Synthesis of peptide nucleic acids (PNA) by submonomer solid-phase synthesis

Abstract: A simple, versatile method for the synthesis of Peptide Nucleic Acids (PNA) from readily available building blocks has been developed. The approach is based on submonomer solid phase synthesis and allows for the structural variation of both the backbone and the nucleobase idechain. The efficiency of the method was demonstrated by the synthesis of PNA oligomers in high purity and good yields. Peptide Nucleic Acids (PNA), oligonucleotide analogs with an achiral { oligo-N-(2-aminoethylglycine)} backbone, have been shown to specifically recognize the complementary sequence of oligonucleotide oligomers. 1 Moreover, PNA/oligonucleotide hybrids are thermally more stable than the corresponding DNA (or RNA) hybrids, 2 and they should possess increased biological stability. 3 Therefore, PNA molecules have potential for the development of gene-targeting pharmaceuticals nd as antagonists for proteins that recognize DNA. 4 In this communication, we describe a simple and highly versatile method for the synthesis of PNA oligomers. Using a "submonomer " approach, 5 PNA molecules were synthesized on polystyrene r sin from inexpensive precursors like bromoacetic acid, a protected ethylenediamine (e.g., 4-methoxybenzyloxycarbonyl (Moz)- ethylenediamine), and a nucleobase derivative (e.g., 1-carboxymethyl-thymine; 6 Scheme 1). In contrast to the original approach for the synthesis of PNA oligomers, 1 the solution-phase ynthesis of N-protected