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Issue 1, 2004
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NMR and UV studies of 3′-S-phosphorothiolate modified DNA in a DNA : RNA hybrid dodecamer duplex; implications for antisense drug design

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Abstract

High-resolution NMR spectroscopy has been used to establish the conformational consequences of the introduction of a single 3′-S-phosphorothiolate link in the DNA strand of a DNA : RNA hybrid. These systems are of interest as potential antisense therapeutic agents. Previous studies on similarly modified dinucleotides have shown that the conformation of the sugar to which the sulfur is attached shifts to the north (C3′-endo/C2′-exo). Comparisons made between NOESY cross-peak intensities, and coupling constants from PE-COSY spectra, for both non-modified and modified duplexes confirm that this conformational shift is also present in the double helical oligonucleotide system. In addition it is noted that in both the dinucleotides and the modified duplex, the conformation of the sugar ring 3′ to the site of modification is also shifted to the north. That this pattern is observed in the small monomeric system as well as the larger double helix is suggestive of some pre-ordering of the sequences. The conclusion is supported by consideration of the 1H chemical shifts of the heterocyclic bases near the site of the modification. The enhanced stability that these conformational changes should bring was confirmed by UV thermal melting studies. Subsequently a series of singly and doubly 3′-S-phosphorothiolate-modified duplexes were investigated by UV. The results are indicative of an additive effect of the modification with thermodynamic benefit being derived from alternate spacing of two modified linkers.

Graphical abstract: NMR and UV studies of 3′-S-phosphorothiolate modified DNA in a DNA : RNA hybrid dodecamer duplex; implications for antisense drug design

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Supplementary files

Article information


Submitted
26 Sep 2003
Accepted
05 Nov 2003
First published
20 Nov 2003

Org. Biomol. Chem., 2004,2, 114-119
Article type
Paper

NMR and UV studies of 3′-S-phosphorothiolate modified DNA in a DNA : RNA hybrid dodecamer duplex; implications for antisense drug design

A. P. G. Beevers, K. J. Fettes, G. Sabbagh, F. K. Murad, J. R. P. Arnold, R. Cosstick and J. Fisher, Org. Biomol. Chem., 2004, 2, 114
DOI: 10.1039/B311923H

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