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WRAP Theses Yilmaz 2016.Pdf A Thesis Submitted for the Degree of PhD at the University of Warwick Permanent WRAP URL: http://wrap.warwick.ac.uk/89300 Copyright and reuse: This thesis is made available online and is protected by original copyright. Please scroll down to view the document itself. Please refer to the repository record for this item for information to help you to cite it. Our policy information is available from the repository home page. For more information, please contact the WRAP Team at: [email protected] warwick.ac.uk/lib-publications Synthesis of Glycomaterials for Multivalent Interactions Gokhan Yilmaz A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry Department of Chemistry September 2016 Declaration Declaration I hereby declare that experimental work contained in this thesis is original research carried out by the author, unless otherwise stated, in the Department of Chemistry at the University of Warwick and Queen Mary University of London, October 2012 and September 2016. No material contained herein has been submitted for any other degree, or at any other institution. Results from other authors are referenced in the usual manner throughout the text. Date: 23 September 2016 Gokhan Yilmaz i Gokhan Yilmaz Table of Contents Table of Contents Declaration………………………………………………………………………………………………………………i Table of Contents…………………………………………………………………………………………………….ii List of Figures………………………………………………………………………………………………………..viii List of Schemes……………………………………………………………………………………………………..xiv List of Tables…………………………………………………………………………………………………………xvi Abbreviations………………………………………………………………………………………………………xvii Acknowledgments………………………………………………………………………………………………..xxi Abstract……………………………………………………………………………………………………………….xxii Chapter 1 Introduction on the preparation of glycomaterials and their interactions with lectins……………………………………………………………………………………………………………..1 1.1. Multivalent carbohydrate-lectin interactions of glycomaterials…………………2 1.2. Synthesis of glycopolymers………………………………………………………………………..5 1.2.1 Conventional free radical polymerization……………………………………………5 1.2.2 Ring-opening polymerization (ROP)…………………………………………………….6 1.2.3 Reversible addition-fragmentation transfer (RAFT) polymerization…….8 1.2.4 Copper-mediated control/living radical polymerization…………………….11 1.3 Synthesis of glyconanoparticles………………………………………………………………..14 1.3.1 Polymeric glyconanoparticles……………………………………………………………15 1.3.2 Metallic glyconanoparticles………………………………………………………………17 1.4 “Click” chemistry for polymer synthesis……………………………………………………19 1.4.1 Copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) reaction……..19 1.4.2 Thiol-ene “click” reaction………………………………………………………………….21 1.5 Lectins………………………………………………………………………………………………………23 1.5.1 Plant lectins………………………………………………………………………………………23 1.5.2 Animal lectins……………………………………………………………………………………25 ii Gokhan Yilmaz Table of Contents 1.6 Analysis of the interactions of glyco-polymers/particles and lectins ………..27 1.7 Biomedical applications of glyco-polymers/particles………………………………..30 1.7.1 Drug and gene delivery……………………………………………………………………..30 1.7.2 Bioimaging and biosensing………………………………………………………………..32 1.7.3. Pathogen inhibitions………………………………………………………………………..33 1.8 Conclusion………………………………………………………………………………………………..35 1.9 References……………………………………………………………………………………………….35 Chapter 2 Self-assembled glyconanoparticles with controlled morphologies for dendritic cell lectin DC-SIGN binding and drug delivery…………………………………………42 2.1 Introduction……………………………………………………………………………………………..43 2.2 Results and Discussion………………………………………………………………………………46 2.2.1 Synthesis of mannose glycomonomer (ManAc)…………………………………46 2.2.2 Synthesis of PEG-Br initiator……………………………………………………………..47 2.2.3 Homopolymerization of MA using PEG-Br initiator…………………………...48 2.2.4 Synthesis of amphiphilic block co-glycopolymers………………………………50 2.2.5 Preparation and characterization of glyconanoparticles via TEM and DLS………………………………………………………………………………………………………………………..54 2.2.6 Interaction between glyconanoparticles and DC-SIGN………………………57 2.2.7 Preparation and characterization of SB216763-loaded micelles………..60 2.2.8 In vitro drug release………………………………………………………………………….64 2.3 Conclusion………………………………………………………………………………………………..66 2.4 Experimental……………………………………………………………………………………………67 2.4.1 Materials…………………………………………………………………………………………..67 2.4.2 Instruments and Analysis………………………………………………………………….67 2.4.3 Synthesis of mannose glycomonomers……………………………………………..69 2.4.4 Synthesis of PEG-Br initiator……………………………………………………………..70 2.4.5 General procedure for SET-LRP…………………………………………………………70 iii Gokhan Yilmaz Table of Contents 2.4.6 Preparation and characterization of glyconanoparticles……………………71 2.4.7 Determination of Binding Ability of Glyconanoparticles by SPR…………71 2.4.8 SB-216763 loaded glyco-micelles preparation…………………………………..72 2.4.9 In vitro drug release………………………………………………………………………….72 4.5 References……………………………………………………………………………………………….73 Chapter 3 pH-sensitive glycopolymer-coated gold nanoparticles: Functional platforms for theranostic applications…………………………………………………………………..75 3.1 Introduction…………………………………………………………………………………..