Metal-Mediated Assembly of 1,N6-Ethenoadenine: From Surfaces to DNA Duplexes

Article abstract of DOI:10.1021/acs.inorgchem.6b00927

The design of multinuclear metal complexes requires a match of the ligand-to-metal vectors and the preferred coordination geometries of the metal ions. Only a few ligands are known with a parallel orientation of N→M vectors that brings the metal ions into

Full text of DOI:10.1021/acs.inorgchem.6b00927

Article
pubs.acs.org/IC
Metal-Mediated Assembly of 1,N6‑Ethenoadenine: From Surfaces to
DNA Duplexes
Soham Mandal,†,‡ Can Wang,§ Rajneesh K. Prajapati,∥ Jutta Kosters,† Sandeep Verma,*,∥ Lifeng Chi,*,§,⊥
̈
and Jens Muller*,†,‡
̈
†Institut fur Anorganische und Analytische Chemie, and NRW Graduate School of Chemistry, Westfalische Wilhelms-Universitat
‡
̈
̈
̈
Munster, Corrensstrasse 30, 48149 Munster, Germany
̈
̈
§Physikalisches Institut, Westfalische Wilhelms-Universitat Munster, Wilhelm-Klemm-Strasse 10, 48149 Munster, Germany
∥Department of Chemistry, DST Thematic Unit of Excellence on Soft Nanofabrication, Indian Institute of Technology−Kanpur,
̈
̈
̈
̈
Kanpur, Uttar Pradesh 208016, India
⊥Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices,
Soochow University, 199 Ren’ai Road, Suzhou, 215123 Jiangsu, People’s Republic of China
S
* Supporting Information
ABSTRACT: The design of multinuclear metal complexes
requires a match of the ligand-to-metal vectors and the
preferred coordination geometries of the metal ions. Only a
few ligands are known with a parallel orientation of N→M
vectors that brings the metal ions into close proximity. We
establish here the adenine derivative 1,N6-ethenoadenine (εA)
as an ideal bis(monodentate) ligand. Scanning tunneling
microscope images of alkylated εA on graphite surface clearly
indicate that these ligands bind to Ag(I) ions. The molecular
structures of [Ag2(1)2](ClO4)2 and [Ag2(2)2](ClO4)2 (1, 9-
ethyl-1,N6-ethenoadenine; 2, 9-propyl-1,N6-propylenoadenine)
confirm that dinuclear complexes with short Ag···Ag distances
are formed (3.0256(3) and 2.984(1) Å, respectively). The
structural motif can be extended to divalent metal ions, as was shown by determining the molecular structure of
[Cu2(1)2(CHO2)2(OH2)2](NO3)2·2H2O with a Cu···Cu distance of 3.162(2) Å. Moreover, when introducing the 1,N6-
ethenoadenine deoxyribonucleoside into parallel-stranded DNA duplexes, even dinuclear Ag(I)-mediated base pairs are formed,
featuring the same transoid orientation of the glycosidic bonds as the model complexes. Hence, 1,N6-ethenoadenine and its
derivatives are ideally suited as bis(monodentate) ligands with a parallel alignment of the N→M vectors for the construction of
supramolecular metal complexes that require two metal ions at close distance.
ligands have rarely been reported,7 and most examples involve
an NCN-type arrangement of the donor atoms. Only very few
examples have been reported of ligands with an NCCN-type
arrangement, i.e., with two atoms located between the two
nitrogen donor atoms rather than one, which significantly
influences the bite angle of the ligand. One of these rare
examples involves a nucleobase derivative, namely, N9-benzyl-
N6-methoxyadenine.8 We recently investigated the DNA lesion
1,N6-ethenoadenine (εA, Chart 1) in the formation of metal-
mediated base pairs.9 Metal-mediated base pairs in general are
applied for a site-specific incorporation of metal complexes into
nucleic acids, combining the evolutionary optimized self-
assembly property of the latter with metal-based functionality.10
In the resulting double helices, the transition metal ions are
located inside the double helices,11 as confirmed by several
INTRODUCTION
■
Nucleobases are well-known nitrogen donor ligands for the
generation of transition metal complexes.1 Depending on the
number of ligands and metal ions, multinuclear and even
supramolecular systems can be created.2 Hence, adenine and its
derivatives have been intensely investigated as building blocks
for coordination polymers.3 The rational design of multinuclear
metal complexes relies on a combination of suitably oriented
metal-to-ligand vectors and preferred coordination environ-
ments of the respective metal ions.4 For example, the formation
of a molecular square is enabled by a 90° angle between the
N1→M and N7→M vectors of N1,N7-dimetalated purine
residues when using linearly coordinating metal ions.5 Ligands
with a parallel alignment of the N→M vectors represent an
interesting addition to the library of building blocks for the
generation of supramolecular metal complexes, as this brings
the metal ions into close distance, a structural feature often
associated with interesting physical properties.6 However, such
Received: April 14, 2016
© XXXX American Chemical Society
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Chart 1. 9-Alkyl-1,N6-ethenoadenine (εA) Derivatives and
Atom Numbering Scheme (1, R = Ethyl; 3, R = Icosyl; 4, R =
Octadecyl)
experimental nucleic acid structures.12 We could show that εA
is capable of forming dinuclear Ag(I)-mediated base pairs,9
which represent a prominent subdivision of metal-mediated
base pairs.13 Our 1H and 15N NMR spectroscopic data showed
that a dinuclear Ag(I) complex is also formed in solution when
using the model nucleobase 9-ethyl-1,N6-ethenoadenine.9 In
this dinuclear complex, the N→M vectors are expected to be
essentially parallel to each other. We therefore set out to
investigate the structural details of metal complexes of N9-
alkylated derivatives of εA in more detail.
