Synthesis of novel peptide nucleic acids carrying hydrophilic side-chain and their properties

Abstract

Three different conformationally constraint peptide nucleic acids (cPNA) have been synthesized. These cPNA are DNA mimics in which the entire deoxyribose phosphate is replaced with L-and D-serylproline or deoxyglycylproline dipeptide units bearing thymine as nucleobase at C-4 position. Their rigid backbones were derived from”cis-D” or (2R,4R)absolute stereochemistry on proline ring alternating with D or L serine or aminoethyl spacers with the aim to improve water solubility of the resulting cPNA. thymine by Mitsunobu reaction followed by coupling with the spacer moiety. The serine spacer were introduced as Fmoc-Ser(OtBu)-OH which could be directly coupled to the intermediate by DCC coupling whereas the deoxyglycyl spacer was introduced by alkylation of the intermediate with activated aziridine. Oligomerization of the cPNA up to 10-mers were achieved by solid phase peptide synthesis methodology employing Fmoc/OtBu fragment coupling strategy using pentafluorophenyl ester or HBTU activation. Preliminary binding stability of these cPNA toward fiuorescence labelled oligoadenylic acid F(dA10) were studied by gel electrophoresis. Lacking of binding of all cPNA oligomers was observed even at high PNA concentration.