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Peptide Nucleic Acids with a Conformationally Constrained Chiral Cyclohexyl‐Derived Backbone
Author(s) -
Lagriffoule Pierre,
Eriksson Magdalena,
Jensen Kristine Kilså,
Nielsen Peter E.,
Wittung Pernilla,
Nordén Bengt,
Buchardt Ole
Publication year - 1997
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.19970030613
Subject(s) - chemistry , circular dichroism , nucleic acid , peptide nucleic acid , stereochemistry , dna , rna , moiety , duplex (building) , residue (chemistry) , nucleic acid analogue , peptide , helix (gastropod) , crystallography , nucleic acid thermodynamics , biochemistry , base sequence , gene , ecology , biology , snail
Peptide nucleic acid (PNA) is an achiral nucleic acid mimic with a backbone consisting of partly flexible aminoethyl 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 ( T m = 1°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 ( T m = −8°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 ( S, S ) isomer more easily than the ( R, R ) isomer. Thermodynamic measurements of H and 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.