RESULTS AND DISCUSSION
■
Molecular Structures of Dinuclear Complexes. First,
the molecular structures of a series of metal complexes of εA
derivatives were determined. Toward this end, 9-ethyl-1,N6-
ethenoadenine (1) was prepared, acting as a model nucleobase
for εA. Figure 1 shows the molecular structure of this ligand,
confirming its composition.
Figure 2. Molecular structures of the cations of the dinuclear Ag(I)
complexes (a) [Ag2(1)2](ClO4)2 and (b) [Ag2(2)2](ClO4)2.
Table 1. Selected Bond Lengths (Å) and Angles (deg) of
[Ag2(1)2](ClO4)2 and [Ag2(2)2](ClO4)2
[Ag2(1)2](ClO4)2
[Ag2(2)2](ClO4)2
Ag1−N7
Ag1−N6a
Ag1−Ag1a
N7−Ag1−N6a
2.120(2)
2.115(2)
2.120(6)
2.095(6)
2.984(1)
169.4(2)
3.0256(3)
169.80(7)
complexes are C2-symmetric, owing to the transoid orientation
of the alkyl substituents.
Reaction of 1 with Cu(NO3)2 gave rise to the formation of a
dinuclear complex, too. This complex features two additional
formato ligands. The generation of formic acid during the
synthesis of the complex may be rationalized in two ways: (i)
copper-catalyzed reduction of atmospheric CO2 (the fixation of
CO2 by copper complexes is well-known),15 possibly using hot
methanol as a reducing agent;16 (ii) copper-catalyzed oxidation
of the solvent methanol (the corresponding ruthenium-
catalyzed reaction is well-established).17 The formate anions
act as μ-O bridging ligands for the Cu(II) ions in the resulting
complex [Cu2(1)2(CHO2)2(OH2)2](NO3)2·2H2O. Figure 3
shows the molecular structure of the complex cation as
determined by single-crystal X-ray diffraction analysis. Relevant
bond lengths and angles are summarized in Table 2.
The Cu(II) ions adopt a square pyramidal coordination
environment with N6, N7, O1W, and O1F in the basal plane
and O1Fa in the apical position. Amounting to 172.63(6)°, the
N6−Cu1−N7 angle is slightly larger than the corresponding
angle in the Ag(I) complexes, leading to an almost parallel
alignment of the N→M vectors. This increase is probably due
to the higher charge of the metal ion and the presence of an
additional bridging formato ligand. The μ-O bridging mode
observed in this complex represents a rare binding mode for
formato ligands. The bond lengths and angles of the
Figure 1. Molecular structure of 9-ethyl-1,N6-ethenoadenine (1).
Hydrogen atoms omitted for clarity.
Reaction of 1 with AgClO4 gave rise to the formation of the
dinuclear complex [Ag2(1)2](ClO4)2. The molecular structures
of this complex and of a closely related system based on 9-
propyl-1,N6-propylenoadenine 2 were determined by single-
crystal X-ray diffraction analysis. Figure 2 shows the molecular
structures of the complex cations [Ag2(1)2]2+ and [Ag2(2)2]2+.
The latter complex was obtained from 9-propyl-N6-propargyl-
adenine in a Ag(I)-catalyzed intramolecular cyclization reaction
similar to the previously reported metal-catalyzed cyclization
reactions of purine derivatives via their endocyclic N3 atom.3i,14
Further experimental insight into this cyclization is given in the
Supporting Information. Relevant bond lengths and angles are
almost identical for both complexes and are listed in Table 1.
Both complexes show rather short Ag−Ag distances of
3.0256(3) and 2.984(1) Å, respectively, clearly indicating the
presence of a stabilizing argentophilic interaction.6 The mutual
attraction of the Ag(I) ions is further corroborated by the fact
that the N7−Ag1−N6a angle slightly deviates from 180°.
