Pentafluorophenyl-phenyl interactions in biphenyl-DNA

Article abstract of DOI:10.1002/chem.200401128

We prepared and investigated oligonucleotide duplexes of the sequence d(GATGAC(X)_nGCTAG)-d(CTAGC(Y)_nGTCATC), in which X and Y designate biphenyl- (bph) and pentafluorobiphenyl- (^5Fbph) C-nucleotides, respectively, and n va

Full text of DOI:10.1002/chem.200401128

FULL PAPER
Pentafluorophenyl–Phenyl Interactions in Biphenyl-DNA
Alain Zahn, Christine Brotschi, and Christian J. Leumann*[a]
Abstract: We prepared and investigat-
ed oligonucleotide duplexes of the se-
quence d(GATGAC(X)nGCTAG)·d(C-
TAGC(Y)nGTCATC), in which X and
Y designate biphenyl- (bph) and penta-
fluorobiphenyl- (5Fbph) C-nucleotides,
respectively, and n varies from 0–4.
These hydrophobic base substitutes are
expected to adopt a zipperlike, inter-
strand stacking motif, in which not only
bph/bph or 5Fbph/5Fbph homo pairs, but
also 5Fbph/bph mixed pairs can be
formed. By performing UV-melting
curve analysis we found that incorpora-
tion of a single 5Fbph/5Fbph pair leads
to a duplex that is essentially as stable
as the unmodified duplex (n=0), and
2.4 K more stable than the duplex with
the nonfluorinated bph/bph pair. The
Tm of the mixed bph/5Fbph pair was in
between the Tm values of the respective
homo pairs. Additional, unnatural aro-
matic pairs increased the Tm by +3.0–
4.4 K/couple, irrespective of the nature
of the aromatic residue. A thermody-
namic analysis using isothermal titra-
tion calorimetry (ITC) of a series of
duplexes with n=3 revealed lower
(less negative) duplex formation en-
thalpies (DH) in the 5Fbph/5Fbph case
than in the bph/bph case, and con-
firmed the higher thermodynamic sta-
bility (DG) of the fluorinated duplex,
suggesting it to be of entropic origin.
Our data are compatible with a model
in which the stacking of 5Fbph versus
bph is dominated by dehydration of
the aromatic units upon duplex forma-
tion. They do not support a model in
which van der Waals dispersive forces
(induced dipoles) or electrostatic
(quadrupole) interactions play a domi-
nant role.
Keywords: biphenyl derivatives
fluoroarenes · isothermal titration
calorimetry oligonucleotides
stacking interactions
·
·
·
Introduction
thogonal to the natural base-pairs in their recognition prop-
erties. Such pairs are of interest for the extension of the ge-
netic alphabet.[9–14]
Hydrogen bonding and stacking interactions between nucle-
obases are the major noncovalent forces that stabilize the
DNA and RNA double helices.[1,2] The relative contribution
of each to stability has been a matter of debate since the dis-
covery of the structure of the double helix. New insight into
the importance of base stacking for DNA structure and
function was obtained by Kool and co-workers, who investi-
gated shape mimics of complementary natural bases that
were devoid of the possibility to form hydrogen bonds.[3–6]
Although such isosters destabilize DNA duplexes, they can
code for each other with high precision in DNA poly-
merase-mediated replication.[7,8] This finding triggered an
extensive search for hydrophobic, aromatic pairs that are or-
Some insight into the physicochemical nature of stacking
interactions has come from studies of small-molecule inter-
actions, mostly in apolar solvents.[15] The stacking of aromat-
ic hydrocarbons on the corresponding fluorohydrocarbons
has been especially well investigated. It is well known that
benzene and hexafluorobenzene have quadrupole moments
of similar magnitudes, but with inverted signs.[16] These two
compounds, both liquids at room temperature, form a solid
aggregate,[17] which is characterized by not only alternating
p stacks, but also lateral alternation between hexafluoroben-
zene and benzene rings.[18] This stacking arrangement is be-
lieved to result from the minimization of electronic repul-
sion of the p systems and maximization of electrostatic and
dispersion forces, and not from charge-transfer interac-
tions.[19–21] Further support for this comes from studies of the
rotational barriers in 1,8-diarylnaphthalenes[22] and from
recent theoretical studies.[23,24] This knowledge is being ap-
plied in the field of crystal engineering.[25,26]
[a] Dipl.-Chem. A. Zahn, Dipl.-Chem. C. Brotschi, Prof. C. J. Leumann
Department of Chemistry and Biochemistry, University of Bern
Freiestrasse 3, 3012 Bern (Switzerland)
Fax : (+41)31-631-3422
E-mail: leumann@ioc.unibe.ch
Stacking interactions in water are more complicated, as
extensive energetic contributions from solvation/desolvation
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2005, 11, 2125 – 2129
DOI: 10.1002/chem.200401128
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2125

of the aromatic systems may interfere with the systemsꢁ in-
trinsic attractive and repulsive forces. From analysis of the
interactions of cationic or anionic porphyrins with benzoic
acid derivatives in water it is known that dispersive mecha-
nisms are dominant over electrostatic or donor–acceptor in-
teractions.[27] In the field of nucleic acids recognition there is
evidence for advantageous di- or quadrupolar interactions
of aromatic hydrocarbons with fluorohydrocarbons as base
replacements. This has been shown for the phenyl/penta-
fluorophenyl case in DNA[28] and PNA,[29] as well as for iso-
steric fluorobenzene/benzimidazole base replacements in
5Fbph/bph, and bph/bph residues were measured by record-
ing UV-melting curves, and for selected cases the thermody-
namic data of duplex formation were recorded by perform-
ing isothermal titration calorimetry (ITC).
