Control of the Chirality and Helicity of Oligomers of Serinol Nucleic Acid (SNA) by Sequence Design

摘要

The construction of an artificial double helix that mimics natural DNA or RNA has been one of the most challenging endeavors in chemistry. Recently, Meggers and co-workers showed that even a simple acyclic propylene glycol with two carbon atoms in the main chain (see (S)-GNA in Figure 1) as a nucleobase tether could form a more stable duplex than that of native DNA or RNA. This pioneering work prompted us to synthesize a new foldamer with three carbon atoms in the main chain, acyclic threoninol nucleic acid (aTNA), from D-threoninol. We found that aTNA has the following properties: 1) duplex formation involves complementary pairing in an antiparallel fashion, as for natural DNA or RNA; 2) owing to the flexibility of the backbone, the single-stranded state does not adopt a characteristic preorganized structure; 3) the thermal stability of the duplex is far greater than that of the natural DNA or RNA duplex and even higher than that of the GNA duplex. Studies on aTNA as well as GNA and peptide nucleic acid (PNA) have confirmed that scaffold rigidity is not a prerequisite for stable duplex formation as previously thought. However, unlike PNA, with an acyclic scaffold, aTNA can not cross-hybridize with either natural DNA or natural RNA. Although A_(15) of (S)-GNA can hybridize with U_(15), the incorporation of several GC pairs severely destabilizes the duplex with RNA. Thus, there are no artificial nucleic acids comprising a fully acyclic backbone with a phosphodiester linkage that can cross-hybridize with DNA or RNA without sequence limitation. We hypothesize that the threoninol scaffold is still not flexible enough to form a duplex with natural DNA or RNA.