Nonetheless, the N7→Ag1 and N6→Ag1a vectors are almost
parallel to each other. Moreover, the structures of both
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Figure 3. Molecular structure of the cation of the dinuclear Cu(II)
complex [Cu2(1)2(CHO2)2(OH2)2](NO3)2·2H2O.
Table 2. Selected Bond Lengths (Å) and Angles (deg) of
[Cu2(1)2(CHO2)2(OH2)2](NO3)2·2H2O
Cu1−N7
Cu1−N6
1.991(2)
1.977(2)
1.982(2)
1.958(1)
2.210(2)
3.162(2)
1.282(3)
1.212(2)
N7−Cu1−N6
172.63(6)
176.36(6)
94.83(6)
92.16(6)
95.21(6)
81.57(5)
98.43(5)
126.5(2)
O1W−Cu1−O1F
O1W−Cu1−O1Fa
N7−Cu1−O1Fa
N6−Cu1−O1Fa
O1F−Cu1−O1Fa
Cu1−O1F−Cu1a
O1F−C1F−O2F
Cu1−O1W
Cu1−O1F
Cu1−O1Fa
Cu1···Cu1a
C1F−O1F
C1F−O2F
Figure 4. (a) Large-scale (100 nm × 100 nm) and (b) high-resolution
(15 nm × 15 nm) STM images of 3 adsorbed on HOPG. Part b also
shows an overlay of the molecular structure of 3. The imaging
conditions are (a) E = −900 mV, I = 100 pA and (b) E = −820 mV, I
= 240 pA. (c) Proposed structural model for the ordered adlayer of 3
on HOPG.
[Cu2(CHO2)2]2+ core agree well with those found in the other
few examples.18 Again, the entire complex is C2-symmetric, as a
result of the transoid orientation of the ethyl substituents on
the N9 positions.
high-resolution STM image (Figure 4b) shows that the bright
stripes are composed of spots with a diameter of 0.6(1) nm.
The individual alkyl chains can be clearly discerned in the dark
stripes, which adopt a parallel arrangement. The measured
length of an alkyl chain amounts to 2.5(1) nm, consistent with
its expected length. The contrast difference originates from the
electronic density difference between aromatic core and alkyl
chain. Each alkyl chain is connected to one bright spot,
representing the εA aromatic core. The intermolecular distance
and molecular conformation demonstrate a flat-lying orienta-
tion of 3 on HOPG with its aromatic cores parallel to the
substrate. A unit cell for the adlayer is outlined in Figure 4b,
with lattice parameters of a = 3.3(1) nm, b = 1.1(1) nm, and ϑ
= 70(2)°, as determined from the STM image. A structural
model for the molecular orientation and the packing in the
adlayer is illustrated in Figure 4c.
In the presence of Ag(I), ligand 3 forms a different adlayer
on HOPG. The deposition of Ag(I) was clearly confirmed by
X-ray photoelectron spectroscopy (XPS) (Supporting Informa-
tion). On the first inspection, the large-scale STM image of the
adlayer (Figure 5a) appears similar to that of 3 without Ag(I).
Again, a well-ordered lamellar structure of alternative bright and
dark stripes is observed. However, close-ups of that image
reveal that the interstripe distance is increased from 3.3(1) to
3.8(1) nm. The lattice parameters as determined from the STM
image amount to a = 1.2(1) nm, b = 3.8(1) nm, and ϑ =
85(2)°. As can be seen from Figure 5b−d, some other details
have changed in the presence of Ag(I), too. The width of the
bright stripes is now larger than in Figure 4b. Moreover, the
aromatic cores in Figure 5b adopt a parallel arrangement
instead of an interdigitated one. When applying optimized scan
conditions, interdigitating alkyl chains are observed (Figure 5c),
while the aromatic cores are dark. The intermittent bright dots
can be assigned to Ag(I) ions. By further increasing the
Structure of the Ag(I) Complex after Deposition on a
Substrate. Having confirmed by X-ray crystallography that
derivatives of εA form dinuclear metal complexes in the solid
state, we reduced the dimensionality of the system under
investigation from 3D to 2D by investigating surface-deposited
compounds. This ensures that potential crystal packing effects
are irrelevant; hence, only π stacking interactions (to the
surface) andwhere applicablehydrogen bonding and metal
coordination affect the structure. Previous reports on the
arrangement of surface-deposited nucleobases had shown
numerous interesting deposition patterns.19 In contrast, the
adsorption of nucleobases to form 2D structures based on
coordinative bonds had been investigated to a much lesser
extent and with a clear focus on tetrad formation.20 We
therefore set out to perform the first investigation of the
formation of metal-mediated base pairs via scanning tunneling
microscopy (STM). To increase the affinity of the surface for
the ligand and to enable a periodic deposition of the latter, we
synthesized the N9-alkylated derivatives 9-icosyl-1,N6-ethenoa-
denine (3) and 9-octadecyl-1,N6-ethenoadenine (4). The
molecular structure of the latter is given in the Supporting
Information. The molecules of 4 are packed in a lamellar
fashion. It can be expected that compound 3, which was applied
in the surface studies because of its slightly longer alkyl chain,
shows a similar behavior.
