Structural Preorganization of Peptide Nucleic Acids: Chiral Cationic Analogues with Five- or Six-Membered Ring Structures

Abstract

The advent of aminoethylglycyl peptide nucleic acids, aegPNAs, as strong and specific DNA/RNA binding agents has triggered much research activity directed towards the development of PNA-based antisense/antigene therapeutics. These efforts have mainly been directed towards further refinement of aegPNA properties such as water solubility, cellular uptake and discrimination between parallel and antiparallel binding modes. Introduction of chirality and also of positive/negative charges in the PNA backbone has met with some success in this direction. The conformational freedom in the nucleobase linker arm and in the backbone aminoethyl and glycyl segments in the aegPNA backbone were found to be causes of unfavourable entropic loss during complex formation. Suitable clamping in the aegPNA backbone may reduce entropic loss and help produce a conformation appropriate for maximum enthalpic benefits from nucleobase recognition. Introduction of constraint by means of five- or six-membered ring structures in the aegPNA and their contributions to maintaining the balance between rigidity and flexibility in the backbone have shown interesting effects on the overall stability of PNA-DNA/RNA complexes. This review presents an account of the literature in this direction. The significant promise of our approach, which makes use of the naturally occurring trans-4-hydroxy-L-proline to arrive at different chirally pure cyclic PNA analogues, is presented in this review, together with the DNA binding properties of the compounds. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)