Phosphite Triester Dimer Amidite for Stable Nucleic Acid Synthesis
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Solution Overview
Problem
Current methods for producing modified nucleic acids with affinity for proteins face challenges such as the instability of dimer amidites during purification, leading to decreased synthesis yields due to labile moieties that are prone to decomposition under conventional deprotection conditions, and the difficulty in removing protective groups without affecting the substituents with binding properties.
Innovation Solution
Development of a nucleic acid synthesizing dimer amidite with nucleoside compounds linked via a phosphite triester bond, allowing for the removal of protective groups under mild conditions in an aprotic solvent, thereby stabilizing the amidite and enabling efficient purification and high-yield nucleic acid synthesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional dimer amidites with phosphate triester bonds are used, then the synthesis process can be completed, but the amidites are decomposed to a considerable extent by purification due to labile moieties
Solution Approach 1:
The patent changes the chemical structure parameter by replacing the phosphate triester bond with a phosphite triester bond in the dimer amidite. This structural modification fundamentally alters the stability characteristics, making the amidite resistant to acid and base decomposition while maintaining its functionality through the phosphite bond that can be selectively deprotected under mild conditions.
Solution Approach 2:
The patent employs a temporary protective group (such as acetyl or benzoyl) attached to the phosphite triester bond that serves its purpose during synthesis and purification, then is intentionally removed under mild deprotection conditions. This temporary structure enables stable purification while being easily discarded when no longer needed.
2Ease of manufacture
If conventional deprotection conditions (concentrated aqueous ammonia at 55°C for 8-15 hours) are used, then protective groups can be removed, but the labile moieties of the amidites are also decomposed
Solution Approach 1:
The patent fundamentally changes the deprotection parameter by transitioning from harsh conditions (concentrated aqueous ammonia, high temperature, long duration) to mild conditions (aqueous or mixed solvents, lower temperature, shorter time). The phosphite triester bond is specifically designed to be deprotected under these gentle conditions, preserving the integrity of the amidite's labile moieties.
Solution Approach 2:
The phosphite triester bond acts as an intermediary structure that selectively responds to mild deprotection conditions. It serves as a temporary link that can be cleanly broken under gentle conditions without affecting other sensitive parts of the molecule, thus mediating between the need for deprotection and the need to preserve stability.
3Adaptability or versatility
If dimer amidites with both acid-labile and base-labile moieties are used, then the substituents can be introduced, but the amidites are decomposed during purification
Solution Approach 1:
The patent changes the chemical stability parameter by using a phosphite triester bond instead of a phosphate triester bond. This modification creates an amidite that is resistant to both acid and base decomposition during purification, while still allowing substituent introduction through the phosphite bond's selective reactivity. The phosphite bond provides a window of stability that accommodates purification processes.
Solution Approach 2:
The patent segments the molecular structure into distinct functional regions: the phosphite triester bond provides stable linkage and selective reactivity, while the substituents and protective groups are attached to specific positions that can be independently manipulated. This segmentation allows the stable phosphite backbone to withstand purification while the functional groups can be introduced and removed as needed.
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
The use of phosphite triester bonded nucleic acid synthesizing dimer amidites facilitates stable production and purification, enhancing the synthesis yield and maintaining the binding properties of the substituents, making it suitable for protein analysis.
Implementation Method 1
two nucleoside compounds are linked with each other via a phosphite triester bond
Implementation Method 2
the protective groups of the phosphoric acid moiety and base can be removed in an aprotic solvent
Data Source
AI summary
To provide an excellent dimer amidite which can be subjected to purification, preferably, whose protective groups can be removed under mild conditions, and a method for synthesizing a nucleic acid using the dimer amidite, a dimer amidite having a structure represented by the following General Formula (1) and a method for synthesizing a nucleic acid including performing condensation reaction of the dimer amidite are provided:wherein in General Formula (1), R1 and R2 each independently represent any one of groups selected from General formulas (2) to (4) and Structural Formulas (12) to (15) with a compound where R1 and R2 are each represent Structural Formulas (12) being excluded: andwherein in the General Formulas (2) to (4), R3 represents any one group represented by the following Structural Formulas (16) to (25):