Initial experiments to investigate the molecular conformation
and adsorption of 3 on an HOPG (highly ordered pyrolytic
graphite) surface indicate that a uniform and well-ordered
monolayer is formed (Figure 4a). Bright and dark stripes
alternately appear in the image showing a lamellar structure. A
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structures reported here clearly indicate a preference for a C2-
symmetric dimer, we set out to investigate the possibility of
incorporating such a transoid Ag(I)-mediated base pair into a
DNA double helix. In contrast to the three-dimensional
arrangement in the crystal structures and the two-dimensional
arrangement in HOPG surface, a metal-mediated base pair
within a DNA duplex can be considered a one-dimensional
arrangement of the metal complex formed from εA and Ag(I).
In principle, two scenarios are possible for a DNA double
helix with transoid orientation of the glycosidic bonds.21 As
shown in Chart 2 using the adenine:thymine base pair as an
Chart 2. Schematic Representations of Adenine:Thymine
and Guanine:Cytosine Base Pairs with Transoid Glycosidic
Bonds (R, R′ = DNA Backbone) in (a) Reversed Watson−
Crick Base Pairs and (b) Reversed Hoogsteen Base Pairs
example, both reversed Watson−Crick base pairing and
reversed Hoogsteen base pairing comply with this structural
requirement. Reversed Watson−Crick base pairs (Chart 2a) are
known to be formed in parallel-stranded DNA duplexes under
neutral conditions,22 whereas reversed Hoogsteen base pairs are
formed under slightly acidic conditions, because their
guanine:cytosine base pairs require protonated cytosine
residues (Chart 2b).23 Several recent reports confirm that
parallel-stranded DNA can accommodate metal-mediated base
pairs, irrespective of the base pairing pattern of the adjacent
canonical nucleobases.13f,24
Figure 5. (a) Large-scale and (b−d) high-resolution STM images of 3
adsorbed on HOPG in the presence of Ag(I). The imaging conditions
are (a) 100 nm × 100 nm, E = −1.2 V, I = 178 pA; (b) 15 nm × 15
nm, E = −1.2 V, I = 178 pA; (c) 15 nm × 15 nm, E = 700 mV, I = 110
pA; (d) 20 nm × 20 nm, E = 850 mV, I = 103 pA. Part c also shows an
overlay of the molecular structure of 3 and Ag(I) ions. (e) Proposed
structural model for the ordered adlayer of the Ag(I) complex of 3 on
HOPG.
In the molecular structures of [Ag2(1)2](ClO4)2, [Ag2(2)2]-
(ClO4)2, and [Cu2(1)2(CHO2)2(OH2)2](NO3)2·2H2O, the N7
positions of both εA derivatives are involved in coordinate
bonding. In order to have the N7 sites of both εA residues face
toward the interior of a DNA duplex (as required for metal-
mediated base pair formation), the scenarios depicted in Chart
3 are feasible. Taking into consideration the geometrical
constraints of duplex DNA, the formation of a C2-symmetric
metal-mediated εA−Mn+−εA base pair with transoid glycosidic
bonds requires that both artificial nucleobases adopt a syn
orientation with respect to their sugar moieties (Chart 3a). For
comparison, the dinuclear Ag(I) complex recently introduced
into regular antiparallel-stranded DNA with additional
Watson−Crick base pairs is depicted in Chart 3b.9 For
completeness, Chart 3c shows an additional geometry
compatible with a parallel strand orientation, albeit with cisoid
orientation of the glycosidic bonds. However, this orientation
appears very unlikely due to the introduction of unfavorable
strain in the sugar−phosphate backbone.
scanning bias, the coordinated Ag(I) ions between two
molecules of 3 become more obvious (Figure 5d). Figure 5e
shows a structural model for the adlayer formed from 3 and
Ag(I). Unfortunately, the resolution of the STM image under
atmospheric conditions is not sufficient to conclude whether
one or two Ag(I) ions are coordinated per pair of 3.
Nonetheless, the STM experiments indicate that the ligands
within each Ag(I) complex are oriented in a head-to-tail
fashion, with the alkyl chains oriented in a transoid manner.
Moreover, the distance between two bright spots in the STM
measurements assigned to Ag(I) amounts to 1.2 nm,
corresponding well to the interatomic Ag(I) distances within
layers of neighboring [Ag2(εA)2]2+ entities in the crystal
structures of [Ag2(1)2](ClO4)2 and [Ag2(2)2](ClO4)2, which
are in the order of 1.0 and 1.3 nm, respectively.
