Triazolyl Donor/Acceptor Chromophore Decorated Unnatural Nucleosides and Oligonucleotides with Duplex Stability Comparable to That of a Natural Adenine/Thymine Pair

Abstract

We report the design and synthesis of triazolyl donor/acceptor unnatural nucleosides via click chemistry and studies on the duplex stabilization of DNA containing two such new nucleosides. The observed duplex stabilization among the self-pair/heteropair has been found to be comparable to that of a natural A/T pair. Our observations on the comparable duplex stabilization has been explained on the basis of possible π-π stacking and/or charge transfer interactions between the pairing partners. The evidence of ground-state charge transfer complexation came from the UV-vis spectra and the static quenching of fluorescence in a heteropair. We have also exploited one of our unnatural DNAs in stabilizing abasic DNA.

Design, Synthesis and Photophysical Property of a Doubly Widened Fused‐Triazolyl‐Phenanthrene Unnatural Nucleoside

“…Thus, the β‐configuration was established via NOESY spectra of FTPhen nucleoside which showed a cross peak between H1′ ‐ H2′α and H1′ ‐ H4′. The β‐anomeric configuration was further confirmed from X‐ray single crystal structure analysis (Figure ) . The X‐ray single crystal analysis revealed that the unit cell of the fused triazolylphenanthrene nucleoside, FTPhen , contained four molecules with one H 2 O in the unit cell with space group P1, cell length, a=7.19, b=10.86, c=20.87 A; cell angles a=82.43, b=88.57, g=84.36 o and cell volume 1608.7 (Figure a‐b).…”

“…Electrostatic potentials mapped as colors on the surfaces showed its hydrophobic character with negative charge density onto the triazole ring indicating significantly less polar nucleoside. The triazolylphenanthrene unit in FTPhen is fully planar in contrary to our earlier reported base TPhen B Do . As the stacking propensity is the reflection of surface area and hydrophobicity of DNA bases and analogues, we calculated these parameters for FTPhen nucleoside .…”

“…Interactions among the unnatural donor‐acceptor nucleobases via charge transfer complexation, however, might have potential impact on DNA duplex stabilization. We, recently, explored the charge transfer (CT) interaction force as a new and efficient force to stabilize a DNA duplex by utilizing our newly designed triazolyl donor/acceptor nucleoside pair . In our previous design we mainly focused on tuning the photophysical property of the triazole linked donor/acceptor aromatics via copper(I)‐catalyzed azide‐alkyne cycloaddition reaction and establishing the CT force to stabilize a hetero duplex without much considering the size and shape mimicry.…”

“…Our results suggested that the triazolyl donor‐acceptor unnatural bases have good selectivity to form hetero‐pair and/or self‐pair via charge transfer and/or π‐stacking interactions. Thus, we are the first, to the best of our knowledge, to explore the possibility of unnatural hetero‐duplex stabilization via charge transfer along with π‐stacking interactions …”

“…The key intermediate 2‐ethynyl‐1,1′‐biphenyl ( 8 ) was synthesized from commercially available 2‐bromoaniline 3 following the route shown in Scheme . On the other hand, the other key intermediate bis‐toluolyl‐1‐azido‐2‐deoxy‐β‐D‐ribofuranose ( 9 a ) was synthesized following our earlier reported protocol . Finally, Cu(I)‐catalysed Husigen azide‐alkyne cycloaddition reaction between β‐azidosugar 9 a and 2‐ethynyl‐1,1′‐biphenyl ( 8 ) yielded the intermediate 5‐iodo‐4‐biphenyl triazolyl nucleoside R in diprotected form which upon treatment with Pd(OAc) 2 generated the desired fused triazolylphenanthrene nucleoside 10 in diprotected form in 68% yield in the same reaction pot (Scheme ) .…”