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

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Abstract

A novel synthetic route for the prepn. of sulfamide- and 3'-N-sulfamate-modified dinucleosides has been developed. The synthesis utilizes 4-nitrophenyl chlorosulfate to prep. 4-nitrophenyl 3'- or 5'-sulfamates, which couple smoothly with the alc. 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. While both modifications result in a shift in the conformational equil. 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 modifications into the DNA sequence d(GCGT10GCG) allowed the duplex melting temp. to be detd. using UV thermal denaturation expts. This reveals that the sulfamide modification significantly destabilizes duplexes with both complementary DNA and RNA. However, the 3'-N-sulfamate modification has little effect on duplex stability and even stabilizes DNA duplexes at low salt concn. 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.

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Oligonucleotides Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (dimers synthesis and nucleic-acid binding properties of sulfamide and N-sulfamate-modified DNA) Conformation (synthesis and nucleic-acid binding properties of sulfamide and N-sulfamate-modified DNA) DNA RNA Role: SPN (Synthetic preparation), PREP (Preparation) (synthesis and nucleic-acid binding properties of sulfamide and N-sulfamate-modified DNA)

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