Incorporation of a Transoid Base Pair into a DNA
Duplex. Interestingly, all structurally characterized metal
complexes of εA derivatives as reported here display a transoid
arrangement of the alkyl substituents at N9. In contrast, the
structure of the εA−Ag(I)2−εA base pair previously incorpo-
rated into a B-DNA duplex exhibits a cisoid orientation of the
glycosidic bonds,9 because such an orientation is a prerequisite
for the formation of regular Watson−Crick base pairs. As the
To probe the formation of a dinuclear εA−Ag(I)2−εA base
pair in parallel-stranded DNA, the oligonucleotide duplex
shown in Chart 4 was synthesized and its physical properties
were investigated in the presence of varying amounts of AgNO3
and at different pH values. The sequence is identical to the one
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Chart 3. Possible Base Pairing Patterns of the εA−Mn+−εA
was also investigated at pH 5.5. The use of these slightly acidic
conditions does not lead to an undesired protonation of 2′-
deoxyethenoadenosine, as its pKa value amounts to 4.18(2)
(Supporting Information). The pKa value of 4.18(2) is in good
agreement with a previously reported value for the respective
ribonucleoside [(4.05(1)].27 Figure 6 shows the UV melting
Base Pair in (a) Reversed Hoogsteen Fashion and (b and c)
a
Hoogsteen Fashion
Figure 6. Melting profile of the DNA duplex under slightly acidic
conditions (pH 5.5) depending on the added equivalents of AgNO3,
monitored at 260 nm (black, 0 equiv; red, 0.5 equiv; blue, 1 equiv;
green, 2 equiv; orange, 3 equiv). The inset shows the increase of the
melting temperature Tm upon the addition of AgNO3 to a solution of
the duplex.
a
Base pairs in parts a and c are compatible with parallel-stranded
curves of the duplex in the presence of increasing amounts of
AgNO3. In the absence of Ag(I), no sigmoid curve can be
observed, indicating that under acidic conditions no parallel-
stranded duplex is formed either. However, the addition of
Ag(I) clearly conveys a significant thermal stabilization to the
duplex so that sigmoid melting curves are observed. The inset
of Figure 6 nicely illustrates that particularly the first 2 equiv of
Ag(I) contribute to this stabilization, indicating that the Ag(I)-
binding site of the oligonucleotide duplex with the highest
affinity binds two ions. This is a good indication that a
dinuclear Ag(I)-mediated base pair is formed. Its formation is
accompanied by an increase in the melting temperature Tm of
∼16 °C [from an estimated 2.5 °C in the absence of Ag(I) to
18.8 °C in the presence of 2 equiv of Ag(I)]. The addition of
excess AgNO3 leads to a minor additional increase in stability
only. This is not unexpected and can probably be attributed to
an electrostatic interaction between the Ag(I) cations and the
negatively charged DNA backbone28 or to additional weaker
binding to the canonical nucleobases.29
To rule out the inadvertent formation of G−Ag(I)−C
Hoogsteen-type base pairs (as previously established within a
triple helix)30 or C−Ag(I)−C base pairs (as well-known to be
formed within B-DNA duplexes),10b a series of control
experiments was performed (Supporting Information), all
confirming that under the experimental conditions such
metal-mediated base pairs are not formed. Hence, the
significant thermal stabilization and the stoichiometric binding
of two Ag(I) ions per duplex confirm the formation of a
dinuclear εA−Ag(I)−εA base pair also within parallel-stranded
DNA.
DNA, base pair in part b with antiparallel-stranded DNA. The relative
strand orientation is indicated by + and −. The glycosidic bond
orientation is displayed, too.
Chart 4. Parallel-Stranded DNA Duplex Used in the
Experiments (X = εA) and Chemical Structure of the
Artificial Nucleoside
used to investigate the εA−Ag(I)2−εA base pair in an
antiparallel-stranded duplex, albeit with parallel strand
orientation.
Under near-neutral conditions (pH 6.8), typically favoring
the formation of reversed Watson−Crick base pairs, no stable
duplexes are formed under the experimental conditions used,
neither with nor without Ag(I) (Supporting Information). This
finding is in agreement with reports that the stability of parallel-
stranded DNA with reversed Watson−Crick base pairs strongly
depends on the adenine:thymine and guanine:cytosine
content.25 Contrasting the behavior of canonical B-DNA,
guanine:cytosine base pairs destabilize parallel-stranded DNA
with reversed Watson−Crick base pairs (cf. the steric clash
depicted in Chart 2a).26 Consequently, as the duplex used in
this study has a comparatively high guanine:cytosine content of
50%, a stable parallel-stranded duplex cannot be formed under
near-neutral conditions, despite the possibility of the presence
of a stabilizing dinuclear Ag(I)-mediated base pair.
