Synthesis and biophysical evaluation of 3′-Me-α-l-LNA – Substitution in the minor groove of α-l-LNA duplexes

The synthesis and biophysical evaluation of 3′-Me-α-l-LNA is reported. The synthesis of the nucleoside building block phosphoramidite was accomplished starting from diacetone glucose. The 3′-Me group was introduced in the desired configuration by hydride mediated opening of an exocyclic epoxide. Inversion of the 2′-hydroxyl group was achieved by means of an oxidation/reduction sequence followed by cyclization onto a 5′-leaving group to assemble the [2.2.1] ring system. Biophysical evaluation of 3′-Me-α-l-LNA modified oligonucleotides showed good duplex thermal stabilizing properties which were similar to α-l-LNA. Mismatch discrimination experiments revealed that 3′-Me-α-l-LNA possess slightly enhanced discrimination properties for the GU wobble base-pair as compared to related nucleic acid analogs.

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