The construction of an artificial double helix that mimics natural DNA or RNA has been one of the most challenging endeavors in chemistry. [1][2][3][4][5][6][7][8][9] 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. [10][11][12][13] 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. [14] 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 singlestranded 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) [15,16] 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.[11] 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.Herein, we propose a new artificial nucleic acid, serinol nucleic acid (SNA, see Figure 1 a), with a 2-amino-1,3-propanediol (serinol) scaffold, which is even more flexible than threoninol. In comparison with aTNA (Figure 1 a), the only structural difference is the lack of a methyl group next to the amino group. However, this small change affords the SNA oligomer a unique stereochemical property: since this methyl group provides chirality, its absence makes the scaffold achiral as well as flexible. Accordingly, the chirality of the "pure" SNA oligomer synthesized from four SNA monomers (or the helicity of its duplex) depends only on its sequence (see below). This property is specific to the SNA oligomer; DNA, RNA, and previously synthesized aTNA all have chirality (or helicity) that is inherently determined by the chirality of the scaffold. [17] In the present study, we first demonstrated this unique stereochemical property and then cross-hybridized the SNA oligomer, which was found to recognize both DNA and RNA sequence specifically.The chemical structure of the SNA oligomer is shown in Figure 1 a. Serinol (2-amino-1,3-propanediol), which, like DNA, has three carbon atoms in its backbone, is an achiral diol. However, modification of the two hydroxy groups with different functional groups to form an SNA mon...

A new foldamer, acyclic threoninol nucleic acid (aTNA), has been synthesized by tethering each of the genetic nucleobases A, G, C, and T to d-threoninol molecules, which were then incorporated as building blocks into a scaffold bearing phosphodiester linkages. We found that with its fully complementary strand in an antiparallel fashion, the aTNA oligomer forms an exceptionally stable duplex that is far more stable than corresponding DNA or RNA duplexes, even though single-stranded aTNA is rather flexible and thus does not take a preorganized structure.

The stabilities of duplexes formed by strands of novel artificial nucleic acids composed of acyclic threoninol nucleic acid (aTNA) and serinol nucleic acid (SNA) building blocks were compared with duplexes formed by the acyclic glycol nucleic acid (GNA), peptide nucleic acid (PNA), and native DNA and RNA. All acyclic nucleic acid homoduplexes examined in this study had significantly higher thermal stability than DNA and RNA duplexes. Melting temperatures of homoduplexes were in the order of aTNA>PNA≈GNA≥SNA≫RNA>DNA. Thermodynamic analyses revealed that high stabilities of duplexes formed by aTNA and SNA were due to large enthalpy changes upon formation of duplexes compared with DNA and RNA duplexes. The higher stability of the aTNA homoduplex than the SNA duplex was attributed to the less flexible backbone due to the methyl group of D-threoninol on aTNA, which induced clockwise winding. Unlike aTNA, the more flexible SNA was able to cross-hybridize with RNA and DNA. Similarly, the SNA/PNA heteroduplex was more stable than the aTNA/PNA duplex. A 15-mer SNA/RNA was more stable than an RNA/DNA duplex of the same sequence.

The construction of an artificial double helix that mimics natural DNA or RNA has been one of the most challenging endeavors in chemistry. [1][2][3][4][5][6][7][8][9] 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. [10][11][12][13] 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. [14] 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 singlestranded 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) [15,16] 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. [11] 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.Herein, we propose a new artificial nucleic acid, serinol nucleic acid (SNA, see Figure 1 a), with a 2-amino-1,3propanediol (serinol) scaffold, which is even more flexible than threoninol. In comparison with aTNA (Figure 1 a), the only structural difference is the lack of a methyl group next to the amino group. However, this small change affords the SNA oligomer a unique stereochemical property: since this methyl group provides chirality, its absence makes the scaffold achiral as well as flexible. Accordingly, the chirality of the "pure" SNA oligomer synthesized from four SNA monomers (or the helicity of its duplex) depends only on its sequence (see below). This property is specific to the SNA oligomer; DNA, RNA, and previously synthesized aTNA all have chirality (or helicity) that is inherently determined by the chirality of the scaffold. [17] In the present study, we first demonstrated this unique stereochemical property and then cross-hybridized the SNA oligomer, which was found to recognize both DNA and RNA sequence specifically.The chemical structure of the SNA oligomer is shown in Figure 1 a. Serinol (2-amino-1,3-propanediol), which, like DNA, has three carbon atoms in its backbone, is an achiral diol. However, modification of the two hydroxy groups with different functional groups to form an SNA mon...

No abstract