Judging by their absolute melting temperatures in the
presence of the εA−Ag(I)2−εA base pair, the antiparallel-
stranded duplex (Tm = 47.7 °C)9 is certainly more stable than
the parallel-stranded one (Tm = 18.8 °C). Nonetheless, the
thermal stabilization brought about by the formation of the
εA−Ag(I)2−εA base pair is larger for the parallel-stranded
As discussed above, the application of slightly acidic
conditions should favor the formation of reversed Hoogsteen
base pairs. Hence, the formation of the oligonucleotide duplex
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EDTA (pH 8.0), 8% sucrose, 0.08% dye (xylene cyanol, bromophenol
blue)]. After purification, the oligonucleotides were desalted by using
NAP10 columns. The desalted oligonucleotides were characterized by
matrix-assisted laser desorption ionization time-of-flight (MALDI-
TOF) mass spectrometry (5′-d(GAG GGA XAG AAA G)-3′ calcd for
[M + H]+, 4130 Da; found, 4129 Da; 5′-d(CTC CCT XTC TTT C)-
3′ calcd for [M + H]+, 3836 Da; found, 3835 Da). MALDI-TOF mass
spectra were recorded on a Bruker Reflex IV instrument using a 3-
hydroxypicolinic acid/ammonium citrate matrix. High-resolution
(positive mode) mass spectra were obtained on a Waters Q-Tof
Premier Micromass HAB 213 mass spectrometer or on an LTQ
Orbitrap XL (Thermo Scientific, Bremen, Germany), equipped with
the static nanospray probe (slightly modified to use self-drawn glass
nanospray capillaries, spray voltage 1.0−1.4 kV, capillary temperature
200 °C, tube lens approximately 50−120 V). During the quantification
of the oligonucleotides, a molar extinction coefficient ε260 of 5.0 cm2
μmol−1 was used for 1,N6-ethenodeoxyadenosine.
Spectroscopy. NMR spectra were recorded using Bruker
Avance(I) 400 and Bruker Avance(III) 400 spectrometers and on a
JEOL-DELTA2 500 spectrometer. Chemical shifts were recorded with
reference to residual DMSO-d5 (DMSO-d6) (1H NMR δ = 2.49 ppm,
13C NMR δ = 39.5 ppm) and residual solvent peak for CD2Cl2 (1H
NMR δ = 5.32 ppm, 13C NMR δ = 53.8 ppm) or with respect to
tetramethylsilane (δ = 0 ppm). The UV melting experiments were
carried out on a UV spectrometer CARY 100 Bio instrument.
Measurements were done in a 1 cm quartz cuvette. The UV melting
profiles were measured at 260 nm in two different buffersacidic [3
μM oligonucleotide duplex, 500 mM NaClO4, 5 mM MES (pH 5.5)]
and near-neutral [3 μM oligonucleotide duplex, 500 mM NaClO4, 5
mM MOPS (pH 6.8)], either in absence or in the presence of AgNO3,
at a heating rate of 1 °C min−1 with data being recorded at an interval
of 0.5 °C. Prior to each measurement, the sample was equilibrated by
heating it to 70 °C followed by cooling to 5 °C at a rate of 1 °C min−1.
Melting temperatures were determined from the maxima of the first
derivatives of the melting curves. Circular dichroism (CD) spectra
were recorded at 5 °C and measured with a J-815 spectropolarimeter
(JASCO) in two different buffersacidic [3 μM oligonucleotide
duplex, 500 mM NaClO4, 5 mM MES (pH 5.5)] and near-neutral [3
μM oligonucleotide duplex, 500 mM NaClO4, 5 mM MOPS (pH
6.8)], either in the absence or presence of AgNO3 using a 1 cm quartz
cuvette.
DNA: the ΔTm values amount to 12 °C for the antiparallel-
stranded duplex with a cisoid base pair9 and to ∼16 °C for the
parallel-stranded double helix. Considering the intrinsic
preference of the dinuclear metal complex for a C2-symmetric
conformation (as evidenced by the molecular structures of the
model complexes), this increased stabilization is likely to be due
to the adoption of a duplex with a transoid orientation of the
glycosidic bonds (Chart 3a) rather than a cisoid orientation
(Chart 3c).
Interestingly, the incorporation of Cu(II) into this parallel-
stranded duplex does not lead to any thermal stabilization
(Supporting Information). Hence, the formation of a Cu(II)-
mediated base pair cannot be concluded. However, when trying
to introduce Cu(II) into the analogous antiparallel-stranded
sequence, a weakly stabilizing (ΔTm = 3 °C) mononuclear
Cu(II)-mediated base pair is formed (Supporting Information).
It is tempting to speculate that a dinuclear metal-mediated base
pair of a divalent metal ion requires the presence of additional
anionic ligands (such as the formato ligands in the model
complex) to overcome the electrostatic repulsion of its
constituting metal ions. Here, the polyanionic nature of the
DNA duplex probably does not allow a close approach of such
anionic ligands; hence, only a mononuclear Cu(II)-mediated
base pair is formed.
