Synthesis of a novel C-nucleoside prodrug for treatment of Hepatitis B Open Access
Wan, Anqi (Spring 2020)
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
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