Results
Synthesis of phosphoramidites: The C-nucleoside 7 was syn-
thesized from 2,3,5-tri-O-benzyl-d-ribono-1,4-lactone[36] and
4’-bromo-2,3,4,5,6-pentafluorobiphenyl (1),[37] by using es-
tablished pathways of C-nucleoside chemistry (see Scheme 1
ꢀ
RNA, in which C F···H hydrogen bonds were also invoked
as stabilizing forces.[30] More recently, the effects of the
number and position of fluorine atoms within fluorinated
DNA bases on duplex stability were evaluated in the “dan-
gling end” motif.[31] The results were consistent with the
notion that dispersive induced dipole attractions between
fluorohydrocarbons and natural base-pairs, rather than at-
tractions between permanent dipoles or quadrupolar inter-
actions, are relevant to stability. For a duplex containing an
internal aromatic, hydrophobic pair, duplex stability is
always higher for fluorinated base surrogates than for the
parent nonfluorinated analogues. This reinforces the solva-
tion argument.[32]
and Supporting Information).[38,39] Lithiation of
1 with
nBuLi, followed by addition to the lactone, resulted in the
formation of the corresponding hemiacetal intermediates.
These were reduced with Et3SiH in the presence of a strong
Lewis acid (BF3·Et2O) to afford only one anomeric form of
the C-nucleoside 2 (b-anomer, as determined by performing
1H NMR nuclear Overhauser effect (NOE) experiments, see
Supporting Information). Debenzylation with BBr3 in
CH2Cl2 (!3) followed by selective protection of the 5’- and
3’-hydroxyl groups with 1,3-dichloro-1,1,3,3-tetraisopropyldi-
We recently proposed a novel, zipperlike, interstrand
stacking recognition motif for oligodeoxynucleotide duplex-
es containing bipyridyl- (bpy) or biphenyl- (bph) C-nucleo-
tide pairs, in which the terminal phenyl rings overlap
(Figure 1).[33–35] The model is supported by the results of mo-
Figure 1. Chemical structures of the biaryl nucleoside analogues investi-
gated, and the proposed interstrand stacking recognition motif of such ar-
omatic units (X) in the center of an oligodeoxynucleotide duplex with
the indicated sequence.
