Synthesis of abasic locked nucleic acid and two seco-LNA derivatives and evaluation of their hybridization properties compared with their more flexible DNA counterparts

To investigate the structural basis of the unique hybridization properties of LNA (locked nucleic acid)(1) three novel LNA derivatives with modified c arbohydrate parts were synthesized and evaluated with respect to duplex sta bilities. The abasic LNA monomer(2) (XL, Figure 1) with the rigid carbohydr ate moiety of LNA but no nucleobase attached showed no enhanced duplex stab ilities compared to its more flexible abasic DNA counterpart (X, Figure 1). These results suggest that the exceptional hybridization properties of LNA primarily originate from improved intrastrand nucleobase stacking and not backbone preorganization. Two monocyclic seco-LNA derivatives, obtained by cleavage of the C1'-O4' bond of an LNA monomer or complete removal of the O 4'-furanose oxygen atom (Z(L) and dZ(L), respectively, Figure 1), were comp ared to their acyclic DNA counterpart(3) (Z, Figure 1). Even though they ar e more constrained than Z, the seco-LNA derivatives ZL and dZL destabilize duplex formation even more than the flexible seco-DNA monomer Z.