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The Design, Synthesis and Enzymatic Evaluation of Aminocyclitol Inhibitors of Glucocerebrosidase

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The Design, Synthesis and Enzymatic Evaluation of Aminocyclitol Inhibitors of Glucocerebrosidase Lakehead University Knowledge Commons,http://knowledgecommons.lakeheadu.ca Electronic Theses and Dissertations Electronic Theses and Dissertations from 2009 2014-01-22 The design, synthesis and enzymatic evaluation of aminocyclitol inhibitors of glucocerebrosidase Adams, Benjamin Tyler http://knowledgecommons.lakeheadu.ca/handle/2453/478 Downloaded from Lakehead University, KnowledgeCommons THE DESIGN, SYNTHESIS AND ENZYMATIC EVALUATION OF AMINOCYCLITOL INHIBITORS OF GLUCOCEREBROSIDASE By Benjamin Tyler Adams A Thesis submitted to The Department of Chemistry Faculty of Science and Environmental Studies Lakehead University In partial fulfillment of the requirements for the degree of Master of Science August 2013 © Benjamin Tyler Adams, 2013 i Abstract Gaucher disease, the most common lysosomal storage disorder, is caused by mutations in the GBA gene which codes for the enzyme glucocerebrosidase (GCase) resulting in its deficiency. GCase deficiency results in the accumulation of its substrate glucosylceramide (GlcCer) within the lysosomes leading to various severities of hepatosplenomegaly, bone disease and neurodegeneration. For most forms of Gaucher disease, the mutations in the GBA gene cause the enzyme to misfold but retain catalytic activity. However, the misfolded mutant enzyme is recognized and degraded by the endoplasmic reticulum-associated degradation (ERAD) pathway prior to delivery into the lysosome. Symptoms begin to show in patients when the function of the defective enzyme drops below 10-20% residual enzyme activity. There are currently three therapeutic approaches to treat Gaucher disease: enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and a relatively recent addition, enzyme enhancement therapy (EET) through the use of pharmacological chaperones. Many pharmacological chaperones are competitive inhibitors that are capable of enhancing lysosomal GCase activity by stabilizing the folded conformation of GCase enabling it to bypass the ERAD pathway. Once the mutant enzyme enters the lysosome, high levels of GlcCer can outcompete the competitive inhibitor binding to the enzyme, thus partially restoring the hydrolytic pathway. For this thesis, a series of alkylated aminocyclitol derivatives have been synthesized and evaluated as competitive inhibitors of GCase with the intent of discovering specific and efficient pharmacological chaperones for Gaucher disease. Importantly, we have discovered that N,O-alklyated inosamines are potent inhibitors of GCase and therefore are lead compounds as a potential new EET for the treatment of Gaucher Disease. ii Based on the potency of the alkylated inosamines as reversible inhibitors, we designed and synthesized several alkylated conduritol aziridine inhibitors to be used as mechanism-based inactivators of GCase. All three aziridine compounds synthesized were potent inhibitors of GCase with ki/Ki values ranging from 3.837 to 3674 mM-1min-1. For comparison purposes, our most potent inhibitor is 37 times more effective than the best published inhibitor of GCase. In addition, the alkylated aziridines were shown to be cell permeable and effective at inhibiting GCase inside of living HeLa cervical cancer cells, thus demonstrating their enormous potential as activity based probes, GCase labeling agents or potential molecular imaging agents for assessing ERT. iii Table of Contents Abstract ............................................................................................................................................. ii List of Tables ..................................................................................................................................... ix List of Figures .................................................................................................................................... ix List of Schemes ................................................................................................................................. xi List of Abbreviations ........................................................................................................................ xii Acknowledgments .......................................................................................................................... xvi Chapter 1: General Introduction .........................................................................................................1 1.1 Glycosidases ................................................................................................................................... 1 1.1.1 Glycosidase Mechanisms ...................................................................................................... 2 1.1.2 Glycosidase Inhibitors ........................................................................................................... 7 1.2 Lysosomal Storage Diseases ........................................................................................................... 8 1.2.1 Enzyme Replacement Therapy ........................................................................................... 12 1.2.2 Substrate Reduction Therapy ............................................................................................. 12 1.2.3 Enzyme Enhancement Therapy .......................................................................................... 13 1.2.4 Gaucher Disease ................................................................................................................. 15 1.2.5 Glucocerebrosidase ............................................................................................................ 16 1.3 Research Objectives ...................................................................................................................... 18 Part A: Aminocyclitol Competitive Inhibitors of Glucocerebrosidase .................................................. 19 1.4 Introduction ............................................................................................................................... 19 1.4.1 Non-covalent Glycosidase Inhibitors ......................................................................................... 19 Chapter 2: Results and Discussion .................................................................................................... 22 2.1 Synthesis .................................................................................................................................... 22 2.1.1 Synthesis of Substrate 2,4-dinitrophenyl-β-D-glucopyranoside (2,4-DNP-β-D-glc) .................. 22 2.1.2 Synthesis of N-alkylated Inhibitors ............................................................................................ 24 2.1.3 Synthesis of O-alkylated Inhibitors and O- and N-alkylated Inhibitors ..................................... 29 2.2 Expression and Purification of a Model β-glucosidase ABG .......................................................... 32 2.3 Enzyme Inhibition Studies with ABG and GCase ........................................................................... 33 2.3.1 Kinetic Analysis of the Inhibition of ABG and GCase by the N-alkylated Inhibitor 3.12 ............ 34 2.3.2 Kinetic Analysis of the Inhibition of ABG and GCase by O-alkylated Inhibitors 3.19, 3.20 and 3.21 ..................................................................................................................................................... 37 iv 2.3.3 Kinetic Analysis of the Inhibition of ABG and GCase by O- and N-alkylated Inhibitors 3.29-3.33 ............................................................................................................................................................ 41 2.3.4 Conclusions and Future Work .................................................................................................... 46 2.3.5 Special Note ............................................................................................................................... 47 Part B: Mechanism-based Aziridine Glucocerebroside Inhibitors ....................................................... 48 3.1 Introduction ............................................................................................................................... 48 3.1.1 Covalent Glycosidase Inhibitors ................................................................................................. 48 Chapter 4: Results and Discussion ..................................................................................................... 52 4.1 Synthesis .................................................................................................................................... 52 4.1.1 Synthesis of Aziridine Inhibitors ................................................................................................ 52 4.2 Kinetic Analysis of the Irreversible Inhibition of ABG and GCase by Aziridine Inhibitors 3.39-3.41 . 55 4.2.1 Inactivation rates of ABG with Inhibitors 3.39, 3.40 and 3.41 ................................................... 57 4.2.2 Inactivation Rates of GCase with Inhibitors 3.39, 3.40 and 3.41 ............................................... 60 4.2.3 Turnover of the Inhibitor-Enzyme Covalent Intermediate ........................................................ 64 4.2.4 Kinetic Analysis of the Inactivation of GCase in Cell Lysates by Aziridine Inhibitors 3.39-3.41 65 4.3 Conclusions and Future Work ..................................................................................................... 68 Chapter 5: Experimental
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