Synthesis of peptide nucleic acid containing aminoethyl linkers

Abstract

A general synthetic method for monomers of Peptide Nucleic Acid (PNA) containing aminoethyl linkers has been developed. These monomers will be used for the synthesis of a PNA system whereby the entire deoxyribose phosphate was replaced by a deoxyglycyl proline dipeptide unit. The proline ring is modified by nucleobases (adenine, thymine, cytosine and guanine) at C-4 position in a cis- and trans-relationship to the carbonyl group which afforded from “cis-D” or (2R, 4S), “trans-L” or (2R, 4S), “trans-D” or (2R, 4S) and “trans-L” or (2S, 4R) absolute stereochemistry on the proline ring. The key reaction is the coupling of proline derivatives and aminoacetaldehyde by reductive alkylation. The reaction condition is simple and provides higher yields than the previously reported methods. Oligomerization of the PNAs up to 10-mers was achieved by solid phase peptide synthesis methodology employing Fmoc fragment coupling strategy and pentafluorophenyl ester activation. Preliminary binding stability of these oligoPNA with nucleic acids suggested that the homothymine decamer PNAs of “cis” isomers binds to poly (adenylic acid) (RNA) with high affinity, whereas no binding to the corresponding poly (deoxyadenylic acid) (DNA) was observed. On the other hand, the “trans” isomers failed to form stable hybrid with poly (adenylic acid) but one of it formed a rather unstable PNADNA hybrid.