palmitoylthio)benzoic acid 44 2.2 Synthesis of 2-nitro-5-(stearoylthio)benzoic acid 45 2.3 Trans-thioesterification of (2,3)-dimercapto-1-propanol 46 2.3.1 Synthesis of (S,S’)-(3-hydroxypropane-1,2-diyl)dihexadecanethiolate 46 2.3.2 Synthesis of (S.S’)-(3-hydroxypropane-1,2-diyl)dioctadecanethiolate 52 2.4 Hydroxyl-group functionalisation 53 2.4.1 Attempted synthesis of (2,3)-bis(palmitoylthio)propyl phosphate 53 2.4.2 Attempted synthesis of (2,3)-bis(palmitoylthio)propyl sulfate 57 2.5 Trans-thioesterification of (2,3)-dimercapto-1-propanesulfonic acid 59 2.5.1 Synthesis of (2,3)-bis(heptadecanoylthio)propane-1-sulfonate 60 2.5.2 Synthesis of (2,3)-bis(pentadecanoylthio)propane-1-sulfonate 64 2.6 Thiol-disulfide interchange of 1d 65 2.6.1 Attempted synthesis of 5-(hexadecyldisulfaneyl)-2-nitro-benzoic acid 65 Chapter 3. Vesicle, kinetics and DCC studies 72 3.1 Vesicle studies 73 3.1.1 DLS and zeta-potential studies of 3a and 3b 73 3.2.1 Encapsulation of 5(6)-carboxyfluorescein into vesicles of 3a and 3b 77 3.1.3 Release of 5(6)-carboxyfluorescein from vesicles composed of 3a and 3b 78 3.2 Dynamic combinatorial chemistry studies 81 3 3.2.1 Introduction 81 3.2.2 Generated dynamic combinatorial libraries from 2a and 2b 83 3.3 Kinetic studies 86 3.3.1 Introduction 86 3.3.2 Stability of 1a 87 3.3.3 Stability of 1a towards methanlyosis 87 3.3.4 Stability of 1a towards hydrolysis 88 3.3.5 Technical issues 88 3.3.6 Trans-thioesterification of 1a with 1d and 1e 89 3.3.7 Trans-thioesterification of 1a with 1i and 1j 93 Chapter 4. Experimental 96 4.1 General materials, instrumentation and other notes 97 4.2 Synthetic methods 99 4.3 DLS and zeta-potential measurements 107 4.4 Encapsulation of 5(6)-carboxyfluorescein 107 4.5 Release of 5(6)-carboxyfluorescein 108 4.6 Kinetic Studies 109 4.6.1 Preparation of buffer and 1a stock solution 109 4.6.2 Trans-thioesterification of 1a with di-thiol sources 110 4.6.3 Trans-thioesterification of 1a with thiol sources 110 Chapter 5. Conclusions and further work 112 5.1 General conclusions 113 5.2 Future work 114 Chapter 6. Annex 118 6.1 1H and 13C spectra 119 References 130 Final word count for dissertation: 26,688 4 List of figures, tables and equations Figure 1.1 Cell membrane. 16 Table 1.1 Lipid classification. 17 Figure 1.2 Chemical structure of glycolipid. 18 Figure 1.3 Chemical structure of cholesterol. 18 Figure 1.4 Chemical structure of glycerol. 19 Figure 1.5 General chemical structure of phospholipid. 19 Figure 1.6 Phospholipid functionalities. 20 Figure 1.7 Hydrophobic effect. 22 Equation 1.1 Packing parameter. 23 Figure 1.8 Micelle structure. 24 Figure 1.9 Rod-like micelle structure. 24 Figure 1.10 Lipid bilayer structure. 25 Figure 1.11 Lipid mobility. 25 Figure 1.12 Vesicle structure. 26 Table 1.2 Vesicle classification. 26 Table 1.3 Lipid bilayer phase states. 27 Figure 1.13 Chemical structures of 1a and TNB2-. 28 Figure 1.14 Reaction mechanism for Ellman’s test. 28 Figure 1.15 Thioester and ester bonding descriptions. 29 Figure 1.16 General reaction scheme for trans-thioesterification. 30 Figure 1.17 General reaction mechanism for trans-thioesterification. 30 Figure 1.18 Thioester hydrolysis reaction mechanism. 30 Figure 1.19 General thioester DCL generation. 31 Figure 1.20 General thioester DCL generation reaction scheme. 31 Figure 1.21 General thioester DCL generation reaction mechanism. 32 Figure 1.22 General thiol-disulfide interchange reaction mechanism. 33 Figure 1.23 General disulfide DCL generation reaction scheme. 33 Figure 1.24 General disulfide DCL generation reaction mechanism. 