The Skaggs Institute
for Chemical Biology

Scientific Report 2006

Chemical Etiology of the Structure of Nucleic Acids

A. Eschenmoser, R. Krishnamurthy, G. Kumar, F. De Riccardis, R. Kondreddi, Y. Osornio, M. Guerrero

During the past year we worked on the following projects.

Oligomers Based on Triazine-Tagged Oligodipeptide and Oligodipeptoid Backbones

We continued our studies on the self- and cross-pairing properties of triazine-tagged oligodipeptides consisting of alternating aspartic (Asp) and glutamic acid (Glu) residues (Fig. 1). Although the oligo-(AspGlu)-dipeptides tagged with 2,4-diaminotriazine had strong cross-pairing with complementary RNA and DNA oligonucleotide sequences, the corresponding oligo-(AspGlu)-dipeptides tagged with 2,4-dioxotriazine, much to our surprise, showed only weak pairing with the natural oligonucleotides. The intrasystem self-pairing of 2,4-diaminotriazine–, 2,4-dioxotriazine–, and 2-amino-4-oxo-triazine–tagged oligo-(AspGlu)-dipeptides was equally weak.

Fig. 1. Formulas of triazine-tagged oligomers. IDA indicates iminodiacetic acid.

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 (pK_a of about 6) vs diaminotriazines (pK_a 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-Aminopyrimidine–Tagged 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).

Fig. 2. Top, Formulas of 5-aminopyrimdine heterocycles. Bottom, Also shown, as a representative example, is the 5-amino-2,4-dioxo–tagged oligomer containing alternating residues of aspartic and glutamic acid.

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-aminopyrimidine–tagged 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-diaminotriazine–tagged oligo-(AspGlu)-dipeptides and 5-amino-2,4-dioxopyrimdine–tagged oligo-(AspGlu)-dipeptides.

Publications

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.