CONCLUSIONS
■
N9-Substituted 1,N6-ethenoadenine derivatives have been
shown to preferentially form C2-symmetric dinuclear complexes
with suitable metal ions. The relative orientation of their N6
and N7 nitrogen donor atoms enables an almost parallel
alignment of the two N→M vectors, as was shown for two
Ag(I) complexes and one Cu(II) complex. Interestingly, this
coordination behavior was confirmed under the most diverse
experimental conditions, i.e., in a two-dimensional adlayer on
HOPG substrate, in three-dimensional crystal structures, and as
a metal-mediated base pair within a DNA duplex. As a result of
the NCCN-type arrangement of the nitrogen donor atoms, this
bis(monodentate) ligand with N→M vectors aligned in parallel
fills a gap in a series of ligands for supramolecular systems and
coordination polymers.
Synthesis of [Ag2(1)2](ClO4)2. 9-Ethyl-1,N6-ethenoadenine9 (1)
(65 mg, 0.35 mmol) was dissolved in dry acetonitrile (15 mL) and was
kept under stirring at room temperature. AgClO4 (87 mg, 0.42 mmol)
was separately dissolved in dry acetonitrile (5 mL) under dark. The
acetonitrile solution of AgClO4 was added dropwise to the solution of
1 under dark at room temperature, with stirring. White precipitation
was observed. The solution was kept under stirring for 12 h. Finally,
the supernatant solution was decanted, and the white precipitate was
washed with chloroform and cold diethyl ether, and dried under
vacuum. Vapor diffusion crystallization in acetonitrile with diethyl
ether as antisolvent gave single crystals suitable for X-ray diffraction
analysis. Yield: 110 mg (0.139 mmol, 79%). Caution! Perchlorate salts
of metal complexes with organic ligands are potentially explosive. 1H NMR
(400 MHz, DMSO-d6): δ (ppm) = 9.55 (s, 1 H, H2, 1JHC = 220 Hz),
8.81 (s, 1 H, H8, 1JHC = 219 Hz), 8.37 (d, 1 H, H11, 1JHC = 201 Hz),
EXPERIMENTAL SECTION
■
STM Measurements. Various adlayers of compound 3 in the
absence and presence of Ag(I) were prepared using a saturated
solution of 3 or a mixture of 3 and AgNO3 in tetradecane. A drop of
the respective solution was deposited onto a freshly cleaved HOPG
surface and dried in a dryer for STM imaging. The STM experiments
were performed on a commercial multimode Nanoscope III scanning
tunneling microscope (Digital Instrument Co., Santa Barbara, CA)
under ambient conditions with mechanically cut Pt/Ir (90:10) tips.
The images were recorded in constant-current mode.
1
7.85 (d, 1 H, H10, JHC = 197 Hz), 4.54 (q, 2 H, CH2), 1.56 (t, 3 H,
Oligonucleotide Synthesis and Characterization. Phosphor-
amidites required for the synthesis of the oligonucleotides were
purchased from Glen Research. The synthesis of the εA phosphor-
amidite is given in the Supporting Information. Syntheses of the
CH3). 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 143.6 (C8), 139.5
(C6), 139.2 (C4), 138.4 (C2), 132.4 (C10), 119.5 (C5), 113.9 (C11),
40.0 (CH2), 15.2 (CH3). 15N NMR (40 MHz, DMSO-d6): δ (ppm) =
233 (N3), 201 (N1), 197 (N7), 189 (N6), 175 (N9). ESI-MS m/z:
688.9293 [M]+ (calcd 688.9291), 481.0759 [M − Ag]+ (calcd
481.0761) where [M]+ = [Ag2(1)2](ClO4)+. Elemental analysis (%):
found, C 27.5, H 2.3, N 17.7; calcd for C18H18N10Ag2Cl2O8, C 27.4, H
2.3, N 17.7.
oligonucleotide strands were performed on a K&A Laborgerate H8
̈
DNA/RNA synthesizer under DMT-off mode by following standard
protocols (except for using ultramild Cap Mix A (THF/pyridine/
phenoxyacetic anhydride) instead of THF/pyridine/acetic anhydride).
