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Synthesis and nucleic-acid-binding properties of sulfamide- and 3'-N-sulfamate-modified DNA

Fettes, Kevin J. and Howard, Nigel and Hickman, David T. and Adah, Steven and Player, Mark R. and Torrence, Paul F. and Micklefield, Jason (2002) Synthesis and nucleic-acid-binding properties of sulfamide- and 3'-N-sulfamate-modified DNA. Journal of the Chemical Society - Perkin Transactions 1 (4). pp. 485-495. ISSN 1364-5463


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Publisher’s or external URL: http://dx.doi.org/10.1039/b110603c


A novel synthetic route for the preparation of sulfamide- and 3'-N-sulfamate-modified dinucleosides has been developed. The synthesis utilises 4-nitrophenyl chlorosulfate to prepare 4-nitrophenyl 3'- or 5'-sulfamates (e.g., 18 and 27), which couple smoothly with the alcohol or amine functionalities of other nucleosides. The conformational properties of the sulfamide- and 3'-N-sulfamate-modified dinucleosides d(TnsnT) and d(TnsoT) were compared with the native dinucleotide d(TpT) using NMR and CD spectroscopy. Whilst both modi cations result in a shift in the conformational equilibrium of the 5'-terminal ribose rings from C2'-endo to a preferred C3'-endo conformation, only the 3'-N-sulfamate-modified dimer exhibits an increased propensity to adopt a base-stacked helical conformation. Incorporation of the sulfamide- and 3'-N-sulfamate modi cations into the DNA sequence d(GCGT(10)GCG) allowed the duplex melting temperature to be determined using UV thermal denaturation experiments. This reveals that the sulfamide modi cation significantly destabilises duplexes with both complementary DNA and RNA. However, the 3'-N-sulfamate modi cation has little effect on duplex stability and even stabilises DNA duplexes at low salt concentration. These results indicate that the 3'-N-sulfamate group is one of the most promising neutral replacements of the phosphodiester group in nucleic acids, that have been developed to date, for therapeutic and other important applications.

Item Type: Article
ID number or DOI: 10.1039/b110603c
Keywords: aminolysis; conformational-analysis; duplex stability; in-vitro; monophosphates; oligonucleotide; phosphodiester linkage; replacement; RNA; THERAPEUTICS
Subjects: Q Science > QD Chemistry
NAU Depositing Author Academic Status: Faculty/Staff
Department/Unit: College of Engineering, Forestry, and Natural Science > Chemistry and Biochemistry
Date Deposited: 09 Mar 2016 01:01
URI: http://openknowledge.nau.edu/id/eprint/987

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