Twisted Intercalating Nucleic Acids – Intercalator Influence on Parallel Triplex Stabilities

Abstract

Abstract Phosphoramidites of several new twisted intercalating nucleic acid (TINA) monomers and the previously discovered ( R )‐1‐ O ‐[4‐(1‐pyrenylethynyl)phenylmethyl]glycerol ( 1 ) were synthesized and used in DNA synthesis. Stabilization of Hoogsteen‐type triplexes was observed in cases of insertion of the novel ( R )‐1‐ O ‐[3‐(naphthalen‐1‐ylethynyl)phenylmethyl]glycerol ( 2 ) as a bulge into homopyrimidine oligodeoxynucleotides (ONs), whereas phenylethynyl and 4‐(biphenylylethynyl) derivatives of TINAs resulted in destabilization of parallel triplexes relative to the wild‐type triplex. It was concluded that TINA monomers should possess at least two fused phenyl rings attached through the triple bond at the 4‐position of bulged ( R )‐1‐ O ‐(phenylmethyl)glycerol in homopyrimidine ONs in order to stabilize parallel triplexes. Slight destabilization of DNA/DNA Watson–Crick type duplexes (Δ T m = 1.0–4.5 °C) was detected for 2 inserted as a bulge, while RNA/DNA duplexes and duplexes with other TINA analogues were considerably destabilized (Δ T m > 6.0 °C). In cases of double insertion of 1 opposite to base inversions in dsDNA, the thermal stabilities of the triplexes were higher than that of the wild‐type triplex, which is a new solution to overcome the problem of targeting homopurine stretches with single base pair inversions. A DNA three‐way junction was considerably stabilized (Δ T m in a range of 10.0–15.5 °C) upon insertion of TINA monomers in the junction point as a bulge. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)