Synthesis and solution structures of new chiral enantiomeric peptide nucleic acid (PNA) dimers

Abstract

The quest to develop new drug therapies based on sequence specific interactions between complementary nucleic acids is an exciting and rapidly growing field of chemical research. In the early 1990s’, Nielsen’s group prepared the first (peptide nucleic acid) PNA oligomer [1], which has an achiral, uncharged pseudopeptide backbone consisting of N-(2-aminoethyl) glycine units while the nucleobases are attached to the glycine nitrogens via methylene carbonyl linkers. Since then. many modified PNAs have been synthesized. In most cases, PNAs were constructed with lysine at the C-terminal of the oligomers, which was designed to improve the solubility of the whole molecule or avoid selfaggregation. Since lysine is a natural amino acid and readily available commercially, we wanted to synthesize a new type of PNA molecule, with lysine as the main chain unit and the nucleobases attached through carbonyl methylene group to the α-NH2 of the amino acids (fig. 1). Although such a structure will separate the adjacent bases by seven bonds and the distances between the bases and the main chain would be three bonds, both one bond more than the natural DNA and PNA designed by Nielsen, we thought that the long aliphatic lysine side chain might make the molecule more flexible. It could thus accommodate itself to a suitable spatial distance when hybridizing to complementary oligonucleotides. Also, we expected the four methylene groups in the backbone unit to give the whole oligomer some hydrophobicity, which, together with the hydrophilic characteristics of lysine itself, may facilate cellular uptake. Although only the D-lysine series (Ib) are supposed to mimic natural oligonucleotides in regard to configuration, the more readily available and inexpensive L-lysine series (Ia) was also investigated. In order to check whether the designed oligomer has the ability to adopt a less extended conformation when hybridizing, we synthesized the corresponding dimers and studied the solution conformations based on the results of 2D-NMR (NOESY) and molecular simulation.