34 Figure 1.25 General reaction scheme of FTT. 34 Figure 1.26 Generation and delivery of extra-terrestrial molecules. 35 5 Figure 1.27 Chemical structure of 6-methyldecandoic acid. 36 Figure 1.28 Reaction scheme for In-vivo enzymatic vesicle triggers. 39 Figure 1.29 Chemical structure of thioester lipid 1a. 39 Figure 1.30 Chemical structure of 1d, 1e and glycerol. 40 Figure 1.31 Trans-thioesterification reaction scheme to synthesize lipids 2a-3c. 40 Figure 1.32 General reaction scheme for hydroxyl phosphorylation and sulfation. 41 Figure 1.33 Thiol-disulfide interchange reaction scheme to synthesis lipids 2f and 3f. 41 Figure 1.34 Chemical structures of disulfide lipids 2f and 3f. 41 Figure 1.35 Reaction scheme for DCL generation via disulfide and thioester exchange reactions. 42 Figure 2.1 Reaction scheme for the synthesis of thioester lipid 1a. 44 Figure 2.2 Mechanism for the conversion of palmitoyl chloride into 1a. 44 Figure 2.3 Reaction scheme for the synthesis of thioester lipid 1b. 45 Figure 2.4 Reaction scheme for the trans-thioesterification of 1d. 46 Figure 2.5 Reaction mechanism for the trans-thioesterification of 1d. 47 Figure 2.6 Chemical structure of (TNB2-) (DIPEA+) salt. 49 Figure 2.7 1H NMR spectra of resulting crude on reaction of 1a with 1d. 49 Figure 2.8 Chemical structures of 2a and 1d with corresponding molecular ion-peaks. 50 Figure 2.9 Overlaid 1H NMR spectra of purified 2a and dimerized by-product. 51 Figure 2.10 Comparison of 1H NMR splitting patterns of 2a and dimerized by-product. 51 Figure 2.11 Chemical structures of possible dimerized by-products of 2a. 52 Figure 2.12 Reaction scheme for the phosphorylation of lipid 2a. 53 Figure 2.13 Reaction mechanism for the generation of a chlorophosphite group. 54 Figure 2.14 Reaction mechanism for the hydrolysis and or E2 elimination of chlorophosphite. 54 Figure 2.15 1H NMR phosphorylation time course studies. 55 6 Figure 2.16 Overlaid 1H NMR spectra of phosphorylated crude and 2a. 55 Figure 2.17 COSY spectra of phosphorylated product. 56 Figure 2.18 Reaction mechanism for intra-molecular acyl-migration of 2a on phosphorylation. 57 Figure 2.19 Chemical structure of acyl-migrated product on phosphorylation. 58 Figure 2.20 Reaction mechanism for intra-molecular acyl-migration of 2a on sulfation. 59 Figure 2.21 Reaction scheme for the trans-thioesterification of 1e. 59 Figure 2.22 Reaction mechanism for the trans-thioesterification of 1e. 60 Figure 2.23 Chemical structure of (3b)DIPEA salt. 62 Figure 2.24 COSY spectra of 3b, showing hidden DIPEA environments. 63 Figure 2.25 Enlarged 1H NMR spectra of thioester lipid 3b. 63 Figure 2.26 Overlaid 1H NMR spectrum of 1a/3b/3a. 64 Figure 2.27 Reaction scheme for the generation of disulfide lipid 1f 65 Equation 2.1 Thiol-disulfide interchange rate law. 66 Figure 2.28 Reaction scheme for competing thiol-disulfide interchange reactions. 66 Figure 2.29 Enlarged 1H NMR spectra of resulting 1f crude. 67 Figure 2.30 Overlaid 1H NMR spectra of 1g and disulfide lipid 1f. 68 Figure 2.31 Reaction scheme for the synthesis of disulfide lipid 2f. 68 Figure 2.32 LCMS spectrum of resulting crude on reaction of 1f with 1d. 70 Figure 3.1 Chemical structure of thioester lipids 3a and 3b. 70 Figure 3.2 Intensity size-distribution graphs of 3a and 3b on DLS analysis. 71 Figure 3.3 Intensity zeta-potential distribution graphs of 3a and 3b 75 Table 3.1 DLS and zeta-potential data. 76 Figure 3.4 Chemical structure of 5(6)-CF. 77 Equation 3.1 Encapsulation efficiency. 78 Equation 3.2 (%) Release of 5(6)-CF. 79 Figure 3.5 Graph of rate of release (%) of 5(6)-CF from vesicles 3a and 3b.
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