Multi-Fluorous Blockmers for Simpler Oligonucleotide Purification
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Solution Overview
Problem
Conventional liquid-phase oligonucleotide synthesis methods require numerous purification steps, are complicated, and use costly fluorous tags with complex structures, making large-scale synthesis difficult.
Innovation Solution
The use of multi-fluorous blockmers with readily available fluorous tags, including protected nucleosides, 5′-end-protected nucleoside phosphoramidites, and fluorous blockmer phosphoramidites, which alter solubility and simplify purification through fluorous solid phase extraction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional liquid-phase synthesis methods are used, then oligonucleotides can be synthesized, but numerous purification steps are required and the process becomes complicated
Solution Approach 1:
The patent introduces a fluorous tag as an intermediary component attached to the oligonucleotide molecule. This fluorous tag enables selective interaction with fluorous solid phase extraction media, acting as a mediator that facilitates simplified purification. The tag allows the oligonucleotide to be captured and released through fluorous-phase interactions, eliminating the need for complex column chromatography procedures while maintaining synthesis effectiveness.
2Ease of manufacture
If conventional fluorous tags are used, then purification can be simplified, but the tags have complicated structure and are not readily available, resulting in high cost
Solution Approach 1:
The fluorous tag is segmented into modular components that can be independently synthesized and then assembled. This segmentation allows each component to be produced through standard chemical synthesis methods using readily available reagents, avoiding the need for complex, proprietary tag structures. The modular nature enables easy customization and reduces overall synthesis complexity and cost.
Solution Approach 2:
The patent modifies the chemical parameters of the fluorous tag to use standard, commercially available functional groups and structural motifs. By changing the tag's chemical parameters to match common building blocks in organic synthesis, the invention eliminates the need for specialized, expensive reagents while maintaining the fluorous properties necessary for simplified purification.
3Quantity of substance
If conventional liquid-phase synthesis methods are used, then oligonucleotide synthesis can proceed, but large-scale synthesis is difficult due to complicated purification requirements
Solution Approach 1:
The fluorous tag serves as a mediator that enables bulk purification of large quantities of oligonucleotide. By attaching this tag to each molecule, the entire batch can be purified simultaneously through fluorous solid phase extraction, rather than requiring individual molecule purification. This mediator approach allows scaling up production while maintaining consistent purification quality across large quantities.
Solution Approach 2:
The patent merges the purification function with the molecular structure itself by incorporating the fluorous tag directly into the oligonucleotide. This merging allows the purification process to act on the entire molecule-tag complex as a single unit, enabling simultaneous purification of large batches and significantly improving productivity for large-scale synthesis operations.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enables simpler and more cost-effective large-scale oligonucleotide synthesis by reducing purification burdens and allowing versatile methods for synthesizing oligonucleotides.
Implementation Method 1
alter solubility and simplify purification through fluorous solid phase extraction
Data Source
AI summary
Provided are a multi-fluorous blockmer using a readily available fluorous tag and capable of reducing burdens of purification, and an oligonucleotide synthesis method using the same. A multi-fluorous blockmer represented by the formula is synthesized: wherein B is a natural or modified nucleobase; R1 is a protecting group that can be removed for deprotection under acidic or neutral conditions; R3 is a protecting group for phosphate; Pro is unprotected, protected, or F-protector, wherein F-protector is O(CH2)n(CF2)mCF3 when the protected moiety of nucleoside base B is O, and is NH(C═O)(CH2)n(CF2)mCF3 when the protected moiety of nucleoside base B is N, wherein n is 1 or 2 and m is an integer of 1 to 20; X is O or S; 1 is an integer of 0 to 58; R7 is (C═O)(CH2)2(C═O)(CH2)n(CF2)mCF3 or a silyl protecting group, wherein n is 1 or 2 and m is an integer of 1 to 20.