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The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000

Chemical Etiology of the Structure of Nucleic Acids

A. Eschenmoser, R. Krishnamurthy, S. Guntha, O. Jungmann, H. Wippo, M. Stanek, A. Luther, H. Huynh, K.-U. Schöning, P. Scholz

In the past year, work in our group centered on the following research areas:

Intrasystem And Intersystem Cross-Pairing In The Pentopyranosyl-(4´→2´) Oligonucleotide Family

We extended our studies on the chemistry of the pentopyranosyl-(4´→2´) and pentopyranosyl-(4´→3´) oligonucleotide families to base sequences that contain all 4 canonical nucleobases. Systematic intersystem cross-pairing studies showed that the base-pairing mode is Watson-Crick throughout. The results also revealed regularities in the sequence dependence of duplex stabilities that are of interest for oligonucleotide chemistry in general, especially interpretation of differences in duplex stability in intersystem cross-pairing that are due to variations in the distribution of purines and pyrimidines among the partner strands.

Synthesis And Base-pairing Properties Of (L)-a-Threofuranosyl-(3´→2´) Oligonucleotides

The discovery of the unexpected base-pairing capabilities of the lyxopyranosyl-(4´→3´) oligonucleotide system led us to extend our studies to an oligonucleotide system that contains a tetrose instead of a pentose as the sugar building block (Fig. 1). The results of these studies are as surprising as they are relevant in the etiologic context: (L)-a-threofuranosyl-(3´→2´) oligonucleotides containing adenine and thymine (or uracil) as nucleobases show cooperative base pairing that is, for oligomers longer than 12mer, comparable in strength and sequence specificity to that of natural RNA. Most important and surprising, the same finding is also true for intersystem cross-pairing between the threofuranosyl system and RNA. These properties make the threofuranosyl-(3´→2´) oligonucleotide system a new and unforeseen focus in the systematic functional screening of potentially natural RNA alternatives.

Synthesis Of A Pyranosyl-rna-mediated Oligopeptide

We pursue the hypothesis that the contemporary process of protein synthesis by ribosomes had an evolutionary precursor, which was based on RNA-mediated formation of oligopeptides by virtue of the nucleic acid's most fundamental chemical property, namely, nucleobase pairing. We are systematically testing a model reaction scheme in the pyranosyl-RNA series by which polypeptide chains might be assembled as the consequence of specific oligonucleotide base pairing on an oligonucleotide template. The process requires a reaction cycle consisting of an internucleotide-(O→N) acyl shift followed by an internucleotide acyl shift and finally an intranucleotide acyl shift. So far, we have shown the occurrence of the last 2 of these 3 processes.

Regioselective Phosphorylation Of Carbohydrates In a-Position to The Anomeric Center

We completed our work on the regioselective a-phosphorylation of aldoses (glycolaldehyde, glyceraldehyde, erythrose, threose, ribose, and the 3 diastereomeric pentoses) with amidotriphosphate as a specific phosphorylation reagent. In the past year, we extended research on this phosphorylation process based on an unprecedented internal phosphate delivery to diamidophosphate as an alternative specific a-phosphorylation reagent.


Eschenmoser, A. Chemical etiology of nucleic acid structure. Science 284:2118, 1999.

Jungmann, O., Wippo, H., Stanek, M., Huynh, H.K., Krishnamurthy, R., Eschenmoser, A. Promiscuous Watson-Crick cross pairing within the family of pentopyranosyl-(4´→2´) oligonucleotides. Org. Lett. 10:1527, 1999.

Krishnamurthy, R., Arrhenius, G., Eschenmoser, A. Formation of glycolaldehyde phosphate from glycolaldehyde in aqueous solution. Orig. Life Evol. Biosph. 29:333, 1999.

Krishnamurthy, R., Guntha, S., Eschenmoser, A. Regioselective a-phosphorylation of aldoses in aqueous solution. Angew. Chem. Int. Ed. 39:2281, 2000.

Reck, F., Wippo, H., Kudick, R., Bolli, M., Ceulemans, G., Krishnamurthy, R., Eschenmoser, A. L-a-Lyxopyranosyl-(4´→3´) oligonucleotides: A base-pairing system containing a shortened backbone. Org. Lett. 10:1531, 1999.



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