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The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998

Chemical Etiology of the Structure of Nucleic Acids

A. Eschenmoser, R. Krishnamurthy, T. Wagner, M. Beier, F. Reck, T. Mueller, P. Waldmeier, G. Ceulemans, R. Micura

In its second year, research in our group focused on 3 projects.

Pentopyranosyl-(4´→2´)-Oligonucleotide Systems

Ribopyranosyl-, lyxopyranosyl-, xylopyranosyl-, and arabinopyranosyl-(4´→2´)-oligonucleotides, in which the nucleobases at the anomeric center are all in the equatorial position, constitute diastereomeric members of a family of constitutional isomers of RNA. According to chemical reasoning, they also could have been possible candidates for Nature's choice of a genetic system. A systematic comparison at the chemical level of the base-pairing properties of these potential nucleic acid alternatives with the corresponding properties of RNA may provide clues as to why RNA, rather than one of these alternatives, eventually became Nature's genetic system.

During the past year, we synthesized the 2 members that had remained inaccessible, namely, the xylopyranosyl- and the arabinopyranosyl-(4´→2´)-oligonucleotide systems. The base-pairing properties of both were surprising. In contrast to expectation, strong base pairing occurs in both, and, most remarkably, the arabinopyranosyl system has a pairing strength that is unprecedented in any known oligonucleotide system, natural or artificial (Fig. 1).

Amazingly, complete base-pairing promiscuity exists among the 4 pentopyranosyl systems; all 4 cross-pair efficiently with each other.

The observations made so far clearly point to the conclusion that Nature did not select a genetic system on the basis of the criterion of maximal base-pairing strength. The search for the relevance of other selection criteria, such as the potential of a system for self-replication, will be pursued. The availability of a complete set of 4 diastereomeric oligonucleotide systems that differ only in the relative configuration of their substituents at the pyranosyl sugar building block offers a unique opportunity to study the structural factors that determine base-pairing properties in oligonucleotide systems in general and to extend current rationalizations of the pairing properties of the natural nucleic acids themselves.

Chemistry of Pyranosyl-Rna

Pyranosyl-RNA, the nucleic acid alternative that consists of the same building blocks as RNA, is the alternative studied most extensively. Most recently, we correlated interstrand base stacking and duplex properties, such as thermal duplex stability, effect of dangling bases on duplex stability, and circular dichroism spectral properties. The comparative study of selected base sequences from both the pyranosyl-RNA and the previously synthesized homo-DNA series revealed a remarkably consistent opposite sequence dependence of these properties in the 2 systems. The rationale for this finding is the opposite direction of the inclination between backbone and base-pair axes (and, therefore, sequence dependence of interstrand stacking) in pyranosyl-RNA and homo-DNA. We expect backbone inclination to be a useful parameter for the structural classification of oligonucleotide duplexes. A hypothetical chemical property of pyranosyl-RNA related to interstrand base stacking is the mediation of a peptide synthesis through preorganization of pyranosyl-RNA--bound α-amino acid building blocks on a pyranosyl-RNA template; this problem is being investigated.

Regioselective Phosphorylation of Carbohydrates

Regioselective phosphorylation of sugars under potentially natural conditions is a long-standing problem of classical prebiotic chemistry. Using amido-triphosphate, a phosphorylating agent derived from metatriphosphate by reaction with ammonia, we showed the existence of a strictly regioselective phosphorylation of the α-position of aldosugars (glycolaldehyde, glyceraldehyde, threose and erythrose, ribose, arabinose, xylose and lyxose) under mild reaction conditions. The regioselectivity of the process is the result of an intramolecular nucleophilic substitution within the reversibly formed substrate-reagent adduct. The process is a new addition to the list of chemical processes that are potentially of prebiotic significance and is expected to open a new pathway for the formation of mononucleotides.


Eschenmoser, A. Thoughts and experiments on a chemical etiology of nucleic acid structure. In: Pioneering Ideas for the Physical and Chemical Sciences. Fleischhacker, W., Schönfeld, T. (Eds.). Plenum, New York, 1997, p. 41.

Groebke, K., Hunziker, J., Fraser, W., Peng, L., Diederichsen, U., Zimmermann, K., Holzner, A., Leumann, C., Eschenmoser, A. Why pentose- and not hexose-nucleic acids? Part V. Purine-purine pairing in homo-DNA: Guanine, isoguanine, 2,6-diaminopurine, and xanthine. Helv. Chim. Acta 81:375, 1998.



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