Chiral analogues of peptide nucleic acids: synthesis of 4-aminoprolyl nucleic acids and DNA complementation studies using UV/CD spectroscopy

Abstract

This paper describes chemical synthesis of prolyl PNAs which are a class of conformationally constrained chiral PNA analogues. The monomers are derived from bridging the ethylenediamine and glycine components of the same unit which leads to PNA based on 4-aminoproline backbone with chirality at C-4 and C-2. The modified monomers corresponding to D-trans and L-trans prolyl-T have been incorporated into standard PNA chains, both at the N-terminus and in the interior to generate chiral PNAs. The complementation studies with DNA employing temperature dependent UV spectroscopy indicated that the chiral modifications in PNA:DNA duplexes imparted both stability and orientational preferences. CD spectral studies of chiral PNA:DNA duplexes suggest that the D-trans antiparallel duplexes have the B-DNA conformation while L-trans PNA:DNA duplexes show departure from B-DNA geometry. Thus, inclusion of even a single backbone constrained, distended chiral monomeric unit such as 4-aminoproline into an achiral PNA chain, either at the N-terminus or in the interior, leads to stabilization of the PNA:DNA hybrid. The linking of a polycation such as spermine at the C-terminus of chiral PNA further enhances the thermal stability of duplexes.