OLIGONUCLEOTIDES COMPOSED OF 2'-DEOXY-1',5'-ANHYDRO-D-MANNITOL NUCLEOSIDES WITH A PURINE BASE MOIETY

2'-Deoxy-D-mannitol nucleosides with a purine base moiety have been co nveniently synthesized starting from 1,5-anhydro-4,6-O-benzylidene-D-g lucito The 3-OH function of 1,5-anhydro-4,6-O-benzylidene-D-glucitol w as selectively protected with tert-butyldimethylsilyl group, and the 2 '-OH function was subsequently converted to the corresponding O-trifla te derivative for the introduction of the nucleobase moieties. These n ucleoside derivatives were transformed to 1,5-anhydro-4-O-(P-(2 oxytri tyl-3-O-(tert-butyldimethylsilyl)-D-mannitol with either a 2-(N-6-benz oyladenin-9-yl) or a 2-(N-2-isobutyrylguanin-9-yl) substituent as the building blocks for oligonucleotide synthesis. The corresponding fully modified oligonucleotides afford considerably less stable duplexes wi th RNA as compared to the 3-deoxy hexitol nucleic acid analogues descr ibed previously, The reason for the lower stability was investigated u sing molecular modeling, MD simulations of single strand MNA(GCGTAGCG) and MNA(GCGTAGCG) complexed with RNA(CGCAUCGC) in aqueous solution we re performed by use of AMBER 4.1 with the particle mesh Ewald (PME) me thod for the treatment of long-range electrostatic interactions, Frequ ent hydrogen bonds between the 3'-hydroxyl and the 6'-O of the phospha te backbone of the following base changed the conformation of the sing le strand as well as the MNA:RNA complex. The MNA:RNA backbone widens up and shows partial unwinding and disruption of base pair hydrogen bo nds consistent with their low hybridization potential.