Oligonucleotides Composed of 2′-Deoxy-1′,5′-anhydro-D-mannitol Nucleosides with a Purine Base Moiety

Article abstract of DOI:10.1021/jo9718511

2′-Deoxy-D-mannitol nucleosides with a purine base moiety have been conveniently synthesized starting from 1,5-anhydro-4,6-O-benzylidene-D-glucitol. The 3-OH function of 1,5-anhydro-4,6-O-benzylidene-D-glucitol was selectively protected with tert-butyldimethylsilyl group, and the 2′-OH function was subsequently converted to the corresponding O-triflate derivative for the introduction of the nucleobase moieties. These nucleoside derivatives were transformed to 1,5-anhydro-4-O-(P-(2-cyanoethyl)-P-(N,N-diisopropylamino)phosphinyl)-2-deoxy-6- O-monomethoxytrityl-3-O-(tert-butyldimethylsilyD-D-mannitol with either a 2-(N⁶-benzoyladenin-9-yl) or a 2-(N²-isobutyrylguanin-9-yl) substituent as the building blocks for oligonucleotide synthesis. The corresponding fully modified oligonucleotides afford considerably less stable duplexes with RNA as compared to the 3-deoxy hexitol nucleic acid analogues described previously. The reason for the lower stability was investigated using molecular modeling. MD simulations of single strand MNA(GCGTAGCG) and MNA(GCGTAGCG) complexed with RNA(CGCAUCGC) in aqueous solution were performed by use of AMBER 4.1 with the particle mesh Ewald (PME) method for the treatment of long-range electrostatic interactions. Frequent hydrogen bonds between the 3′-hydroxyl and the 6′-O of the phosphate backbone of the following base changed the conformation of the single strand as well as the MNA:RNA complex. The MNA:RNA backbone widens up and shows partial unwinding and disruption of base pair hydrogen bonds consistent with their low hybridization potential.