The most accessible chemical property that parallels the incongruity of pairing behavior of the 2,4-disubstituted triazines and 5-aminopyrimidines relative to the standard of the canonical nucleobases is the pKa value (Fig. 2). The juxtaposition points to a correlation between differences in pKa values (Δ-pKa) of pairs of complementary bases and the pairing strength of the bases: the smaller the Δ-pKa value of a pair of complementary 2,4-dioxo and 2,4-diamino pairing partners (compared with the standard difference of about 5 pKa units for the canonical pair of bases), the weaker is the pairing (in aqueous solution at neutral pH). The trend of this correlation points in the opposite direction of the one described in the literature for Δ-pKa values of the relative strengths of hydrogen bonds in nonaqueous media.
Our observations indicate that 2,4-disubstituted-1,3,5-triazines and 2,4-disubstituted-5-aminopyrimidines, 2 families of heterocycles deemed to be of generational simplicity comparable to that of the canonical nucleobases, yet offering chemically wider opportunities for backbone tagging, are functionally inferior to the family of Watson-Crick bases because of reasons that seem intrinsically chemical. The findings provide a chemical illustration of the view that the canonical nucleobases represent a functional optimum in informational base pairing in aqueous solution.
Oligomers Based on 5-aminopyrimidine–Tagged 2′→3′-Phosphodiester–linked Glyceric Acid Backbones
We are continuing our search for structurally and generationally simpler informational systems, that is, systems considered to have the capability of being assembled from potentially prebiotic source molecules. Recently, we synthesized oligomers derived from a 2′→3′-phosphodiester–linked* glyceric acid backbone that has 2,4-disubstituted 5-aminopyrimidines attached to the carboxyl group via an amide bond at the 5 amino position as recognition elements (Fig. 3), and we are examining the base-pairing properties of the synthesized molecules. We expect that these systems will show base pairing because systems with similar backbone connections, namely 2′→3′-phosphodiester–linked β-D-lyxopyranosyl nucleic acids and 2′→3′-phosphodiester–linked α-D-threofuranosyl nucleic acids, can show Watson-Crick base pairing.
We have completed the synthesis of the requisite building block and the machine-assisted automated oligmer synthesis of 2,4-dioxo-5-aminopyrimidine (5-aminouracil)–tagged nucleic acid with a glyceric acid backbone. We have made the oligomer containing six 5-aminouracil units and have begun to explore its base-pairing properties. Preliminary results validate our expectations; we found a strong base pairing between this oligomer and polydeoxyadenosine.
Egli, M., Pallan, P.S., Pattanayek, R., Wilds, C.J., Lubini, P., Minasov, G., Dobler, M., Leumann, C.J., Eschenmoser, A. Crystal structure of homo-DNA and Nature's choice of pentose over hexose in the genetic system. J. Am. Chem. Soc. 128:10847, 2006.
Mittapalli, G.K., Kondreddi, R.R., Xiong, H., Munoz, O., Han, B., De Riccardis, F., Krishnamurthy, R., Eschenmoser, A. Mapping the landscape of potentially primordial informational oligomers: oligodipeptides and oligodipeptoids tagged with triazines as recognition elements. Angew. Chem. Int. Ed. 46:2470, 2007.
Mittapalli, G.K., Osornio, Y.M., Guerrero, M.A., Kondreddi, R.R., Krishnamurthy, R., Eschenmoser, A. Mapping the landscape of potentially primordial informational oligomers: oligodipeptides tagged with 2,4-disubstituted 5-aminopyrimidines as recognition elements. Angew. Chem. Int. Ed. 46:2478, 2007.