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The Skaggs Institute
for Chemical Biology


Scientific Report 2005




Chemical Etiology of the Structure of Nucleic Acids


A. Eschenmoser, R. Krishnamurthy, O. Munoz, H. Xiong, G. Kumar, F. De Riccardis, R. Kondreddi, S. Eppacher, J. Nandy

During the past year we worked on the following projects.

Triazine-Tagged Amino Acid Derivatives

Our earlier work on the synthesis of C-nucleosides with a family of allopurines (formerly isopurines) led us to consider the triazines (2,4-diamino-triazines and their oxygen analogs) as alternative nucleobases that may be able to function as informational base pairs through a type of hydrogen-bond arrangement that differs from the canonical Watson-Crick type with its pairing axis parallel to the nucleosidic bond. Because carboxyl groups can easily be converted to suitably functionalized triazine rings, a large variety of oligomer backbones tagged with informational triazines (instead of conventional nucleobases) could be envisioned (Fig. 1).

Fig. 1. 2,4-Diamino-triazine–tagged oligomeric systems.

In collaboration with B. Han, Swiss Federal Institute of Technology, Zürich, Switzerland, we developed the triazination of the carboxyl group of a variety of α-amino acids such as glycine, serine, cysteine, aspartic acid, glutamic acid, β-amino-alanine, and α-carboxy-glycine to produce correspondingly triazine-tagged building blocks of potentially informational oligomers.

Oligomers Based On Triazine-Tagged Backbones

Of the 2 planned variants (compounds 1 and 2 in Fig. 1) of ethylenediamine-based oligomer systems containing triazine as recognition elements, we were able to synthesize and study oligomers (up to dodecamer) of 1 of them (2 in Fig. 1). As expected, oligomers of this chemical structure underwent efficient cross-pairing with polyuracil (RNA) and polythymine (DNA) (Table 1). However, to our surprise, the backbones of oligomers of this type were unstable because of a triazine-assisted eliminative fragmentation.

A comparative conformational analysis relative to RNA (tagged with the conventional nucleobases) of oligomer backbones tagged with triazines predicted that oligodipeptides of type 2 and 4 (Fig. 1) might be oligomer systems that cross-pair with RNA, whereas oligopeptides of type 3 should not (or less efficiently so). Experimental results obtained so far are in accord with the analysis, except that oligopeptides of type 3 also cross-pair with RNA, yet much more weakly than those of type 4 do (Table 1). The oligopeptides of type 4, composed of a triazine-tagged oligomer consisting of alternating glutamic and aspartic acid residues, cross-pairs with RNA (polyuracil) strongly (Table 1). Studies on the self-pairing and cross-pairing properties of type 4 are under way.

Table 1. Tm values of duplexes formed by the triazine-tagged oligomers 2–5 with RNA and DNA*
System
Tm (℃)
DNA
poly(T)
RNA
poly(U)
DNA
 d(T12)
RNA
r(T12)
2        

12-mer

44.1 29.2 30.3 28.5
3        
6-mer <6 <10
12-mer 26.6 33.1 11.0 28.0
4        
6-mer 41.7 50.0 32.2 42.8
12-mer 59.4 65.0 53.8 57.2
5        
8-mer 26.7 19.7 n.m. n.m.
12-mer 35.2 29.1 22.7 n.m.
*Measurements were made at 260 nm, c Å 5 μM + 5 μM in 1 M NaCl, 10 mM NaH2PO4, 0.1 mM Na2EDTA, pH 7.0. Tm values are given in degrees Celsius (°C) and are derived from maxima of the first derivative of the heating curve. – indicates no pairing observed, n.m. = no measurement, = in 0.15 M NaCl, T = thymine, U = uracil, d = DNA, r = RNA.

A variation of oligodipeptide system 3 is the oligodipeptoid of the type 5 (Fig. 1), constructed from the iminodiacetic acid unit, wherein the triazine- and carboxylate-containing side chains are now appended to the nitrogen atoms along the backbone, making this system achiral. We used a solid-support strategy starting from the requisite monomers to synthesize oligomers (up to dodecamer). The resultant oligodipeptoids cross-paired with RNA (polyuracil) and DNA (polythymine) (Table 1).

Publications

Ferencic, M., Reddy, G., Wu, X., Guntha, S.G., Nandy, J., Krishnamurthy, R., Eschenmoser, A. Base-pairing systems related to TNA containing phosphoramidate linkages: synthesis of building blocks and pairing properties. Chem. Biodivers. 1:939, 2004.

Han B., Jaun, B., Krishnamurthy, R., Eschenmoser, A. Mannich type C-nucleosidations in the 5,8-diaza-7,9-dicarba-purine family. Org. Lett. 6:3691, 2004.

Han, B., Rajwanshi, V., Nandy, J., Krishnamurthy, R., Eschenmoser, A. Mannich-type C-nucleosidations with 7-carba-purines and 4-amino-pyrimidines. Synlett 744, 2005, Issue 4.

 

Albert Eschenmoser, Ph.D.
Professor