The base-pairing properties of triazine-tagged oligo-(AspAsp)-dipeptides paralleled the trends observed in the oligo-(AspGlu)-dipeptide series, but, as expected, were consistently weaker in base-pairing strength.
A variation of the oligo-(AspAsp)-dipeptide shown in Figure 1B is the achiral oligodipeptoid derived from iminodiacetic acid units (Fig. 1C). Again, oligodipeptoids containing 2,4-diaminotriazines cross-paired with RNA and DNA oligonucleotides, but no discernible pairing occurred with the 2,4-dioxotriazine tagged oligopeptoids.
Our studies indicate that the family of triazine-based recognition elements lacks the balance in pairing strength characteristic of the purine-pyrimidine combination in the natural series, presumably because of the imbalance in protophilicity of dioxotriazines (pKa of about 6) vs diaminotriazines (pKa of about 3.9), in an aqueous environment. Such imbalance in pairing potential leads to the conclusion that triazines, irrespective of their generational simplicity, would have been functionally incapable of fulfilling the role of recognition elements in a primordial genetic system. This realization has led us pursue the following project.
Oligomers Based on 5-AminopyrimidineTagged Oligodipeptide Backbones
Oligomerization of hydrogen cyanide, a potentially prebiotic reaction generally assumed to have acted as the primordial source of the canonical nucleobases adenine and guanine, produces in addition pyrimidines, not the canonical ones, but mostly 5-aminopyrimidines, which do not play a role in contemporary biology (Fig. 2).
Chemical reasoning makes a study of the base-pairing properties of the members of this family highly desirable; they not only can potentially act as substitutes in the 2 canonical Watson-Crick base pairs but also offer a unique opportunity to tag polypeptide chains bearing recurring carboxyl functions by using simple (regioselective) amide formation. We have synthesized 5-aminopyrimidinetagged oligo-(AspGlu)-dipeptides (up to hexadecamers) by using all 4 members of the family and have explored the base-paring properties of the tagged dipeptides. Preliminary results indicated cross-pairing between all of these recognition elements with the corresponding complementary RNA and DNA oligonucleotides, although the 5-aminopyrimidine heterocycles have stark differences in base-pairing strength. Also, cross-pairing occurs between the 2,4-diaminotriazinetagged oligo-(AspGlu)-dipeptides and 5-amino-2,4-dioxopyrimdinetagged oligo-(AspGlu)-dipeptides.
Eschenmoser, A. Searching for nucleic acid alternatives. Chimia 59:836, 2005.
Mittapalli, G.K., Osornio, Y.M., Guererro, M.A., Reddy, K.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., in press.
Mittapalli, G.K., Reddy, K.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., in press.
Wagner, T., Han, B., Koch, G., Krishnamurthy, R., Eschenmoser, A. Tautomerism in 5,8-diaza-7,9-dicarbaguanine. Helv. Chim. Acta 88:1960, 2005.