lecular dynamics simulations and by preliminary 1H NMR
data. This motif is well suited to a more detailed study of
stacking interactions, as it can be extended to at least seven
internal, consecutive, aromatic pairs in an oligonucleotide
duplex without the break down of the double helix struc-
ture.[35] Here we describe the synthesis and incorporation
into oligonucleotides of the pentafluorobiphenyl (5Fbph) C-
nucleoside (Figure 1). The thermal stabilities (Tm) of duplex-
es containing one, three, and four consecutive 5Fbph/5Fbph,
Scheme 1. Reagents and conditions: a) 1 (1 equiv), nBuLi (1 equiv), THF,
ꢀ788C, 1 h, then 2,3,5-tri-O-benzyl-d-ribono-1,4-lactone (1 equiv) in
THF, ꢀ788C!RT, 16 h; b) Et3SiH (5 equiv), BF3·OEt2 (5 equiv), CH2Cl2,
ꢀ788C!RT, 16 h; c) BBr3 (3.5 equiv), CH2Cl2, ꢀ788C, 4 h; d) 1,3-di-
chloro-1,1,3,3-tetraisopropyldisiloxane (1.2 equiv), pyridine, RT, 16 h;
e) 1,1’-thiocarbonyldiimidazole (1.2 equiv), CH3CN, RT, 16 h; f) AIBN
(0.2 equiv), tris(trimethylsilyl)silane (1.5 equiv), toluene, 858C, 30 min;
g) (HF)3·NEt3 (10 equiv), THF, RT, 16 h; h) 4,4’-dimethoxytrityl (DMTr)
chloride (1.2 equiv), pyridine, RT, 4 h; i) [(iPr2N)(NCCH2CH2O)P]Cl
(1.5 equiv), iPr2NEt (3 equiv), THF, RT, 1.5 h.
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Chem. Eur. J. 2005, 11, 2125 – 2129

Interactions in Biphenyl-DNA
FULL PAPER
siloxane (TIPDSCl2) in pyridine afforded the TIPDS-pro-
tected nucleoside 4 in acceptable yield. The 2’-hydroxyl
group was then removed by performing Barton–McCombie
deoxygenation. For this, 4 was converted to the correspond-
Thermal denaturation studies: Complementary oligodeoxy-
nucleotides were mixed in a 1:1 stoichiometry and subjected
to UV-melting curve analysis (Table 1). This data reveals
that insertion of one bph/bph pair decreases the Tm of the
duplex relative to that of the unmodified duplex by 2.5 K,
whereas insertion of a 5Fbph/5Fbph does not change the Tm.
For additionally inserted aromatic couples, an average in-
crease in Tm of 3.0–4.4 K/pair was observed. In all cases, du-
plexes containing only 5Fbph residues are thermally more
stable (+2.2 to +2.7 K) than duplexes containing the same
number of bph residues. The Tm of mixed bph/5Fbph pairs
are always in between those of the homo pairs.
ing
thiocarbimidazolide
5
by
using
1,1’-thiocar-
bonyldiimidazole in CH3CN, followed by treatment with
tris(trimethylsilyl)silane (TTMSS) and catalytic amounts of
a,a’-azoisobutyronitrile (AIBN) in toluene, to give the
TIPDS-protected 2’-deoxynucleoside 6 in high yield. Finally,
cleavage of the TIPDS protection group under mild condi-
tions ((HF)3·NEt3 in THF) afforded the 2’-deoxy-C-nucleo-
side 7 in good yield. The C-nucleoside 7 was subsequently
converted into the corresponding 4,4’-dimethoxytrityl
(DMTr)-protected phosphoramidite building block 9 by
using standard conditions. Treatment of 7 with 4,4’-dime-
thoxytritylchloride (DMTrCl) in pyridine (!8), followed by
addition of [(iPr2N)(NCCH2CH2O)P]Cl under slightly basic
conditions (iPr2NEt) in CH2Cl2, yielded phosphoramidite 9
in an overall yield of 5%.
Isothermal titration calorimetry: To obtain a picture of the
thermodynamic data of duplex formation we performed iso-
thermal titration calorimetry experiments at 301.4ꢁ0.1 K
with duplexes containing three consecutive, modified, aro-
matic pairs. The heat versus time signals obtained for a rep-
resentative case (bph/bph) are shown in Figure 2 (top). Nor-
Synthesis of oligonucleotides: The 5Fbph-modified oligonu-
cleotides (for sequences see Table 1) were synthesized in the
trityl-off mode on a 1 mmol scale by using standard phos-
Table 1. Tm data for duplex melting obtained from UV-melting curves
(260 nm).
5’-d(GATGAC(X)nGCTAG)
3’-d(CTACTG(Y)nCGATC)
n
X
Y
Tm [8C][a]
0
1
1
3
4
1
3
4
1
3
4
1
3
4
–
T
–
A
45.0
47.9
44.9
52.1
55.9
44.5
51.9
55.1
44.0
51.5
55.0
42.5
49.9
53.2
5Fbph
5Fbph
5Fbph
5Fbph
5Fbph
5Fbph
bph
5Fbph
5Fbph
5Fbph
bph
bph
bph
5Fbph
5Fbph
5Fbph
bph
bph
bph
bph
bph
Figure 2. Isothermal titration calorimetry (T=301.4 K). Top: heat signal
versus time for the titration of d(GATGAC(bph)3GCTAG) (c=10.0 mm)
with d(CTACTG(bph)3CGATC) (c=99.8 mm) in NaH2PO4 (10 mm),
NaCl (150 mm), pH 7.0; bottom: corresponding normalized heat signal
versus molar strand ratio.
