Synthesis of a cyclopentane amide DNA analogue and its base pairing properties

Article abstract of DOI:10.1081/NCN-120022837

cpa-DNA monomers containing the bases adenine and thymine have been synthesized starting from the known compound 1 in 12 steps. Partially and fully modified cpa-thymidine and cpa-adenosine containing oligodeoxynucleotides were synthesized by standard olig

Full text of DOI:10.1081/NCN-120022837

This article was downloaded by: [National Sun Yat-Sen University]
On: 28 December 2014, At: 05:55
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
Synthesis of a Cyclopentane Amide DNA Analogue and
Its Base Pairing Properties
Dae-Ro Ahn a , Markus Mosimann a & Christian J. Leumann a b
a Department of Chemistry and Biochemistry , University of Bern , Bern, Switzerland
b Department of Chemistry and Biochemistry , University of Bern , Freiestrasse 3, 3012,
Bern, Switzerland
Published online: 31 Aug 2006.
To cite this article: Dae-Ro Ahn , Markus Mosimann & Christian J. Leumann (2003) Synthesis of a Cyclopentane Amide DNA
Analogue and Its Base Pairing Properties, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1207-1210, DOI: 10.1081/
NCN-120022837
To link to this article: http://dx.doi.org/10.1081/NCN-120022837
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1207–1210, 2003
Synthesis of a Cyclopentane Amide DNA Analogue and
Its Base Pairing Properties
Dae-Ro Ahn, Markus Mosimann, and
*
Christian J. Leumann
Department of Chemistry and Biochemistry, University of Bern,
Bern, Switzerland
ABSTRACT
cpa-DNA monomers containing the bases adenine and thymine have been synthe-
sized starting from the known compound 1 in 12 steps. Partially and fully modi-
fied cpa-thymidine and cpa-adenosine containing oligodeoxynucleotides were
synthesized by standard oligonucleotide chemistry. Fully modified homo-cpa-A
sequences lead to duplex destabilization by ꢀ1.4ꢁC=mod. relative to DNA. As
its congener bca-DNA, cpa-DNA prefers left-handed duplex formation where
possible.
We have recently reported on the synthesis and pairing properties of the new
DNA analogue bicyclo[3.2.1]-amide (bca) DNA.[1] In this DNA analogue the bases
are attached via a linear amide linker, as in PNA, to a conformationally constrained
DNA-backbone unit. This structural difference results in lengthening of the distance
between the backbone and the base relative to DNA. In order to establish the impor-
tance of the structural rigidity of the bca backbone on the pairing properties, we
*Correspondence: Christian J. Leumann, Department of Chemistry and Biochemistry,
University of Bern, Freiestrasse 3, 3012 Bern, Switzerland; E-mail: leumann@ioc.unibe.ch.
1207
DOI: 10.1081/NCN-120022837
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1208
Ahn, Mosimann, and Leumann
Figure 1. Representation of the chemical structures of DNA, bca-DNA and cpa-DNA, high-
lighting the number of bonds between base and backbone.
designed a structurally simpler variant cpa-DNA, in which the six-membered ring is
absent (Fig. 1).
Starting from the known compound 1,[2] we synthesized the enantiopure phos-
phoramidite building blocks with the bases A and T in 12 steps according to
Sch. 1. A series of oligonucleotides with single substitution of tcpa, as well as comple-
tely modified oligonucleotides with acpa and tcpa were prepared by standard phos-
phoramidite chemistry. Complex formation of the thus prepared sequences
was then analyzed with natural and modified complements by means of UV-
melting curves (Tm) and CD-spectroscopy. According to the Tm data (Table 1),
Scheme 1. a. i) mCPBA, CH2Cl2, rt, 42%; ii) TBAF, THF, rt, 93%; b. BnNCO, toluene,
90ꢁC, 79%; c. NaH, DMF, rt, 76%; d. Ac2O, DMAP, pyridine, rt, 97%; e. PLE, phosphate
buffer, pH ¼ 7, 30ꢁC, 31%; f. 8N KOH, 80ꢁC EtOH, 82%; g. 10% Pd=C, H2, MeOH, rt,
98%. h. EDC, base acid (A or T), DMF, rt, 65% for 9a, 66% for 9b; i. i) 9-chloro-(9-phe-
nyl)-xanthene, pyridine DMSO, rt, ii) TBDMS-Cl, imidazole, DMF, rt; 33% from 9a, 31%
from 9b; j. TBAF, THF, rt, 92% from 10a, 98% from 10b; k. (iPr2N)PCl(OC2H4CN),
DIPEA, THF, rt, 59% from 11a, 63% from 11b.

Cyclopentane Amide DNA Analogue
1209
Table 1. Tm values of duplexes (ꢁC) total oligonucleotide conc.: 5 mM in 10 mM Na-caco-
dylate, 1M NaCl, pH ¼ 7.0.
d(tcpa
)
dTd(tbca
)
d(T)9
d(T)5dtcpad(T)4
d(T)10
10
10
d(acpa
)
15.5
< 1a
n.m
n.m
21.6
4.2
28.3
20.1
19.1
n.m
17.5
9.7
4.0
32.1
24.5
23.6
9
d(A)10
r(A)10
dTd(abca
n.mb
n.m
n.m
)
8.1
10
aconc. ¼ 4 mM.
bn.m ¼ no Tm observed.
Figure 2. CD spectra of duplexes (exper. conditions as indicated in Table 1). Solid:
d(A)10=d(T)10; dash: r(A) 10=d(T)10; dot: d(acpa)9; dash dot: d(acpa)9=d(T)9; thick solid: d(acpa)9=
d(tcpa)10.
monomodification (not unexpectedly) lead to strong duplex destabilization relative
to complementary natural duplexes (ꢀ14.6ꢁC=mod. for DNA, ꢀ14.8ꢁC=mod. for
RNA).
The modified thymidine oligomer d(tcpa
)
10 was not able to form duplexes with a
corresponding homoadenosine oligomer of any backbone type investigated except
with d(acpa)9. However, the homoadenosine oligomer d(acpa
was able to form
)
9
duplexes with homothymidine oligomers of any backbone investigated although
with considerable loss in affinity relative to DNA ( < ꢀ1.4ꢁC=mod.).
Interestingly the CD traces of duplexes containing d(acpa)9 were enantiomorphic
to that of natural DNA, indicative for left-handed duplex structures (Fig. 2). The
single strand d(acpa)9 itself seems to be preorganized as a left-handed helix contrary
to that of dTd(abca
)10 that is preorganized as right handed helix (data not shown). It
seems therefore that removing the six-membered ring of the bicyclic backbone
promotes the left-handed helix formation.

1210
Ahn, Mosimann, and Leumann
REFERENCES
1. (a) Egger, A.; Leumann, C. Syn. Lett. 1999, 913 pp; (b) Ahn, D-R.; Pitsch, S.;
Lehmann, C.; Leumann, C. Chem. Eur. J. in press.
2. Livinghouse, T.; Stevens, R.V. J. Am. Chem. Soc. 1978, 100, 6479 pp.