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Synthesis of 5‐(1,2,3‐Triazol‐4‐yl)‐2′‐deoxyuridines by a Click Chemistry Approach: Stacking of Triazoles in the Major Groove Gives Increased Nucleic Acid Duplex Stability
Author(s) -
Kočalka Petr,
Andersen Nicolai K.,
Jensen Frank,
Nielsen Poul
Publication year - 2007
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700410
Subject(s) - click chemistry , phosphoramidite , stacking , duplex (building) , chemistry , oligonucleotide , nucleic acid , deoxyuridine , dna , triazole , uracil , combinatorial chemistry , alkyl , stereochemistry , crystallography , organic chemistry , biochemistry
A general protocol for converting alkyl and aryl halides into azides and for converting these in situ into 1,4‐disubstituted triazoles was applied with 5‐ethynyl‐2′‐deoxyuridine. This afforded three modified 2′‐deoxyuridine analogues with either unsubstituted or 1‐phenyl‐/1‐benzyl‐substituted triazoles in their 5‐positions. Modelling demonstrates coplanarity of the two heteroaromatic rings, and UV spectroscopy showed the uracil p K a values to be almost unchanged. The three nucleosides were introduced into nonamer oligonucleotides by phosphoramidite chemistry. The heteroaromatic triazoles became positioned in the major grooves of the short dsDNA and DNA–RNA duplexes. While single modifications led to decreased duplex stability, the stacking of four consecutive modifications led to enhanced duplex stability, especially for DNA–RNA duplexes. The duplex structures were studied by CD spectroscopy and molecular dynamics simulations, which supported the conjecture that the duplex stabilizing effect is due to efficient stacking of the heteroaromatic triazoles.