Chapter 8 - Chiral Acyclic PNA Modifications: Synthesis and Properties

Abstract

Abstract The introductory section of the review will contain the description of a relatively new class of artificial biopolymers – polyamide nucleic acid (PNA) mimics. Their characteristic structural features and the most significant properties will be discussed. A particular focus will be on chiral PNA modifications, since the presence of a chiral center determines PNA preorganization and side-residue functional groups may impart new favorable properties to such molecules. In the main section , synthesis and physicochemical studies of modified chiral PNAs containing various substituents in α- and γ-positions of the pseudopeptide backbone, which can be based on various amino acids – Ala, Arg, Lys, Cys, Asp, Glu, and Ser – will be presented. Phosphonate and fluorescent modifications of the Lys-derived backbones as well as –OSO 3 H and mini-polyethylene glycol (PEG) modifications of the Ser-derived PNAs will be considered. In the section on PNA monomer synthesis , methods for obtaining initial pseudopeptide fragments will be overviewed. Two main approaches will be compared (and probably summarized in a table): (1) condensation of the pseudopeptide with carboxymethylated derivatives of the protected heterocyclic bases; (2) conversion of the pseudopeptide to the corresponding bromo(chloro)acyl derivative with subsequent alkylation of the protected (or unprotected) heterocycle and the introduction of an appropriate protecting group if necessary. The protecting group strategies used in the synthesis of chiral PNAs will also be described. Finally, investigation of the regioselective alkylation of the heterocycle base derivatives in PNA monomer synthesis by means of nuclear magnetic resonance (NMR) spectroscopy will be reviewed. A special subsection will be devoted to the determination of the enantiomer purity of the monomers by direct and indirect chromatographic and spectral methods. The section on the synthesis of chiral PNA oligomers will summarize modern protocols of solid-phase synthesis, including the submonomer strategy, and the approaches to minimization of racemization. Methods for the determination of oligomer optical purity and the investigation of oligomer chirality (preorganization) by means of NMR and circular dichroism (CD) spectroscopy will be discussed. Hybridization and some other physicochemical properties of chiral PNAs will be analyzed and compared with those of achiral PNAs and other oligonucleotide analogues. Literature data on biological activity of various PNAs (eg, Lys- and Arg-derived) will also be presented if available. The conclusive section will contain a resume of the comparative analysis of the literature data and our view on the prospects of using acyclic chiral PNA modifications in biology and medicine.