Synthesis of an oligonucleotide analogue of ethenoadenosine

Article abstract of DOI:10.1081/NCN-120022819

A phosphoramidite building block derived from 11-carboxy-1,N ⁶-ethenoadenosine has been prepared to be used in a solid supported oligonucleotide synthesis.

Full text of DOI:10.1081/NCN-120022819

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Synthesis of an Oligonucleotide Analogue of
Ethenoadenosine
Niangoran Koissi a b & Harri Lönnberg a b
a University of Turku, Department of Chemistry , Turku, Finland
b University of Turku, Department of Chemistry , Vatselankatu 2, 20014, Turku, Finland
Published online: 31 Aug 2006.
To cite this article: Niangoran Koissi & Harri Lönnberg (2003) Synthesis of an Oligonucleotide Analogue of Ethenoadenosine,
Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1135-1137, DOI: 10.1081/NCN-120022819
To link to this article: http://dx.doi.org/10.1081/NCN-120022819
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1135–1137, 2003
Synthesis of an Oligonucleotide Analogue
of Ethenoadenosine
*
Niangoran Koissi and Harri Lonnberg
*
¨
University of Turku, Department of Chemistry, Turku, Finland
ABSTRACT
A phosphoramidite building block derived from 11-carboxy-1,N6-ethenoadeno-
sine has been prepared to be used in a solid supported oligonucleotide synthesis.
DNA damage by toxic agents compromises the coding potential and strand
integrity of genetic material. An increasing number of bifunctional chemical agents
are known to form covalent cyclic adducts with DNA bases by bridging two nitrogen
atoms on a single base. While cyclic adducts as such may be classified as mutagenic
DNA lesion, those bearing additional functional groups that are able to interfere
with the base-pairing are of particular interest. Besides miscoding, such adducts
may possibly give rise to inter- or intrastrand cross-linking of DNA, or they may
result in irreversible binding of proteins to the DNA backbone. Halogen substituted
malonaldehydes, formed intracellularly from mutagenic halo compounds,[1] are
known to give 11-formyl-1,N6-etheno adducts when reacted with adenosine,[2–4]
*Correspondence: Niangoran Koissi and Harri Lo¨nnberg, University of Turku, Department
of Chemistry, Vatselankatu 2, 20014 Turku, Finland; Fax: þ358 2 3336700; E-mail: niko@
utu.fi.
1135
DOI: 10.1081/NCN-120022819
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

¨
Koissi and Lonnberg
1136
and under oxidative stress conversion to 11-carboxy-1,N6-etheno adducts appears
plausible. To learn more about the effects that the latter base modification exerts
on the duplex stability and coding properties of DNA, convenient methods for the
insertion of the adduct in any position within any oligonucleotide sequence are
needed. For this purpose, the adducted nucleoside should be converted to a building
block which is compatible with conventional protocols of solid-supported oligonu-
cleotide without any marked modifications. We now report on preparation of such
a phosphoramidite building block derived from 11-carboxy-1,N6-ethenoadenosine.
The synthesis is outlined below.
RESULTS AND DISCUSSION
A possible route to obtain 11-carboxy-1,N6-ethenoadenosine involves oxidation
of 11-formyl-1,N6-ethenoadenosine known to be formed in a relatively high yield
upon treatment of adenosine with 2-bromomalonaldehyde in aqueous solution at
low pH.[4] This approach, as well as the reaction of 3-alkoxy-2-halo-3-oxopropanal
with adenosine in aqueous solution, however, leads to laborious purification. By
contrast, 50-O-(4,40-dimethoxytrityl)-20-O-(tert-butyldimethylsilyl)adenosine when
reacted with 2-bromo-3-ethoxy-3-oxoprolenal in aqueous dioxane (dioxane : water
2 : 1, v=v) gave protected 11-ethoxycarbonyl-1,N6-ethenoadenosine in a 60% yield.
Similarly, the reaction with 2-chloro-3-methoxy-3-oxopropanal gave protected 11-
methoxycarbonyl-1,N6-ethenoadenosine, but in a lower yield. The 30-hydroxy group
was then phosphitylated with 2-cyanoethyl-N,N,N0,N0-tetraisopropylphosphorami-
dite to obtain a building block that can be used in a solid-supported oligonucleotide
chain assembly by a normal phosphoramidite strategy. Studies at a monomer level
have shown that the ethoxycarbonyl group may be hydrolyzed in aqueous alkali
to a carboxylate group without other modifications in the ethenoadenine ring sys-
tem. Accordingly, brief treatment of the fully protected oligonucleotide with aqueous
sodium hydroxide before ammonolytic deprotection of the base moieties should
give the carboxyetheno adducted oligomer. By contrast, direct ammonolysis of the
protected oligonucleotide will give a carbamoyletheno adduct that is highly fluores-
cent.[5] On using amines as a cleaving agent instead of ammonia, various N-alkyl- or
N-arylcarbamoyletheno adducts are obtained.

Synthesis of Oligonucleotide Analogue of Ethenoadenosine
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1137
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