An Isocytidine Derivative with a 2‐Amino‐6‐methylpyridine Unit for Selective Recognition of the CG Interrupting Site in an Antiparallel Triplex DNA

Abstract

Sequence-specific recognition of duplex DNA mediated by triple helix formation offers a potential basis for oligonucleotide therapy and biotechnology. However, triplex formation is limited mostly to homopurine strands, due to poor stabilization at CG or TA base pairs in the target duplex DNA sequences. Several non-natural nucleosides have been designed for the recognition of CG or TA base pairs within an antiparallel triplex DNA. Nevertheless, problems including low selectivity and high dependence on the neighboring bases remain unsolved. We thus synthesized N(2)-arylmethyl isodC derivatives and incorporated them into triplex-forming oligonucleotides (TFOs) for the selective recognition of the CG base pair within antiparallel triplex DNA. It was shown that an isodC derivative bearing a 2-amino-6-methylpyridine moiety (AP-isodC) recognizes the CG base pair with high selectivity in antiparallel triplex DNA irrespective of the flanking base pairs.

Aminopyridinyl–Pseudodeoxycytidine Derivatives Selectively Stabilize Antiparallel Triplex DNA with Multiple CG Inversion Sites

“…The p K a values of Me AP‐ΨdC and AP‐ΨdC were determined to be 6.3 and 6.1, respectively (Figure S3). In our previous study, protonation to the 2‐aminopyridine unit of AP‐isodC, a related analogue with Me AP‐ΨdC, was supported by the fact that the triplex stability was greater at pH 6 than at pH 7.5 . Accordingly, we speculated that that the 2‐aminopyridine unit is protonated and interacts with the guanine base by hydrogen bonding (Figure ).…”

Development of Novel Functional Molecules Targeting DNA and RNA

“…49,50) A 2,5-diamino-3-methylpyridine unit ( Me AP) was first attempted in order to conjugate isocytidine (isodC) as an additional binding unit for the remote guanine base. 51,52) However, as the isodC derivative was unstable, a methylpyridine unit was introduced to the pseudocytosine base (ΨdC) [53][54][55] (Fig. 15).…”

Synthesis of 2′‐deoxy‐4‐aminopyridinylpseudocytidine Derivatives for Incorporation Into Triplex Forming Oligonucleotides

“…Therefore, it is desired to develop innovative artificial nucleic acid derivatives. Recently, we designed the novel iso‐dC derivatives for the recognition of the CG mismatch site based on the T/CG triplet structure (Okamura et al., , ). Based on the result of an NMR study, thymidine can form one hydrogen bond with the cytosine base within the CG base pair in the antiparallel triplex DNA formation.…”

“…However, there is an intrinsic limitation to the formation of the stable triplex DNA against the target duplex DNA sequence under physiological conditions. We have been studying the design and synthesis of the artificial nucleoside analogues for the recognition of the TA or CG inversion sites with a high selectivity and stability (Okamura, Taniguchi, & Sasaki, 2013, 2014. Recently, we found and reported that the TFOs containing novel C-nucleoside analogues, i.e., the 2 -deoxy-4-aminopyridinylpseudocytidine derivatives, formed the stable triplex DNA containing the CG inversion site with a high selectivity (Okamura, Taniguchi, & Sasaki, 2016;Wang, Taniguchi, Okamura, & Sasaki, 2017, 2018.…”