Towards a DNA-like duplex without hydrogen bonds

Article abstract of DOI:10.1081/NCN-120022831

The inverse quadrupolar moments of the phenyl and pentafluorophenyl residues in the base pair P-F⁵ promotes strong intramolecular stacking interactions in DNA duplexes. The more natural base pairs are replaced by this novel pair the higher the thermodynamic stability of the resulting duplex if they are arranged in an alternating fashion.

Full text of DOI:10.1081/NCN-120022831

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Towards a DNA-Like Duplex Without Hydrogen Bonds
Gérald Mathis a b , Rolf Schütz a & Jürg Hunziker 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: Gérald Mathis , Rolf Schütz & Jürg Hunziker (2003): Towards a DNA-Like Duplex Without Hydrogen Bonds,
Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 1183-1185
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1183–1185, 2003
Towards a DNA-Like Duplex Without
Hydrogen Bonds
*
´
Gerald Mathis, Rolf Schu¨tz, and Ju¨rg Hunziker
Department of Chemistry and Biochemistry, University of Bern,
Bern, Switzerland
ABSTRACT
The inverse quadrupolar moments of the phenyl and pentafluorophenyl residues
in the base pair P-F5 promotes strong intramolecular stacking interactions in
DNA duplexes. The more natural base pairs are replaced by this novel pair the
higher the thermodynamic stability of the resulting duplex if they are arranged
in an alternating fashion.
Based on the recent observation that hydrophobic effects can be exploited in
addition to complementary hydrogen bonding to create novel base pairs,[1,2], we
have incorporated the pentafluorophenyl-(F5) and phenyl-C-deoxyribosides (P)
shown below (Fig. 1) into synthetic oligonucleotides. The inverse quadrupolar
moments of the phenyl and pentafluorophenyl residues are expected to lead to
edge-to-edge attractive intermolecular forces.[3,4]
The synthesis of phenyl-2-deoxyriboside phosphoramidite has been described
before.[5] The novel pentafluorophenyl congener F5 was prepared starting from 2-
deoxyribonolactone (Sch. 1).[6] Silyl-protected 2-deoxyribonolactone 2 was added
´
*Correspondence: Gerald Mathis, Department of Chemistry and Biochemistry, University of
Bern, Freiestrasse 3, CH-3012 Bern, Switzerland; E-mail: gerald.mathis@ioc.unibe.ch.
1183
DOI: 10.1081/NCN-120022831
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1184
Mathis, Schu¨tz, and Hunziker
Figure 1. Structures of the monomers used to investigate the stability of F5-P base pairs in
oligodeoxynucleotide.
to lithiopenta-fluorobenzene. The intermediate hemiacetal was reduced in situ with
Et3SiH to give an inseparable 9:1-mixture (b=a) of the two anomers 3. These could
be separated by chromatography after deprotection of the deoxyribose moiety and
reprotection as 50-dimethoxytrityl ethers. Pentafluorophenyl-b-d-riboside phosphor-
amidite building block 4 was then obtained by standard phosphitylation. Oligo-
nucleotides containing P and F5 (Table 1) were prepared using a regular solid-phase
DNA synthesis protocol.
When incorporated in the middle of a 10-mer DNA duplex, one or two F5-P
pairs lead to destabilization as judged from thermal melting profiles. However, if
four consecutive pairs of alternating sequence are present, duplex stability exceeds
that of the corresponding reference duplex with four A-T base pairs in the same posi-
tions.
Experiments towards the enzymatic replication of P-F5 base pairs have not been
successful so far. The F5 triphosphate could not be incorporated opposite P by DNA
polymerase I (Klenow fragment) under running start or primer extension conditions.
Scheme 1. (a) Br2, H2O, r.t., 4d, dark. (b) (iPr2SiCl)2O, imidazole DMF, r.t., 24 h, 83% (from
1). (c) BuLi, C6F5Br, Et2O, ꢀ78ꢁC, 3.5 h. (d) BF3-Et2O, Et3SiH, CH2Cl2, ꢀ78ꢁC to 0ꢁC, over-
night, 22% (from 2). (e) TBAF, THF, r.t., 2.5 h, 87%. (f) DMTCl, DMAP, py., r.t., 3.5 h, 70%.
i
i
(g) Pr2NP(Cl)OCH2CH2CN, Pr2EtN, THF, r.t., 1 h, 92%.

DNA-Like Duplex Without Hydrogen Bonds
1185
Table 1. Tm value [ꢁC] determined from UV melting experiment (Duplex concentration:
4 mM. Buffer: 10 mM Na2PO4, 150 mM NaCl, pH 7.0. Detection at 260 nm, Tm ¼ mean value
of three melting curve, heating rate ¼ 0.5ꢁC=min) and thermodynamic data (Duplex concen-
tration: 1–32 mM. Buffer: 10 mM NaH2PO4, 150 mM NaCl, pH 7.0).
DTm=mod
DHꢁ
[kcal=mol]
DSꢁ
[cal=mol.K]
DGꢁ (25ꢁC)
[kcal=mol]
Oligonucleotide
Tm [ꢁC]
45.0
[ꢁC]
d(CTGAATCGAC)ꢂ
d(GTCGATTCAG)
d(CTGAPTCGAC)ꢂ
d(GTCGAF5TCAG)
–
ꢀ77.6
ꢀ61.5
ꢀ213
ꢀ175
ꢀ13.8
ꢀ9.1
30.6
ꢀ14.4
d(CTGATATCAG)2
d(CTGAGCTCAG)2
d(CTGAF5PTCAG)2
d(CTGF5PF5PCAG)2
38.0
48.5
30.0a
44.0
–
ꢀ67.5
ꢀ82.3
–
ꢀ94.3
ꢀ192
ꢀ231
–
ꢀ273
ꢀ10.1
ꢀ13.3
–
ꢀ13.0
þ10.5
ꢀ4.0
þ1.5
aMonomolecular hairpin at 4 mM.
In conclusion, complementary charge distribution as in the phenyl=pentafluoro-
phenyl C-nucleosides F5 and P comprises a novel design principle for artificial base
pairs. The results from this study highlight the importance of favorable intrastrand
stacking interactions in the thermodynamic stabilization of oligonucleotide duplexes.
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