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Improvements in automated PNA synthesis using Boc/Z monomers
T Koch1, H F Hansen, P Andersen
1PNA Diagnostics A/S, Copenhagen, Denmark.
Summary
An optimized automated protocol for peptide nucleic acid (PNA) synthesis achieves approximately 90% yield for a 17-mer PNA. This efficient method utilizes specific reagents and conditions for high coupling efficiency in automated PNA synthesis.
Area of Science:
- Organic Chemistry
- Biotechnology
- Medicinal Chemistry
Background:
- Automated synthesis of peptide nucleic acids (PNAs) is crucial for developing novel therapeutic agents and research tools.
- Existing PNA synthesis protocols may suffer from suboptimal yields and efficiency, necessitating optimization.
- The Boc/Z strategy offers a robust framework for PNA assembly.
Purpose of the Study:
- To report an optimized automated protocol for PNA synthesis.
- To achieve high product yield and coupling efficiency in automated PNA synthesis.
- To demonstrate the scalability of the developed protocol.
Main Methods:
- Utilized a Boc/Z synthesis strategy with in situ neutralization of the deprotected amine.
- Employed molar excess of monomers activated with HATU for 60 s prior to resin delivery.
- Maintained activated monomer concentration at 0.08 M during couplings, employing heteroselective solvation.
- Incorporated acetic anhydride as a capping reagent followed by a piperidine wash.
Main Results:
- Achieved approximately 90% product yield for a test 17-mer PNA under optimal conditions.
- Obtained an average coupling yield of 99.4%, indicating high efficiency.
- Demonstrated the protocol's applicability from 5 mumol scale up to 10-50 mumol scale on an ABI 433A automated synthesizer.
Conclusions:
- The reported automated PNA synthesis protocol is highly efficient and optimized.
- The protocol enables high-yield synthesis of PNAs with excellent coupling efficiency.
- The method is scalable, making it suitable for various research and development applications in PNA chemistry.