bph
bph
bph
[a] c=1.2 mm in NaH2PO4 (10 mm), NaCl (150 mm), pH 7.0. Estimated
error in Tm =ꢁ0.58C.
phoramidite chemistry. The coupling time was extended to
10 min for the modified units. In the coupling step, tetrazole
was replaced by 5-(ethylthio)-1H-tetrazole. Coupling yields
for the modified units, as judged from detritylation, were
within the same range as for nonmodified building blocks
(>98%). After detachment from the solid support and de-
protection under standard conditions (conc. NH3, 558C,
16 h), the oligomers were purified by conducting HPLC, and
their structural integrity was verified by performing electro-
spray ionization mass spectrometry (ESI-MS, see Supporting
Information). The bph-modified oligonucleotides were pre-
pared as described previously.[35]
malization and integration of the heat capacity data gives
the enthalpy of duplex formation, which was plotted against
the molar ratio of the two single strands (Figure 2, bottom).
The association constant K and the entropy change (DS)
were obtained by applying a nonlinear fit and were used to
calculate the free energy (DG). The corresponding data for
the three cases with bph/bph, bph/5Fbph, and 5Fbph/5Fbph
pairs are given in Table 2.
The free energy (DG) values are in accordance with the
thermal melting (Tm) data. The duplex containing only
5Fbph residues is 0.9 kcalmolꢀ1 more stable than the corre-
sponding duplex containing only bph residues. The stability
Chem. Eur. J. 2005, 11, 2125 – 2129
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2127

C. J. Leumann et al.
Table 2. Thermodynamic data of duplex formation obtained by perform-
ing isothermal titration calorimetry (ITC). (For experimental conditions,
see legend for Figure 2.)
rangements of the two phenyl rings, although the nonplanar-
ity is much more pronounced in the case of the 5Fbph, as dis-
cernible from the rotation barrier in the gas phase (approxi-
mately 11 kcalmolꢀ1 for 5Fbph and 2 kcalmolꢀ1 for bph).[41]
Thus, the higher stability achieved by the 5Fbph pair may be
explained by superior stacking interactions with the neigh-
boring natural base-pairs rather than by structural factors.
One striking observation from the Tm data is that a
duplex containing a single 5Fbph or bph base-pair has a level
of thermal stability similar to that of the corresponding un-
modified duplex, and that the stability increases as each sub-
sequent hydrophobic base-pair is added. This is not the case
for duplexes containing edge-to-edge arrangements of hy-
drophobic fluorinated or nonfluorinated shape mimics of
natural base-pairs,[32] and demonstrates the importance of in-
terstrand as opposed to intrastrand stacking interactions for
duplex stability.
5’d(GATGACXXXGCTAG)
3’d(CTACTGYYYCGATC)
[a]
X
Y
-DHITC
-DSITC
-DGITC
[kcalmolꢀ1
]
[calKꢀ1 molꢀ1
]
[kcalmolꢀ1
]
5Fbph
5Fbph
bph
5Fbph
bph
bph
84.4ꢁ0.5
82.4ꢁ0.4
88.6ꢁ0.4
243ꢁ2
237ꢁ2
260ꢁ2
11.1ꢁ0.1
11.0ꢁ0.1
10.2ꢁ0.1
[a] Calculated for T=301.4 K.
of the mixed duplex lies within this range. Interestingly, the
enthalpy of duplex formation (DH) is 4.2 kcalmolꢀ1 more fa-
vorable in the bph duplex than in the 5Fbph duplex. Thus,
the higher thermodynamic stability of the 5Fbph duplex is of
entropic and not enthalpic origin.
