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Highly efficient solid phase synthesis of oligonucleotide analogs containing phosphorodithioate linkages
D C Capaldi1, D L Cole, V T Ravikumar
1Isis Pharmaceuticals, 2292 Faraday Avenue, Carlsbad, CA 92008, USA.
Nucleic Acids Research
|April 11, 2000
Summary
A new triester method enables the synthesis of deoxynucleoside phosphorodithioate dimers using a novel reagent. This method efficiently creates phosphorodithioate diesters, demonstrated by synthesizing a DNA strand with alternating linkages.
Area of Science:
- Organic Chemistry
- Nucleic Acid Chemistry
- Synthetic Chemistry
Background:
- Phosphorothioate modifications are crucial in nucleic acid therapeutics.
- Existing methods for phosphorodithioate synthesis have limitations.
Purpose of the Study:
- To develop an efficient and clean triester method for synthesizing deoxynucleoside phosphorodithioate dimers.
- To introduce a novel dithiophosphorylating reagent for improved synthesis.
Main Methods:
- A new reagent, DPSE-SP(S)Cl(2) (2-diphenylmethylsilylethyl dithiophosphoryl chloride), was synthesized and utilized.
- The DPSE protecting group was rapidly removed using tetra-butylammonium fluoride.
- A penta-decathymidylic acid with alternating phosphorodithioate/phosphate linkages was synthesized to demonstrate utility.
Main Results:
- The novel reagent enabled the quantitative formation of phosphorodithioate diesters.
- The synthesized diesters were uncontaminated by phosphorothioates.
- The method successfully produced a DNA oligomer with alternating phosphorodithioate and phosphate linkages.
Conclusions:
- The described triester method provides a robust route for synthesizing deoxynucleoside phosphorodithioate dimers.
- The novel DPSE protecting group offers efficient deprotection, facilitating clean phosphorodithioate synthesis.
- This advancement has implications for the synthesis of modified oligonucleotides with potential therapeutic applications.