…………76 3.2 Results and Discussion………………………………………………………………………………79 3.2.1 Synthesis of D-mannose methacrylate glycomonomer (ManMac)….…79 3.2.2 Synthesis of homo/co-polymers via RAFT………………………………………….80 3.2.3 Reduction of the RAFT end group of homo/co-polymers…………………..83 3.2.4 Preparation of polymer-substituted AuNPs……………………………………….86 3.2.5 Synthesis and characterization of AuNPs-polymer-Cys-DOX………………90 3.2.6 In vitro drug release studies………………………………………………………………93 3.2.7 Cell culture studies……………………………………………………………………………95 3.2.7.1 Cytotoxicity……………………………………………………………………………….95 3.2.7.2 Radioactivity………………………………………………………………………………96 3.2.7.3 Cell imaging……………………………………………………………………………….98 3.3 Conclusion………………………………………………………………………………………………..99 3.4 Experimental…………………………………………………………………………………………..100 3.4.1 Materials…………………………………………………………………………………………100 3.4.2 Instruments and Analysis………………………………………………………………..101 3.4.3 Synthesis of D-mannose acrylate glycomonomers…………………………..102 3.4.4 General procedure for RAFT polymerization……………………………………103 3.4.5 Reduction of the RAFT End Group of the obtained polymers…………..104 iv Gokhan Yilmaz Table of Contents 3.4.6 Preparation of PMAA-Substituted AuNPs………………………………………..104 3.4.7 Construction of pH-sensitive AuNPs-polymer-Cys-DOX bioconjugates………………………………………………………………………………………………………104 3.4.8 In vitro drug release studies…………………………………………………………….105 3.4.9 Cell culture studies………………………………………………………………………….106 3.4.9.1 Cytotoxicity studies………………………………………………………………….106 3.4.9.2 Cell imaging studies…………………………………………………………………106 3.4.9.3 Radioactivity studies…………………………………………………………………107 3.5 References……………………………………………………………………………………………..107 Chapter 4 Reversible single-chain glycopolymer folding via host-quest interaction and its effect on lectin binding…………………………………………………………………………….110 4.1 Introduction……………………………………………………………………………………………111 4.2 Results and Discussion……………………………………………………………………………113 4.2.1 Synthesis of D-mannose acrylamide glycomonomer (ManAcm)…..….113 4.2.2 Synthesis of adamantane acrylate monomer (AdAc)……………………….114 4.2.3 Synthesis of β-cyclodextrin azide (β-CD-N3)…………………………………….116 4.2.4 Synthesis of β-cyclodextrin acrylate monomer (CDAc)…………………….116 4.2.5 Synthesis of p((DMA)10-r-(Adac)2) macro-RAFT agent………………………119 4.2.6 Synthesis of well-defined tri-block copolymers……………………………….120 4.2.7 Reversible single-chain folding studies of the obtained glycopolymers……………………………………………………………………………………………………..124 4.2.8 Lectin binding studies……………………………………………………………………..128 4.2.8.1 Turbidimetry assay…………………………………………………………………..130 4.2.8.2 Quantitative Precipitation Assay………………………………………………131 4.2.8.3 Surface Plasmon Resonance (SPR) measurements…………………...133 4.3 Conclusion………………………………………………………………………………………………134 4.4 Experimental…………………………………………………………………………………………..135 v Gokhan Yilmaz Table of Contents 4.4.1 Materials…………………………………………………………………………………………135 4.4.2 Instruments and Analysis………………………………………………………………..135 4.4.3 Synthesis of D-mannose acrylamide glycomonomer……………………….137 4.4.4 Synthesis of adamantane acrylate monomer…………………………………..138 4.4.5 Synthesis of mono-6-deoxy-6-azido-β-cyclodextrin…………………………138 4.4.6 Synthesis of β-cyclodextrin acrylate monomer………………………………..139 4.4.7 Synthesis of p((DMA)10-r-(Adac)2) macro-RAFT agent………………………140 4.4.8 Synthesis of well-defined triblock copolymers…………………………………140 4.4.9 Single-chain folding studies…………………………………………………………….140 4.4.10 Lectin binding studies……………………………………………………………………141 4.4.10.1 Turbidimetry assay………………………………………………………………..141 4.4.10.2 Quantitative Precipitation Assay……………………………………………141 4.4.10.3 Surface Plasmon Resonance………………………………………………..….142 4.5 References……………………………………………………………………………………………..142 Chapter 5 S-glucosyl substituted 2-oxazolines and their binding to lectins………….144 5.1 Introduction……………………………………………………………………………………………145 5.2 Results and Discussion……………………………………………………………………………147 5.2.1 Synthesis of S-glucosyl substituted 2-oxazoline glycomonomer (Ac4Glc- S-Ox)……………………………………………………………………………………………………………………147 5.2.2 Synthesis of ButenOx and DecenOx…………………………………………………149 5.2.3 Microwave-assisted copolymerization…………………………………………....151 5.2.4 Thiol-ene Photoaddition Reactions of copoly(EtOx-ButenOx)s, copoly(EtOx-DecenOx)s and copoly(EtOx-ButenOx-DecenOx-Ac4Glc-S-Ox) using Ac4Glc-SH…………………………………………………………………………………………………………….154 5.2.5 Deprotection of the obtained copolymers………………………………………156
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