CD spectroscopy: To follow structural changes as the
number n of 5Fbph pairs increases, and to support the inter-
strand stacking model, we recorded CD spectra of the corre-
sponding duplexes (Figure 3). The CD spectra are reminis-
cent of those for B-DNA. It is very likely that the gradual
Although a high resolution structure of this zipper motif
has not yet been characterized, experimental evidence for it
has been obtained from the results of molecular modeling,[33]
1H NMR analysis, and from Tm and CD data in various se-
quence contexts.[35] Therefore, the data described in this
paper are relevant to the discussion of the general contribu-
tion of energy to stacking in an aqueous environment, and
in particular, to fluorinated versus nonfluorinated aromatic
hydrocarbons. In this context, the zipper motif can be re-
garded as an alternative to the “dangling end” model that
has been used by Kool and co-workers to describe base
stacking interactions in DNA.[40] Moreover, it raises the pos-
sibility of studying multiple aromatic residues in the center
of the helix that have stacking contacts to either aromatic
residues in the counter strand, or to natural adjacent base-
pairs on both faces.
Extension of n to three and four in the duplex sequence
results in an alternating stack of aromatic residues from
each strand. If quadrupolar effects were energy determining,
then the duplex with the mixed (5Fbph/bph) stack should
show the highest stability. Considering the calorimetric data
of Table 2 it becomes clear that this is not the case. The sta-
bility of the bph/5Fbph system is similar to that of the 5Fbph/
5Fbph stack and only 0.9 kcalmolꢀ1 greater than the bph/bph
stack. The thermal melting (Tm) data (Table 1) also reflect
this behavior. The insertion of three and four aromatic pairs
results in parallel Tm increases regardless of the nature of
the aromatic unit. Therefore, the difference between Tm
values for duplexes with four 5Fbph and four bph pairs, re-
spectively, (2.7 K) is essentially the same as the difference
for duplexes with only one 5Fbph or bph pair, respectively,
(2.5 K). We can conclude that quadrupolar effects of penta-
fluorophenyl/phenyl interactions do not contribute measura-
bly to the stacking energy in this case. This is in contrast to
aryl/fluoroaryl systems in both the solid state, in which
quadrupolar effects generally dictate structure,[17,18,26,42] and
in organic solvents, in which electrostatic models also
apply.[22b,43]
Figure 3. CD spectra of duplexes containing 0–4 5Fbph base-pairs (X=
Y=5Fbph); c=3.6 mm in NaH2PO4 (10 mm), NaCl (150 mm), pH 7.0, T=
208C.
red-shift of the negative maximum from 254 nm to 240 nm
for increasing numbers of 5Fbph residues reflects the increas-
ing contribution of the 5Fbph chromophore to the CD, and
not a change in the general structural motif. Furthermore,
the CD spectra are very similar to those of the bph duplex-
es.[35] The CD spectra are thus in accordance with a structure
containing highly ordered, aromatic units.
Discussion and Conclusions
The thermal melting analysis of the duplexes containing one
single 5Fbph/5Fbph or bph/bph pair shows an increased ther-
mal stability of 2.5 K for the former duplex. Interestingly,
this indicates that coplanarity of the two phenyl rings in the
biarylic unit is not necessary for the stability of this motif.
Indeed, both systems are expected to have nonplanar ar-
Small, but statistically significant, differences in the en-
thalpies of duplex formation were revealed by ITC analysis,
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Chem. Eur. J. 2005, 11, 2125 – 2129

Interactions in Biphenyl-DNA
FULL PAPER
in which bph pairing was more exothermic than 5Fbph pair-
ing (Table 2). Assuming that there is no significant differ-
ence in single-strand energies at the temperature used in the
experiment, the higher thermodynamic stability of the 5Fbph
duplex is of entropic origin. This fact does not support the
dominance of attractive van der Waals or electrostatic inter-
actions between the hydrophobic residues. It is, however, in
accordance with an enhanced hydrophobic effect for 5Fbph,
arising from desolvation. This is supported by the generally
higher values for log P and the larger surface areas of the
fluoroaryls.[32]
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In conclusion, our data are compatible with a model in
which the energies of the 5Fbph versus bph interactions are
dominated by dehydration of the aromatic units during
single-strand to duplex transition. They do not support a
model in which van der Waals dispersive forces (induced di-
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Experimental Section
Experimental details for the reactions and products of Scheme 1, for oli-
gonucleotides containing 5Fbph residues, as well as for UV-melting curve
analysis, CD spectroscopy, and isothermal titration calorimetry can be
found in the Supporting Information.
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Acknowledgements
Financial support from the Swiss National Science Foundation (CJL,
grant number 200020–100178) and from the Roche Research Foundation,
Basel (AZ) is gratefully acknowledged.
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Received: November 8, 2004
Published online: February 15, 2005
Chem. Eur. J. 2005, 11, 2125 – 2129
www.chemeurj.org
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2129