Solid phase synthesis of a metronidazole oligonucleotide conjugate

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Bioconjugation

Background:

• Oligonucleotide conjugates are promising therapeutic agents.
• Metronidazole is a widely used antibiotic.
• Developing efficient synthesis methods for drug-oligonucleotide conjugates is crucial.

Purpose of the Study:

• To develop a direct, solid-phase synthesis method for an oligonucleotide-metronidazole conjugate.
• To identify mild deprotection and cleavage conditions that preserve the integrity of metronidazole.

Main Methods:

• Solid-phase synthesis using the phosphoramidite method.
• Utilized controlled pore glass (CPG) as the solid support.
• Tested mild conditions (20% Et(3)N in pyridine, then conc. NH(3) (aq) at rt for 30 min) for deprotection and cleavage.

Main Results:

• Successful direct, solid-phase synthesis of the oligonucleotide-metronidazole conjugate.
• Mild conditions effectively removed protecting groups and cleaved the conjugate from the CPG support.
• Standard conditions (conc. NH(3) (aq) at 55°C for 16 h) resulted in cleavage of the metronidazole drug.

Conclusions:

• A robust method for synthesizing metronidazole-oligonucleotide conjugates via solid-phase synthesis has been established.
• Mild deprotection and cleavage conditions are essential to prevent drug degradation.
• This method facilitates the development of novel antibiotic-oligonucleotide therapeutics.