Molecular construction of sulfonamide antisense oligonucleotides

Korotkovs, Valerijs and Reichenbach, Linus F. and Pescheteau, Clémentine and Burley, Glenn A. and Liskamp, Rob M. J. (2019) Molecular construction of sulfonamide antisense oligonucleotides. Journal of Organic Chemistry, 84 (17). pp. 10635-10648. ISSN 0022-3263 (https://doi.org/10.1021/acs.joc.9b00941)

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Abstract

An efficient and scalable synthesis of new oligonucleotide monomers was developed for replacement of the phosphodiester backbone of RNA by a sulfonamide-containing backbone to enable construction of sulfonamide antisense oligonucleotides (SaASOs). It was shown that by employing these sulfonamide RNA (SaRNA) monomers, it was possible to synthesize oligomers in solution. The properties of a sulfonamide moiety replacement were evaluated by incorporation of a SaRNA-monomer into a DNA strand and performing thermal stability tests of the resulting DNA and RNA-double-strand hybrids. Although sulfonamide modification caused a decrease in melting temperature (Tm) of both hybrids, it was lower for the sulfonamide-containing DNA–RNA hybrid than that for the sulfonamide-containing DNA–DNA hybrid.

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