New nucleoside analogues for the recognition of pyrimidine-purine inversion sites

Article abstract of DOI:10.1081/NCN-120022835

A new nucleoside designed to enhance triplex stability has been synthesised in 15 steps starting from sugar 2. This pathway contains the sugar derivative 9 which is a useful intermediate for the introduction of other natural and unnatural bases into the 2′-aminoethoxy nucleoside containing scaffold.

Full text of DOI:10.1081/NCN-120022835

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New Nucleoside Analogues for the Recognition of
Pyrimidine-Purine Inversion Sites
Sabrina Buchini a b & Christian J. Leumann a
a Department of Chemistry and Biochemistry , University of Bern , Bern, Switzerland
b Department of Chemistry and Biochemistry , University of Bern , Freiestrasse 3, CH-3012,
Bern, Switzerland
Published online: 31 Aug 2006.
To cite this article: Sabrina Buchini & Christian J. Leumann (2003) New Nucleoside Analogues for the Recognition
of Pyrimidine-Purine Inversion Sites, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1199-1201, DOI: 10.1081/
NCN-120022835
To link to this article: http://dx.doi.org/10.1081/NCN-120022835
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1199–1201, 2003
New Nucleoside Analogues for the Recognition of
Pyrimidine-Purine Inversion Sites
*
Sabrina Buchini and Christian J. Leumann
Department of Chemistry and Biochemistry, University of Bern,
Bern, Switzerland
ABSTRACT
A new nucleoside designed to enhance triplex stability has been synthesised in 15
steps starting from sugar 2. This pathway contains the sugar derivative 9 which is
a useful intermediate for the introduction of other natural and unnatural bases
into the 20-aminoethoxy nucleoside containing scaffold.
Strong and sequence specific triple helix formation of oligonucleotides with a
DNA target duplex can selectively interfere with gene expression on the level of tran-
scription (antigene strategy).[1,2] Despite considerable efforts directed to the removal
of the homopurine=homopyrimidine sequence requirement for stable DNA triple
helix formation by third strand oligonucleotides, a general recognition motif by third
strands for any given DNA sequence is still elusive. We recently reported that selec-
tive recognition of a cytosine-guanine base pair within the parallel DNA triple helical
binding motif can be achieved by a DNA third strand containing 5-methyl-pyrimi-
din-2-(1H)-one (4HT).[3] Nonetheless the stability of the resulting triple helix is quite
*Correspondence: Sabrina Buchini, Department of Chemistry and Biochemistry, University of
Bern, Freiestrasse 3, CH-3012 Bern, Switzerland; E-mail: buchini@ioc.unibe.ch.
1199
DOI: 10.1081/NCN-120022835
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1200
Buchini and Leumann
Figure 1. a) HCl (2% w=w), MeOH, 3.5 h, R.T., 63%. b) TIPS-Cl (1.2 eq.), pyridine, 1 h,
R.T., 83%. c) BrCH2CO2Me (5 eq.), NaH (2.2 eq.), DMF, 10 h, ꢀ10ꢁC-R.T., 77%. d) LiBH4
(4 eq.), THF=MeOH (4=1), 1 h, 0ꢁC, 94%. e) Ph3P (1.4 eq.), LiN3 (4 eq.), CBr4 (1.4 eq.), DMF,
9 h, 0ꢁC-R.T. f) TsCl (2 eq.), NEt3 (2.1 eq.), DMAP (0.1 eq.), CH2Cl2, overnight, R.T., 93%.
g) LiN3 (2 eq.), DMF, 1.5 h, 90ꢁC, 96%. h) Lindlar catalyst (50% w=w), H2, THF, overnight,
R.T., quantitative. i) Et3N (1 eq.), CF3CO2Et, 4 h, R.T., 89%. l) (13) (1.05 eq.), HMDS (0.5
eq.), TCS (0.5 eq.), CH3CN, 13 h, R.T. m) Ac2O=AcOH=H2SO4, 14 h, R.T., 91%. n) (13)
(1.05 eq.), BSA (2.6 eq.), SnCl4 (1 eq.), CH3CN, 2 h, 0ꢁC, 55%. r) i. POCl3 (2.2 eq.), DMF
(2.4 eq.), 2 h, 70ꢁC, 83%. ii. H2O, overnight, K2CO3, 30%. s) i. Na (2.3 eq.), Urea (1.2 eq.),
EtOH, 2d, reflux. ii. HCl 25% (pH ¼ 2), 1d, reflux, 50%. o) Na2CO3 an. (10% w=w), MeOH,
30 min., R.T., 90%. p) DMT-Cl (2 eq.), pyridine, 5 h, R.T., 75%. q) iPr2NEt (3 eq.), [(iPr2N)
(NCCH2CH2O)P]Cl (1.5 eq.), THF, 2 h, R.T., 75%.

New Nucleoside Analogues
1201
low. It has also been described that the presence of a 20-aminoethoxy function
enhances the affinity of the triplex forming oligonucleotide for its complementary
DNA double strand.[4] By combining those two elements, we synthesised the new
nucleoside analogue 1 which is expected to improve the stability of the triple helices
at pyrimidine-purine inversion sites. Three different approaches for the synthesis of 1
were investigated. First, we tried to modify the base starting from ribothymidine, via
sulphur-oxygen exchange at C4, followed by reduction with Raney-Ni. Unfortu-
nately this route revealed to be more problematic than expected, mainly due to over-
reduction of the base. In the second strategy, the base 13 was synthesised in two steps
starting from propionaldehyde diethylacetal[5,6] and then coupled to the sugar. Here
we encountered problems with the introduction of the 20-O-aminoethyl chain due to
the instability of the base during the necessary transformations. Finally, we found
a promising synthetic pathway (Fig. 1) which includes compound 9, a potentially
useful intermediate for the introduction of various bases into the 20O-aminoethyl
nucleoside scaffold at a late stage.
Methyl b-d-ribofuranoside 3 was synthesised starting from ribose and then pro-
tected with dichloro-1,1,3,3-tetraisopropyldisiloxane. Alkylation of the protected
sugar 4 with methyl bromoacetate followed by reduction of the methyl ester, tosyla-
tion and replacement of the tosyloxy group by azide yielded the azidoethyl derivative
6. After reduction of the azide and protection of the resulting amine, the sugar was
acetylated (! 9) in order to facilitate the nucleosidation step.[7] Phosphoramidite 1
was successfully obtained by standard procedures. Compound 1 will be incorporated
into oligonucleotides and its binding=pairing properties will be studied.
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