The challenge of peptide nucleic acid synthesis

Abstract

The main strategies for the synthesis of Peptide Nucleic Acids (PNAs): key molecules as DNA/RNA mimics that can hybridize complementary chains of nucleic acids with high affinity and specificity.

A safety-catch protecting group strategy compatible with Boc-chemistry for the synthesis of peptide nucleic acids (PNAs)

“…The protected PNA monomers were prepared following the most widely used protocol in the literature. 6 It consists of a convergent synthetic scheme in which the two moieties, i.e. , the protected aminoethylglycine backbone and the protected nucleobase acetic acid derivative, are synthesized independently and then made to react to obtain the final PNA monomer.…”

“…The protected PNA monomers were prepared following the most widely used protocol in the literature. 6 It consists of a convergent synthetic scheme in which the two moieties, i.e., the protected aminoethylglycine backbone and the protected nucleobase acetic acid derivative, are synthesized independently and then made to react to obtain the final PNA monomer. Thus, Boc-N-2-aminoethylglycine with the carboxylic group protected as ester and the nucleobases acetic acid (N 6 -Msz-adenine-9-yl)acetic acid ( 4) and (N 4 -Msz-cytosine-1-yl)acetic acid (5) were synthesized.…”

“…Although PNAs are analogues of oligonucleotides, they are prepared following a Solid-Phase Synthesis (SPS) strategy similar to that used for peptides. 6 In this regard, two temporary protecting groups for the amino terminal of the PNA monomer are mainly used, namely the tert -butyloxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. One of the main challenges in PNA SPS is the aggregation of the PNA chain during their elongation, which jeopardizes their synthesis.…”

Triplex-forming peptide nucleic acids as emerging ligands to modulate structure and function of complex RNAs

“…10). 95 Assembling of PNA oligomers consists of standard solid phase synthesis steps: attaching of monomer to the growing chain of PNA using carboxylic acid activating reagents such as HATU, optional capping of unreacted amino groups by acetylation, and removal of the Fmoc protection. PNA monomers with the canonical nucleobases and unmodified aminoethylglycine (AEG) backbone are commercially available, but monomers carrying modified nucleobases for triplex-forming PNAs (as shown throughout the article) need to be custom synthesized from AEG backbone and the corresponding carboxylic acid derivatives (as exemplified for M in Fig.…”

Reflections on a Copenhagen–Minneapolis Axis in Bioorganic Chemistry

“…It was hoped that well-defined PNA sequences could hybridize with each other or with single-stranded DNA or RNA partners, in a highly specific manner dictated by the classical Watson–Crick complementarity of the bases. Indeed, this plan came to fruition in the laboratory, as described in the foundational studies from Copenhagen [ 179 , 181 , 182 , 183 , 184 , 185 , 186 ] and has been summarized most recently in a review by Albericio and coworkers [ 187 ].…”