High physiological thermal triplex stability optimization of twisted intercalating nucleic acids (TINA)

Abstract

The structure of the monomer (R)-1-O-[4-(1-pyrenylethynyl)phenylmethyl]glycerol (1) in twisted intercalating nucleic acids (TINA) was optimized for stabilizing interactions between the intercalator and surrounding nucleobases when used as a triplex forming oligonucleotide (TFO). Enhancement of π–π interactions with nucleobases of the TFO was achieved by increasing the aromatic surface using the (R)-1-O-[4-(1-pyrenylethynyl)naphthylmethyl]glycerol monomer (2). Bulge insertion of 2 in the middle of a Hoogsteen-type triplex increased the triplex thermal stability, ΔT_m = +2.0 °C compared with 1 at pH 7.2. Syntheses and thermal denaturation studies of triplexes and duplexes are described for three novel TINA monomers. The influence of π–π interactions, link length and the positioning of the ether in the linker in the TINA derivatives are described.