A new type of acyclic, achiral nucleoside analogue. How does it simulate nucleosides?

Article abstract of DOI:10.1081/NCN-120022621

The new monomer 1 seems to be an excellent mimic of nucleosides with different sugar conformations (north, south, and envelope), because of the relatively free rotation around γ, δ, and χ. The rotation around χ is primarily controlled by the repulsion bet

Full text of DOI:10.1081/NCN-120022621

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A New Type of Acyclic, Achiral Nucleoside Analogue.
How Does It Simulate Nucleosides?
Asger B. Petersen a , Thomas Boesen a & Otto Dahl a b
a Department of Chemistry , University of Copenhagen , The H.C. Ørsted Institute ,
Copenhagen, Denmark
b University of Copenhagen, Department of Chemistry , Universitetsparken 5, DK-2100,
Copenhagen, Denmark
Published online: 31 Aug 2006.
To cite this article: Asger B. Petersen , Thomas Boesen & Otto Dahl (2003) A New Type of Acyclic, Achiral Nucleoside
Analogue. How Does It Simulate Nucleosides?, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 731-733, DOI: 10.1081/
NCN-120022621
To link to this article: http://dx.doi.org/10.1081/NCN-120022621
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 731–733, 2003
A New Type of Acyclic, Achiral Nucleoside Analogue.
How Does It Simulate Nucleosides?
*
Asger B. Petersen, Thomas Boesen, and Otto Dahl
Department of Chemistry, University of Copenhagen, The H.C. Ørsted Institute,
Copenhagen, Denmark
ABSTRACT
The new monomer 1 seems to be an excellent mimic of nucleosides with different
sugar conformations (north, south, and envelope), because of the relatively free
rotation around g, d, and w. The rotation around w is primarily controlled by
the repulsion between H6 and the two hydrogen atoms on C40 and not pi conjuga-
tion between the double bond and the nucleobase. A viable synthesis of the
guanine monomer 8 is described.
DFT calculations on 1 without OH groups by Steen Hammerum (Department
of Chemistry, University of Copenhagen) showed that pi conjugation between the
nucleobase and the double bond is insignificant compared to a repulsion between
H6 and the two hydrogen atoms on C40. The energy minimum for rotation around
w was found for w ¼ 56ꢀ (13 kJ=mol lower than the energy for w ¼ 0ꢀ).
*Correspondence: Otto Dahl, University of Copenhagen, Department of Chemistry, Univer-
sitetsparken 5, DK-2100 Copenhagen, Denmark; Fax: +45 35 52 02 12; E-mail: dahlo@
kiku.dk.
731
DOI: 10.1081/NCN-120022621
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

732
Petersen, Boesen, and Dahl
Using a minimized structure of 1 (w ¼ 30ꢀ) with uracil, Thomas Boesen[1] calculated
that a 360ꢀ rotation around d gave structures that differed less than 1 kJ=mol in
energy, while rotation around g was hindered only by repulsion between HO40
and H6 (max. 12 kJ=mol).
SYNTHESIS OF THE GUANINE MONOMER 8
The opening of the epoxide 2 was tried with different guanine derivatives without
succes. These included N2-isobutyrylated guanine and NaH, fully silylated guanine
and fluoride, guanine on Al2O3, and N2-acetylated-O6-diphenylcarbamylated
guanine with NaH, which gave either no opening or mixtures of N7=N9 alkylated
guanine derivatives. However, 2-amino-6-chloropurine (GCl) with K2CO3 as the
deprotonating agent (NaH led to degradation of the chloro guanine) gave solely
the N9 alkylated product 3.
Elimination of the tertiary alcohol 5 with SOCl2,[5] gave a mixture of several dif-
ferent elimination products (less than 10% 7) and substitution of the alcohol with
chloride. Elimination via thiophosphate 6 with sodium t-amylate under anhydrous
conditions gave 7 as the sole elimination product.
The synthesis described in Sch. 1 was achived in 19% overall yield and needed
only purification by column chromatography of compound 3, the remaining com-
pounds were purified by recrystallizations.
Scheme 1. a) K2CO3 (cat.), DMF, 110 ꢀC, 6h; b) NaOCH2CH2CN, THF, rt, 3h; c) i) TMSCl,
py, rt, 5 h, ii) isobutyric anhydride, rt, 18 h, iii) Et3Nꢁ3HF, rt, 12 h; d) i) (EtO)2PCl, py, 20 min,
ii) S8, rt, 1 h; e) t-amylONa, THF, rt, 24 h; f) BCl3, DCM, ꢂ78 ꢀC, 4 h.

Acyclic, Achiral Nucleoside Analogue
733
Figure 1. Overlayed Structuresꢃ A) 1 þ B-helix thymidine (from a DNA=DNA B-helix);
B) 1 þ 20F-ara-thymidine (from a DNA=DNA modified B-helix); C) 1 þ DNA A-helix thymi-
dine (from a RNA=DNA A-helix); D) 1 þ DNA A-helix thymidine (from a RNA=DNA A-
helix, 1 minimized). 1 in A, B, and C have w ¼ 7ꢀ, 2ꢀ, and 12ꢀ while 1 in D (1 minimized)
has w ¼ 27ꢀ. (ꢃThe new monomer was drawn with ChemDraw and PM3 minimized with
Hyperchem 7 (except 1 and D), the nucleoside structures were taken from the crystal struc-
tures. The crystal structures were downloaded from NDB (The Nuclei Acid Database):
Ref.[2] (BD0023); B: Ref.[3] (BD0007); C & D: Ref.[4] (AH0005). The overlay comparisons
was made in Macromodel with the help from Per-Ola Norrby (DTU, Lyngby, Denmark):
A, B & C: Compared by distance minimization between N1, O2, N3, and O4 in the nucleo-
bases and pairwise distance minimization between O30 and O50 in the sugar and O30 and
O40 in the new monomer by rotation around g, d, and w in 1. D: Compared by distance mini-
mization between N1, O2, N3, and O4 in the nucleobases and pairwise distance minimization
between O30 and O50 in the sugar and O30 and O40 in the new monomer by energy minimiza-
tion of 1 in Macromodel.)
Synthesis of the monomer 8 without the isobutyryl group has been described in a
Japanese patent,[5] using a route similar to ours, but in much lower yield.
CONCLUSION
Our new analogue seems to be an excellent mimic of nucleosides with different
sugar conformations (Fig. 1). However, a reduced binding of oligonucleotides modi-
fied with 1 to DNA and RNA has been observed. The reason for this is under investi-
gation.
A viable synthesis of the guanine monomer 8 has also been made.
REFERENCES
1. Boesen, T., Ph.D. Thesis; University of Copenhagen, Jan. 2001.
2. Kielkopf, C.L.; Ding, S.; Kuhn, P.; Rees, D.C. J. Mol. Biol. 2000, 296, 787–801.
3. Tereshko, V.; Minasov, G.; Egli, M. J. Am. Chem. Soc. 1999, 121, 470–471.
4. Xiong, Y.; Sundaralingam, M. Nucleic Acids Res. 2000, 28, 2171–2176.
5. Nakayama, T.; Ito, T.; Morisawa, Y.; Ikeuchi, K.; Takase, H.; Murakami, Y.
Preparation of acyclic purine derivatives as antiviral agents. JP7048374, Febru-
ary 1995, in Japanese.