Synthesis and Properties of Oligonucleotides Containing LNA-Sulfamate and Sulfamide Backbone Linkages

Belma Zengin Kurt, Debashis Dhara, Afaf H. El-Sagheer and Tom Brown. Org. Lett 26 (19), 4137-4141, 2024.

oligonucleotides containing LNA-O3'?N5' sulfamate-LNA and DNA-N3'?N5' sulfamide-LNA linkages were synthesized using a standard solid-phase dinucleotide phosphoramidite strategy. The method could potentially be carried out on a large scale. These new backbone modifications, particularly LNA-O3'?N5' sulfamate-LNA, hybridize to complementary RNA with high affinity and show strong resistance to enzymatic degradation.


Oligonucleotides hold great promise as therapeutic agents but poor bioavailability limits their utility. Hence, new analogues with improved cell uptake are urgently needed. Here, we report the synthesis and physical study of reduced-charge oligonucleotides containing artificial LNA-sulfamate and sulfamide linkages combined with 2?-O-methyl sugars and phosphorothioate backbones. These oligonucleotides have high affinity for RNA and excellent nuclease resistance.