Efficient synthesis and cell-based silencing activity of siRNAS that contain triazole backbone linkages

An efficient synthesis of siRNAs modified at the backbone with a triazole functionality is reported. Through the use of 4,4′-dimethoxytrityl (DMT) phosphoramidite chemistry, triazole backbone dimers were site-specifically incorporated throughout various siRNAs targeting both firefly luciferase and g...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (4), p.1722-1726
Main Authors: Efthymiou, Tim C., Huynh, Vanthi, Oentoro, Jaymie, Peel, Brandon, Desaulniers, Jean-Paul
Format: Article
Language:English
Subjects:
Azides - chemistry
Base Sequence
Biological and medical sciences
chemistry
Click Chemistry
Gene silencing
Gene Silencing - drug effects
glyceraldehyde-3-phosphate dehydrogenase
Huisgen dipolar cycloaddition
luciferase
Luciferases - antagonists & inhibitors
Medical sciences
messenger RNA
Modified nucleoside
Molecular Sequence Data
Molecular Structure
Pharmacology. Drug treatments
Real-Time Polymerase Chain Reaction
reporter genes
RNA interference
RNA, Small Interfering - chemical synthesis
RNA, Small Interfering - pharmacology
Short interfering RNA
small interfering RNA
Triazole linkage
triazoles
Triazoles - chemical synthesis
Triazoles - pharmacology
Trityl Compounds - chemistry
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Summary:An efficient synthesis of siRNAs modified at the backbone with a triazole functionality is reported. Through the use of 4,4′-dimethoxytrityl (DMT) phosphoramidite chemistry, triazole backbone dimers were site-specifically incorporated throughout various siRNAs targeting both firefly luciferase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts as representatives of an exogenous and endogenous gene, respectively. Following the successful silencing of the firefly luciferase reporter gene, triazole-modified siRNAs were also found to be capable of silencing GAPDH in a dose-dependent manner. Backbone modifications approaching the 3′-end on the sense strand were tolerated without compromising siRNA potency. This study highlights the compatibility of triazole-modified siRNAs within the RNAi pathway, and the modification’s potential to impart favorable properties to siRNAs designed to target other endogenous genes.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.12.104