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Dual modifications (base and sugar) in siRNA have the potential to overcome off-target effects and impart nuclease resistance.Here we present the synthesis and detailed structural analysis of N 3 -methyluridine and 2'-alkoxy/fluoro-N 3 -methyluridine modifications, the rationally designed modifications for oligonucleotide therapeutics. Using X-ray crystallography and 1 H NMR spectral data, it is clear that the C2'-endo conformation of N 3methyluridine switches to the C3'-endo pucker state preferentially due to the introduction of electron-withdrawing 2'-alkoxy or fluoro substituents. DFT study confirms that the modifications preferentially acquire the C3'-endo conformation. NBO analysis indicates that in the presence of the 2'-alkoxy/fluoro substituents, the C3'-endo conformation is stabilized due to n O4' !σ* C1'-N1 anomeric as well as σ C3'-H !σ* C2'-R and σ C1'-C2' !σ* C3'-OH hyperconjugation effects. The WÀ C hydrogen bond energies of the modified nucleosides were calculated using the DFT and SAPT methods at the modified base pair regions, and it was observed that one of the hydrogen bonds gets disrupted due to the presence of the N 3 -methyl group, causing significant decline in hydrogen bond energy. These detailed structural studies will help to expand the scope of these destabilizing modifications in the rational design of RNAi-based therapeutics.

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