Chemical Etiology of the Structure of Nucleic Acids
A. Eschenmoser, R.
Krishnamurthy, G.R. Vavilala, J. Nandy, T. George, O. Munoz, H. Xiong
the last year we worked on the following projects.
C-Nucleosidation with (Potentially Natural) Nucleobase Alternatives
We continued our exploration of C-nucleosidation
chemistry that began with 5,8-diaza-7,9-dicarba-2,6-diaminopurine (compound 1, isopurine,
in Fig. 1) and extended our studies to include pyrimidine derivatives (compounds 58,
Fig. 1) and (modified) purine nucleobases (compounds 911, Fig. 1). These bases
were selected because they can be derived from potentially prebiotic building blocks. For the
C-nucleosidation studies, we used aldosugars, such as threofuranosyl (12 in Fig. 1) and
ribofuranosyl (13 in Fig. 1) derivatives, and corresponding iminium ions, derivatives
of 3,4-dihydroxy- (14 in Fig. 1) and 3,4-diamino-pyrrolines (15 in Fig. 1), as
|Fig.1. The pyrimidines, purines, and sugar substrates used in
the C-nucleosidation studies.
Formation of nucleosides occurred with
pyrimidines 7 and 8 and purines 9 and 10. C-nucleosidations with
aldosugars as substrates were more sluggish reactions, with lower yields and less stable products
than those with the iminium ion counterparts. In some instances (e.g., compounds 1, 9,
and 10), we explored C-nucleosidation chemistry with acyclic (aliphatic) iminium ions.
C-nucleosides derived from pyrrolinium salts were stable compounds, in contrast to those derived
from aliphatic iminium salts. The stability of C-nucleosides correlates inversely with the ease
of C-nucleosidation. The investigations done at Scripps Research were complemented by corresponding
studies of all 4 members of the 5,8-diaza-7,9-dicarba-purine family (14 in Fig.
1) done at the Swiss Federal Institute of Technology (ETH) in Zürich, Switzerland.
Informational Oligomers Based on Oligoserine Phosphoramidate Backbones
We are investigating oligomers constructed
from the monomeric units derived from serine and linked via a phosphoramidate backbone containing
a triazine heterocyclic base. We completed the synthesis of an appropriately derivatized serine-triazine
monomer unit, and we are searching for conditions for the solid-support synthesis of oligomers.
Structural Properties of (L)-α-Threofuranosyl-(3´→2´)
We continue to examine the structural properties
oligonucleotides (TNAs). With M. Egli, Vanderbilt University, Nashville, Tennessee, we determined
the crystal structure of an A-form DNA duplex of the self-complementary sequence [d(GCGTATM)A*d(CGC)]2
containing a single (L)-α-threofuranosyl-(3´→2´)-adenine
(A*) and compared it with the crystal structure of a B-form DNA duplex [d(CGCGAA)T*d(TCGCG)]2
containing a single (L)-α-threofuranosyl-(3´→2´)-thymine
(T*); (TM = 2´-O-methyl-thymidine).
In both A- and B-form duplexes containing a TNA nucleotide, the structure of the TNA unit is similar
but the TNA units (PP) distance is more similar to that of an A-form DNA duplex than
to that of a B-form DNA duplex (Fig. 2). Therefore, TNA seems to be a good mimic of the A-form of DNA
and, by extension, of RNA, rather than a good mimic of the B-form of DNA. This observation offers
an explanation as to why TNA hybridizes more strongly with RNA than with DNA and why RNA is a better
template than DNA for ligating TNA fragments.
|Fig. 2. Conformations adopted by TNA and DNA nucleotides in B- and A-form
duplexes. A, TNA unit T*7 in B-form. B, DNA unit T20 in B-form. C, TNA unit
A*7 in A-form. D, DNA unit A15 in A-form. Asterisks indicate the directions
of the backbone chain. Bold arrows indicate the exo (TNA) or endo (DNA) position
of the indicated carbon atom.
Delgado, G., Krishnamurthy, R.
Assignment of the 1H and 13C NMR spectra of N2,N6-dibenzoyl-N2,N9-bis(2´,3´-di-O-benzoyl-(α)-L-threofuranosyl)-2,6-diaminopurine.
Rev. Soc. Quìm. México 47:216, 2003.
The TNA-family of nucleic acid systems: properties and prospects. Orig. Life. Evol. Biosph. 34:277,
Pallan, P.S., Wilds, C.J., Wawrzak,
Z., Krishnamurthy, R., Eschenmoser, A., Egli, M. Why does
TNA cross-pair more strongly with RNA than with DNA? An answer from x-ray analysis. Angew. Chem.
Int. Ed. 42:5893, 2003.
Pitsch, S., Wendeborn, S., Krishnamurthy,
R., Holzner, A., Minton, M., Bolli, M., Miculka, C., Windhab, N., Micura, R., Stanek, M., Jaun,
B., Eschenmoser, A. The β-D-ribopyranosyl-(4´2´)-oligonucleotide
system (pyranosyl-RNA): synthesis and resumé of base-pairing properties.
Helv. Chim. Acta 86:4270, 2003.