Synthesis of 4-substituted 1H-benzimidazole 2'-deoxyribonucleosides and utility of the 4-nitro compound as universal base

Abstract

The stereoselective synthesis of 4-substituted 1H-benzimidazole 2'-deoxyribonucleosides is described. Regioisomeric (N-1 and N-3) beta-D-deoxyribonucleosides 2a-c and 3a-c were formed. C-13-NMR Chemical shifts of the 1H-benzimidazole 2'-deoxy-beta-D-ribofuranosides were correlated with point charges of C-atoms as well as with Hammett constants of the exocyclic substituents. Phosphonate and phosphoramidite building blocks of 4-nitro-1H-benzimidazole 2'-deoxyribofuranoside (2a) were prepared (see 4a, b). Oligonucleotides of the d(A(20)) type were synthesized in which the two central dA bases were replaced by 4-nitro-1H-benzimidazole residues. They were hybridized with oligomeric dT and related oligomers having the other conventional bases opposite to the 4-nitro-1H-benzimidazole moieties. Within these duplexes (12 . 13, 12 . 14, 12 . 15, and 12 . 16), the destabilization was almost independent of the mismatch which is required for a universal base. The thermodynamic data indicate that the 4-nitro-1H-benzimidazole residues do not form H-bonds with opposite bases but are stabilizing the duplex by stacking interactions and favorable entropic changes.