Peptide nucleic acids with a conformationally constrained chiral cyclohexyl-derived backbone

Journal article, 1997

Peptide nucleic acid (PNA) is an achiral nucleic acid mimic with a backbone consisting of partly flexible amino-ethyl glycine units. By replacing the aminoethyl portion of the backbone by an amino cyclohexyl moiety, either in the (S,S) or the (R,R) configuration, we have synthesized conformationally constrained PNA residues. PNA oligomers containing (S,S)-cyclohexyl residues were able to form hybrid complexes with DNA or RNA, with little effect on the thermal stability (Delta T-m = +/- 1 degrees C per (S,S) unit, depending on their number and the sequence). In contrast, incorporation of the (R,R) isomer resulted in a drastic decrease in the stability of the PNA-DNA (or RNA) complex (Delta T-m = -8 degrees C per (R,R) unit). In PNA-PNA duplexes, however, the (R,R)- and (S,S)-cyclohexyl residues only exerted a minor effect on the stability, and the complexes formed with the two isomers are of opposite handedness, as evidenced from circular dichroism spectroscopy. In some cases the introduction of a single (S,S) residue in a PNA 15-mer improves its sequence specificity for DNA or RNA. From the thermal stabilities and molecular modeling based on the solution structure of a PNA-DNA duplex determined by NMR techniques, we conclude that the right-handed helix can accommodate the (SIS) isomer more easily than the (R,R) isomer. Thermodynamic measurements of Delta H and Delta S upon PNA-DNA duplex formation show that the introduction of an (S,S)-cyclohexyl unit in the PNA does indeed decrease the entropy loss, indicating a more conformationally constrained structure. However, the more favorable entropic contribution is balanced by a reduced enthalpic gain, indicating that the structure constrained by the cyclohexyl group is not so well suited for DNA hybridization.