Synthesis of a novel C-nucleoside prodrug for treatment of Hepatitis B Pubblico

Abstract

In an effort to treat newly emerging HBV viral strains effectively, there is a need to develop novel nucleoside analogs with improved biological properties. Nucleot(s)ide based anti- HBV agents suppress the HBV viral replication by inhibiting the key polymerase activity known as reverse transcriptase. C-nucleosides offer a more stable alternative to the conventional nucleoside analogs, due to their stable C-C linkage in place of common C-N glycosidic bond. We designed a novel C-nucleoside analog and its phosphoramidate prodrug for targeting HBV and the prodrug was synthesized successfully in 10 steps with overall yield of 2.84%.

Table of Contents

Introduction 1

Figure 1. Life cycle of HBV 2

Figure 2. Phosphorylation of nucleoside analogs 3

Figure 3. Structures of current nucleoside analogues to HBV infection 5

Figure 4. N-nucleoside and C-nucleoside 6

Figure 5. Structure of GS-6620 6

Figure 6. Novel C-nucleoside and its prodrug 7

Results and discussion 8

Scheme 1. Attempted synthesis 8

Scheme 2. Synthesis of protected lactol 9

Scheme 3. Oxidation of lactol to lactone 10

Scheme 4. Coupling of lactone to nucleobase 11

Scheme 5. Synthesis of C-Nucleoside 12

Scheme 6. Synthesis of phosphoramidate prodrug (Method 1) 13

Scheme 7. Synthesis of phosphoramidate prodrug (Method 2) 13

Experimental 14

References 25 

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.A.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic
Parola chiave	C-nucleoside Prodrug
Committee Chair / Thesis Advisor	Dr. Dennis Liotta , Emory University
Committee Members	Dr. William Kelly, Emory University Dr. Huw Davies, Emory University

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