Synthesis and Anti-Viral Activity of Novel 3,6-dioxa-[3.2.0]bicyclonucleoside Nucleotide Analogs Öffentlichkeit

Abstract

This study involves the design and synthesis of novel 3,6-dioxa-[3,2,0]bicyclonucleoside analogs as potential hepatitis C virus RNA-dependant RNA polymerase inhibitors. Both enantiomers of thymidine, 5-Fluorocytidine, cytidine, 6-Methoxypuridine and adenosine analogs were synthesized respectively. A convergent strategy was employed in the synthesis. The sugar moieties were synthesized from a chiral source, including carbohydrates and amino acid and coupled with various nucleoside bases though Vorbrüggen reactions. An intramolecular SN2 reaction completed the synthesis. The bicyclic nucleoside analogs were tested in HCV replicon assay in Huh 7 Clone B cells for anti-HCV activity. Triphosphates of some chosen analogs were also synthesized for biological testing in order to exclude overlooking any potent inhibitor because of a poor phosphorylation step. The triphosphate compounds were tested in HCV RdRp enzymatic assay.

Table of Contents

1 Synthesis and Anti-Viral Activity of Novel 3,6-dioxa-[3.2.0]bicyclonucleoside Nucleotide Analogs

1.1 Statement of Purpose

1.2 Introduction

1.2.1 Hepatitis C Virus

1.2.2 HIV and HIV/HCV coinfection

1.2.3 Nucleoside RNA dependant RNA Polymerase Inhibitors and Their Triphosphates

1.3 Background

1.3.1 General Approaches of Nucleoside Synthesis

1.3.2 Oxetane Ring Formation

1.3.3 Bicyclic Nucleoside Analogs

1.3.4 Syntheses of Nucleoside Triphosphates

1.4 Design and Syntheses of 3,6-dioxa-[3.2.0]bicyclonucleoside Analogs

1.4.1 Syntheses of D-3,6-Dioxa-[3.2.0]bicyclonucleoside Analogs

1.4.2 Syntheses of L-3,6-Dioxa-[3.2.0]bicyclonucleoside Analogs

1.4.3 Syntheses of Nucleoside Triphosphates

1.5 Biological Activities

1.6 Conclusion

2 Experimental Section

2.1 General Notes

2.2 Syntheses of D-3,6-dioxa-[3.2.0]bicyclonucleoside Analogs

2.3 Syntheses of L-3,6-dioxa-[3.2.0]bicyclonucleoside Analogs

2.3.1 Route Starting from L-xylose

2.3.2 Route Starting from D-glutamic acid

2.4 Syntheses of Nucleoside Triphosphates

3 Abbreviations and Definitions

4 References

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic Chemistry, Pharmaceutical
Stichwort	nucleotide HCV polymerase inhibitors anti-HCV nucleoside
Committee Chair / Thesis Advisor	Liotta, Dennis C, Emory University
Committee Members	Lutz, Stefan, Emory University Liebeskind, Lanny S, Emory University

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