Tightly linked morpholino-nucleoside chimeras: new, compact cationic oligonucleotide analogues

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Organic Synthesis

Background:

• Native oligonucleotides possess a polyanionic phosphodiester backbone, leading to poor nuclease stability and low cellular uptake.
• These limitations hinder the effective biological application of native oligonucleotides.
• Backbone modifications, especially charge alterations, are key strategies for improving oligonucleotide properties.

Purpose of the Study:

• To synthesize and characterize novel oligonucleotide analogues with a modified backbone.
• To investigate the potential of these analogues for improved biological applications.

Main Methods:

• Synthesis of oligonucleotide analogues incorporating morpholino and ribo-/deoxyribonucleoside units.
• Utilizing a synthetic protocol compatible with standard protecting groups (trityl, dimethoxytrityl) and azido functionality.
• Extension of the protocol for the synthesis of higher oligomers (chimeras).

Main Results:

• Successful synthesis of new oligonucleotide analogues featuring a morpholino unit linked via a nucleoside's 5'-amino group.
• Demonstrated compatibility of the synthetic route with common protecting groups and azido functionality.
• Chimeric oligonucleotides exhibit positive charge in aqueous media due to the N-alkylated tertiary amine structure of the morpholino unit.

Conclusions:

• The novel oligonucleotide analogues present a positively charged backbone, potentially overcoming issues of nuclease sensitivity and cellular uptake.
• The developed synthetic strategy is versatile and allows for the creation of more complex chimeric structures.
• These modified oligonucleotides show promise for advancing oligonucleotide-based therapeutics and diagnostics.