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Hydroxymethyl Cytidine As a Potential Inhibitor for Hepatitis C Virus

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Hydroxymethyl Cytidine As a Potential Inhibitor for Hepatitis C Virus A Thesis entitled Synthesis of 2’- Hydroxymethyl Cytidine as a Potential Inhibitor for Hepatitis C Virus Polymerase Enzyme by Ali Hayder Hamzah Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Medicinal Chemistry _________________________________________ Dr. Amanda C. Bryant-Friedrich, Committee Chair _________________________________________ Dr. Hermann Von Grafenstein, Committee Member _________________________________________ Dr. Caren L. Steinmiller, Committee Member _________________________________________ Dr. Amanda C. Bryant-Friedrich, Dean College of Graduate Studies The University of Toledo August 2016 Copyright 2016, Ali Hayder Hamzah This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Synthesis of 2’- Hydroxymethyl Cytidine as a Potential Inhibitor for Hepatitis C Virus Polymerase Enzyme by Ali Hayder Hamzah Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Medicinal Chemistry The University of Toledo August 2016 Hepatitis C virus infection (HCV) is a major cause of liver disease. Due to the asymptomatic nature of the infection, large populations are unware of their infection and become carriers, with progression to chronic stage including liver cirrhosis and hepatocellular carcinoma. Currently, there are seven genotypes and several subtypes of HCV; genotype 1 is the most global distributed form, acquired predominantly through illegal intravenous drug injection. HCV heterogeneity and high replication rates, lead to mutant formation and consequent reinfection. The diseases’ lack of susceptibility to antiviral agents facilitates chronic infection and as such is most challenging when searching for a cure. For decades, the standard of care (SOC) was a combination of PEGylated interferon-α (PEGINF-α) and ribavirin. A Sustained viral response (SVR) was achieved in only a low percentage and was limited to some genotypes and associated with serious adverse effects. It is therefore urgent to develop compounds which have pan-genotype activity, and have increased bioavailability and improved safety profiles. iii A better understanding of the viral life cycle and the determination of the crystal structure of HCV NS5B polymerase enzyme, led to identification of multiple points of intervention to disrupt viral protein synthesis and to interrupt the viral life cycle. Many development stages for these drugs were halted because of either low barrier to resistance or high toxicity. The catalytic site of HCV polymerase is the most conserved motif among HCV and other polymerases and is responsible for HCV RNA replication. It is considered the primary focus in the effort to synthesize molecules targeting the inhibition of HCV life cycle. In our project, we developed a new synthetic pathway toward synthesis of hydroxy methyl cytidine as a potential substrate of the enzyme with an inhibitory effect through working as a chain terminator for nucleotide polymerization. iv Dedicated to my wife Sura and to my father Acknowledgements I would like to express my gratitude to my advisor Dr. Amanda C. Bryant Friedrich for providing me an opportunity to be a part of her research group and for all of her support throughout the two years of graduate study. This work would not have been possible without her guidance, knowledge, and personal experience. Sincere gratitude to all professors in the College of Pharmacy and Pharmaceutical Sciences and the department of Medicinal and Biological Chemistry for their unlimited continuous support. Special thanks to my committee members Dr. Caren L. Steinmiller and Dr. Hermann Von Grafenstein. Thank you to all my lab members for their support and for sharing their chemistry knowledge and experience during my research work, especially Bader.Alabdullah for his support, encouragement and help me with my research. Also I would like to thank Dr. Fernand Mel Bedi who supported me during the research and writing. To my friends Salam AL Maliki and Hassan Al Hadad, thank you for everything. A great thanks to my sponsor the Higher Committee for Education Development in Iraq (HCED) for their financial support during my study. Finally, to my family and my life, my wife Sura and my kids, I cannot do anything without their unlimited support. vi Table of Contents Abstract .............................................................................................................................. iii Acknowledgements ............................................................................................................. vi Table of Contents ...............................................................................................................vii List of Tables ...................................................................................................................xii List of Figures .................................................................................................................. xiii List of Schemes…………………………………………………………………………..xv List of Abbreviations ........................................................................................................ xvi List of Symbols ................................................................................................................. xix 1 Introduction… …………………………………………………………………….1 1.1 Hepatitis C Virus Epidemiology ........................................................................1 1.1.1 Prevalence and Incidence of Hepatitis C Virus (HCV) ......................2 1.1.2 Mode of Transmission for HCV .........................................................3 1.1.3 HCV Genotype Distribution……………………………………...…4 1.2 HCV Structure………………………………………………………………..6 1.2.1 Viral Genome Organization………………………………………6 1.2.2 HCV Proteins……………………………………………………..8 1.2.2.1 Structural Proteins………………………………………...9 1.2.2.2 Non-Structural Proteins…………………………………11 1.3 HCV Life Cycle……………………………………………………………...13 vii 1.3.1 HCV Attachment, Entry and Fusion…………………………….13 1.3.2 RNA Translation and Post-Translation Processing……………..16 1.3.3 HCV RNA Replication………………………………………….17 1.3.4 HCV Assembly and Release…………………………………….18 1.3.5 HCV Circulating Forms…………………………………………19 1.4 HCV Pathogenesis………………………………………………………….20 1.4.1 HCV Induced Apoptosis………………………………………..20 1.5 HCV Progression and Complication ……………………………………...22 1.6 HCV Treatment…………………………………………………………….24 1.6.1 Indirectly Acting Antiviral Agents…………………………….24 1.6.2 Direct Acting Antiviral Agents (DAAs)……………………….26 2 Background……………… ....................................................................................29 2.1 The Structural Feature of HCV NS5B RdRp Protein………………………..29 2.2 HCV NS5B RdRp Activities and the Mode of Action………………………31 2.3 The HCV NS5B RdRp as a Potential Drug Target…………………………..35 2.4 Inhibitors of HCV NS5B Polymerase………………………………………..36 2.4.1 Nucleoside and Nucleotide inhibitors (NIs)………………….….36 2.4.1.1 Sugar Modified NIs………………………………………37 2.4.1.2 Base Modified NIs……………….....................................42 2.4.2 Non-nucleoside Inhibitors of NS5B (NNIs) ………………………………..42 3 Results and Discussion…………………………………………………………45 viii 3.1 Overview on the Synthesis of Nucleosides Analogs…………..…………45 3.2 Design and Synthesis of 2-C-hydroxymethyl Ribose…………………….46 3.2.1 Synthesis of 5-((benzoyloxy) methyl)-3-oxotetrahydrofuran-2, 4- diyl dibenzoate (19)……………………………………………………………………..47 3.2.2 Synthesis of 5-((benzoyloxy) methyl)-3- methylenetetrahydrofuran-2, 4-diyl dibenzoate (20)……………………………………48 3.2.3 Synthesis of 5-((benzoyloxy) methyl)-3-hydroxy-3- (hydroxymethyl) tetrahydrofuran-2, 4-diyl dibenzoate (21)…………………………….51 3.3 Synthesis of Glycosyl Donor……………………………………………….52 3.3.1 Synthesis of 3-acetoxy-3-(acetoxymethyl)-5-((benzoyloxy) methyl) tetrahydrofuran-2, 4-diyl dibenzoate (32)………………………………………52 3.3.2 Synthesis of 5-((benzoyloxy) methyl)-3-(((tert butyldimethylsilyl) oxy) methyl)-3-hydroxytetrahydrofuran-2, 4-diyl dibenzoate 2133……………………55 3.3.3 Synthesis of 3-acetoxy-5-((benzoyloxy) methyl)-3-(((tert butyldimethylsilyl) oxy) methyl) tetrahydrofuran-2, 4-diyl dibenzoate (34)……………57 3.4 Synthesis of Hydroxy Methyl Cytidine…………………………………....57 3.4.1 Synthesis of 5-(4-acetamido-2-oxopyrimidin-1(2H)-yl)-4- acetoxy-4-(acetoxymethyl)-2-((benzoyloxy) methyl) tetrahydrofuran-3-yl benzoate (43a)…………………………………………………………………………………….59 4 Conclusions and Future Work…………………………………………………64 4.1 Conclusions ……………………………………………………………….64 4.2 Future Work ……………………………………………………………….65 ix 5 Experimental procedures ……………………………………………………...67 5.1 Materials…………………………………………………………………...67 5.2 Structural Analysis………………………………………………………..67 5.2.1 NMR Analysis…………………………………………...…67 5.2.1.1 1H-NMR…………………………………….…….67 5.2.1.2 13C-NMR…………………………………………69 5.2.2 Mass Spectrometry………………………………………….69 5.2.2.1 ESI-MS……………………………………………69 5.2.2.2 High Resolution Mass Spectroscopy……………………..69 5.3 Chromatographic Methods……………………………………………………..69 5.3.1 Thin Layer Chromatography (TLC)……………………………..69 5.3.2 Flash Chromatography…………………………………………..70 5.4 Other Equipment and devices………………………………………………….70 5.5 Synthesis of 4-amino-1-(3, 4-dihydroxy-3, 5-bis (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidin-2(1H)-one……………………………………………..71 5.5.1 5-((benzoyloxy) methyl)-3-oxotetrahydrofuran-2, 4-diyl dibenzoate (19)……………………………………………………………………………………….71 5.5.2 5-((benzoyloxy) methyl)-3-methylenetetrahydrofuran- 2, 4-diyl dibenzoate
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