6′-Substituted Bridged Nucleosides Without Isomer Separation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing bridged nucleosides, such as 2′,4′-BNA, face challenges with low enzyme resistance and potential hepatotoxicity, and their synthesis often requires complicated isomer separation, limiting their industrial applicability and yield.
Innovation Solution
A bridged nucleoside with a substituent at the 6′ position, represented by specific chemical formulas, is developed to enhance enzyme resistance and binding affinity for ssRNA without the need for isomer separation, allowing for higher yields and improved industrial productivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a substituent such as a methyl group or a methoxy methyl group is introduced at the 6′ position of 2′,4′-BNA, then binding affinity for ssRNA and enzyme-resistant ability are improved, but production requires isomer separation operations which complicates the process
Solution Approach 1:
The patent introduces a cyclopropyl group at the 6′ position of the nucleoside, creating an asymmetric substituent that prevents isomer formation. This asymmetric structure ensures that only one stereoisomer is produced during synthesis, eliminating the need for complex isomer separation operations while maintaining improved enzyme resistance and binding affinity.
2Reliability
If a cyclopropyl group is introduced at the 6′ position to avoid isomer separation, then binding affinity for ssRNA and enzyme-resistant ability are maintained, but synthesis yields are not sufficiently satisfactory
Solution Approach 1:
The patent optimizes various synthesis parameters including reaction conditions, catalysts, and reagents to improve the yields of the cyclopropyl-substituted nucleoside synthesis. By adjusting these parameters, the patent achieves sufficiently satisfactory yields while maintaining the advantageous properties of the cyclopropyl group (avoiding isomer separation and preserving enzyme resistance).
Solution Approach 2:
The patent employs specific intermediates and protecting groups in the synthesis pathway that facilitate higher yields. These intermediaries enable more efficient chemical transformations and improve overall synthesis efficiency without compromising the final product's enzyme-resistant ability or binding affinity.
3Reliability
If 2′,4′-BNA is used to achieve high binding affinity for ssRNA, then oligonucleotide therapeutic potential is improved, but enzyme resistance is low and hepatotoxicity is induced
Solution Approach 1:
The patent introduces a substituent at the 6′ position of the nucleoside sugar ring, which is a local modification that specifically enhances enzyme resistance and eliminates hepatotoxicity without affecting the overall structure responsible for binding affinity. This localized change allows the molecule to maintain high binding affinity for ssRNA while gaining improved safety and stability profiles.
Data Source
AI summary
Disclosed are a bridged nucleoside and a nucleotide using the same. The nucleoside of the present invention is represented by the formula (I) below. The bridged nucleoside of the present invention is usable as a substitute for a phosphorothioate-modified nucleic acid, which has a risk of, for example, accumulation in a specific organ. The bridged nucleoside also has excellent industrial productivity.