Indole in DNA: Comparison of a Nucleosidic with a Non-Nucleosidic DNA Base Substitution

The synthetic incorporation of indole as an artificial DNA base into oligonucleotides by two different structural approaches is described. For both types of modification, the indole moiety is attached through the C-3 position to the oligbnucleotides. As a mimic of natural nucleosides, the indole nucleoside of beta-2'-deoxyribofuranoside (In) was synthesized. The corresponding In-modified duplexes were compared with duplexes that contained the indole group connected through (S)-3-amino-1,2-propanediol as an acyclic linker between the phosphodiester bridges of the ohgonucleotides. This linker was tethered to the C-3 position of the indole heterocycle either directly (In) or by a carbamate function (In'). The melting temperatures of the corresponding indole-modified DNA duplexes were measured and compared. Interestingly, not only the In' and In modifications but also the natural-like In base surrogate destabilize the DNA duplex strongly. This result supports our approach to apply the acyclic glycol linker to incorporate aromatic molecules as artificial DNA base substitutions. The major advantage of acyclic glycol linkers [such as the applied (S)-3-amino-1,2-propanediol] is that the corresponding modifications are synthetically more easily and readily accessible, as it avoids the preparation of the nucleosidic bond and the separation and purification of the alpha- and beta-anomers. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)