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Title The design and synthesis of novel pro-drugs for the treatment of nephropathic cystinosis
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Degree PhD
Degree Level doctoral
University/Publisher Robert Gordon University
Abstract Cystinosis is a metabolic disorder characterised by the abnormal accumulation of the amino acid cystine in cells leading to a slow destruction of all major organs. If patients diagnosed with cystinosis are untreated, death due to kidney failure ensues in the second decade of life. A number of studies have shown the ability of the drug cysteamine (Cystagon®) to lower cystine accumulation within cells resulting in reduced organ and tissue damage. Cysteamine therapy however, is associated with a number of side effects involving the gastrointestinal tract and the central nervous system. Most of these arise due to the large amount of cysteamine present in the stomach and gut following administration. In addition, cysteamine possesses an unpleasant taste and smell, resulting in poor patient compliance. In an attempt to overcome these problems, a number of pro-drug derivatives of cysteamine and cystamine, the disulfide analogue of cysteamine, have been synthesised and evaluated. Pro-drugs were synthesised using a route established in our laboratories. Briefly, cystamine dihydrochloride was basified and allowed to react with a number of cyclic anhydrides under basic conditions. The resulting di-acids were reacted with carbonyldiimidazole and monoBoc-cystamine to yield the desired pro-drugs. Removal of the tBoc-protecting group was achieved in a facile manner by use of trifluoroacetic acid to yield product. The efficacy of the synthesised pro-drugs was determined by incubation of 50μM compound in a suspension of cultured cystinotic fibroblasts, with 50μM cysteamine as control. Cell growth was measured at 72 h and the level of thiol determined. All except one of the pro-drugs tested were significantly more effective than the control at lowering the cystine burden of the cells. Further work will concentrate on repeating these studies and evaluating a more robust Structure Activity Relationship for these compounds. The overall aim of all this work remains the production of an odourless, tasteless and orally active treatment for cystinosis and, if possible, improve on the current dosing regimen of every 6h. By using pro-drugs, cysteamine will be chemically camouflaged and hence, the side effects associated with its administration will be minimised or even entirely abolished.
Subjects/Keywords 610; Cystagon ; Cysteamine ; Cystamine ; Pro-drugs ; Multicomponent crystals ; Nephropathic Cystinosis ; Peptide synthesis
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Country of Publication uk
Record ID handle:10059/1227
Repository ethos
Date Indexed 2020-06-17

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…3.1.3. Methods 67 3.1.3.1. Synthesis of Cystamine Pro-drugs Derivatives [1-4] 67 3.1.3.1.1. Synthesis of Cystamine - Succinate (Pro-drug 1) 67 3.1.3.1.1.a. Synthesis of N,N’-Disuccinoylcystamine - Diamide (A) 68…

…Cysteamine Tartrate Monohydrate (1) 122 4.1.2.6. Cysteamine Tartrate Mixture 123 13 4.1.2.6.a. Cystamine Tartrate (2) 4.1.2.6.b. Cystamine Bitartrate Dihydrate (3) 123 123 4.2. Synthesis of novel cystamine Pro-drugs

…synthetic pro-drugs on levels of cystine 152 CHAPTER 5 Conclusions 156 5.1. Conclusion and future work CHAPTER 6 References 157 159 Presentations and Publications 178 Publications 179 Conference Proceedings 179 APPENDICES 180 14 CHAPTER 1…

…Treatment and prevention of early manifestations 31 1.4.1. Cysteamine 33 1.4.2. Problems associated with cysteamine treatment 37 1.5. Pro-drug approach 39 1.6. Research Progress 48 1.7. Aims of Project 50 CHAPTER 2 Multicomponent Crystals 52…

…Calorimetry (DSC) 61 2.3.4. Infra-Red (IR) Spectroscopy 61 2.3.5. X- Ray Crystallography 62 CHAPTER 3 64 Experimental 3.1. Synthesis of Novel Cystamine Pro-drug Derivatives 65 3.1.2. Materials 65 3.1.2.1. Instrumentation 65…

…3.1.3.1.1.b. Synthesis of Imidazolide Derivative (1) 68 3.1.3.1.1.c. Deprotection of Pro-drug (1) 69 3.1.3.1.2. Synthesis of Cystamine Glutarate – Pro-drug (2) 69 3.1.3.1.2.a. Synthesis of N,N’-Diglutaroylcystamine…

…Diamide (B) 70 3.1.3.1.2.b. Synthesis of Imidazolide Derivative (2) 70 3.1.3.1.2.c. Deprotection of Pro-drug (2) 70 3.1.3.1.3. Synthesis of Cystamine Citraconate – Pro-drug (3) 71 3.1.3.1.3.a. Synthesis of N…

…N’-Citraconoylcystamine - Diamide (C) 71 3.1.3.1.3.b. Synthesis of Imidazolide Derivative (3) 71 3.1.3.1.4. Synthesis of Cystamine Maleioate – Pro-drug (4) 72 3.1.3.1.4.a. Synthesis of N,N’-Maleioylcystamine…

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