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Antisense pro-drugs: 5'-ester oligodeoxynucleotides

N N Polushin¹, J S Cohen

¹Cancer Pharmacology Section, Georgetown University Medical Center, Washington DC 20007.

Nucleic Acids Research

|December 11, 1994

Summary

Synthesizing lipophilic oligonucleotides for enhanced cellular uptake was challenging. A novel method using specific protecting groups and ethanolamine achieved successful synthesis of 5'-palmitoyl oligodeoxynucleotides.

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Area of Science:

Oligonucleotide synthesis
Medicinal chemistry
Drug delivery

Background:

Lipophilic oligonucleotides offer potential as antisense pro-drugs due to improved cellular uptake.
The ester bond linkage for lipophilic modification is susceptible to degradation during standard oligonucleotide deprotection methods.

Purpose of the Study:

To develop a robust synthesis strategy for 5 eal-ester oligonucleotides resistant to deprotection conditions.
To enable the efficient production of lipophilic oligodeoxynucleotides for potential therapeutic applications.

Main Methods:

Utilized base-labile tert-butylphenoxyacetyl amino protecting groups (t-BPA).
Employed an oxalyl-controlled pore glass (CPG) anchor group.
Developed a novel deprotection protocol using ethanolamine (EA) instead of aqueous ammonia.

Main Results:

Successfully synthesized 5 eal-palmitoyl oligodeoxynucleotides with good yields.
Demonstrated the stability of the 5 eal-ester linkage under the new deprotection conditions.
Overcame the lability issues associated with traditional oligonucleotide synthesis.

Conclusions:

The developed method provides a reliable route for synthesizing 5 eal-ester modified oligonucleotides.
This advancement facilitates the creation of novel antisense pro-drugs with enhanced delivery capabilities.
The combination of t-BPA protecting groups, oxalyl-CPG anchor, and EA deprotection is effective for lipophilic oligonucleotide synthesis.

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