Post synthesis, the oligonucleotides were cleaved from the solid
support and deprotected by treating them with 0.05 M K2CO3 in
methanol (4 h, ambient temperature). Thereafter, they were purified
by denaturing urea polyacrylamide gel electrophoresis [gel solution, 7
M urea, 1 M TBE buffer, 18% polyacrylamide−bis(acrylamide) (29:1);
loading buffer, 11.8 M urea, 42 mM Tris/HCl (pH 7.5), 0.83 mM
Synthesis of 9-Propyl-N6-propargyladenine. 9-Propyl-6-
chloropurine3c (2.00 g, 10.2 mmol, 1 equiv) was dissolved in n-
butanol (10 mL) followed by the addition of propargylamine (1.31
mL, 2 equiv) and stirring for 15 min. After this triethylamine (1.69 mL,
1.2 equiv) was added, and the reaction mixture was refluxed for 4 h
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DOI: 10.1021/acs.inorgchem.6b00927
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Article
with constant stirring. Progress of the reaction was observed by thin-
layer chromatography (TLC). After this time, n-butanol was
evaporated under high vacuum and the compound was purified by
column chromatography eluting with methanol/chloroform (2:98) to
afford a white powder. Yield: 1.50 g (7.45 mmol, 73%). 1H NMR (500
MHz, DMSO-d6): δ (ppm) = 8.23 (s, 1H, H2), 8.15 (s, 1H, H8), 8.06
(br, 1H, exocyclic NH), 4.20 (br, 2H, N−CH2), 4.08 (t, 2H, N−CH2),
Synthesis of 9-Octadecyl-1,N6-ethenoadenine (4). 1,N6-
Ethenoadenine9 (0.50 g, 3.1 mmol), n-iodooctadecane (1.13 g, 2.97
mmol), and potassium carbonate (0.434 g, 3.14 mmol) were
suspended in a mixture of dimethylformamide (150 mL) and
tetrahydrofuran (20 mL). The mixture was stirred under reflux at 80
°C for 72 h and then allowed to cool to room temperature. It was
subsequently poured into ice-cold distilled water (150 mL) to yield a
flocculent yellow precipitate. The water layer was pipetted out, and the
residue was washed successively with distilled water (2 × 50 mL) and
n-pentane (3 × 40 mL) and dried. The crude product was purified by
column chromatography [SiO2, ethyl acetate/methanol (11.5:1 to
9:1)], to obtain 4 as a white solid. Single crystals suitable for X-ray
diffraction analysis were obtained by slow evaporation of its solution in
THF. Rf: 0.27 in ethyl acetate/methanol (15:2). Yield: 0.41 g (1.0
2.99 (s, 1H, acetylenic H), 1.77 (m, 2H, CH2), 0.79 (t, 3H, CH3). 13
C
NMR (125 MHz, DMSO-d6): δ (ppm) = 154.3, 152.7, 149.6, 141.7,
119.7, 82.5, 72.8, 45.1, 29.5, 23.3, 11.4. ESI-MS m/z: 216.1241 [M +
H]+ (calcd 216.1249).
Synthesis of [Ag2(2)2](ClO4)2. In a 25 mL round-bottom flask,
wrapped with aluminum foil, 9-propyl-N6-propargyladenine (20 mg,
0.093 mmol) was dissolved in methanol (5 mL). To this, aqueous
AgClO4 solution was added (prepared in situ by the 1:1 addition of
Ag2CO3 and HClO4 in water) dropwise with constant stirring. A white
complex started precipitating out with the addition of the silver salt
solution. Stirring was continued for another hour. After this time, the
precipitate was filtered carefully to avoid direct light and washed with
water (4 × 5 mL) and methanol (4 × 5 mL) to remove any traces of
unreacted metal salt and ligand. The product so obtained was dried
under high vacuum. The yield was almost quantitative. Caution!
Perchlorate salts of metal complexes with organic ligands are potentially
1
mmol, 34%). H NMR (400 MHz, THF-d8, 300 K): δ (ppm) = 8.99
(s, 1H, H2), 8.00 (s, 1H, H8), 7.84 (d, J = 1.6 Hz, 1H, H11), 7.46 (d, J
= 1.5 Hz, 1H, H10), 4.30 (m, J = 7.1 Hz, 2H, NCH2), 1.92 (m, J = 7.2
Hz, 2H, NCH2CH2), 1.33−1.27 (m, ∼30 H, CH2), 0.88 (t, J = 6.6 Hz,
3H, CH3). 13C NMR (100 MHz, THF-d8, 300 K): δ (ppm) = 142.7
(C6), 141.1 (C8), 140.0 (C4), 136.6 (C2), 133.9 (C10), 124.8 (C5),
111.6 (C11), 44.7 (NCH2), 31.2 (NCH2CH2), 32.9, 30.6 (8 × C),
30.5, 30.4, 30.3, 30.1, 27.5, 23.5 (CH2), 14.4 (CH3). ESI-MS m/z:
412.3430 [M + H]+ (calcd 412.3435). Elemental analysis (%): found,
C 72.9, H 9.9, N 17.0; calcd for C25H41N5, C 72.9, H 10.0, N 17.0.
X-ray Crystallography. X-ray diffraction data crystal data were
collected with graphite-monochromated Mo Kα radiation (λ =
0.71073 Å) on a Bruker Venture diffractometer (1, 4, [Ag2(1)2]-
(ClO4)2, [Cu2(1)2(CHO2)2(OH2)2](NO3)2·2H2O) and a Bruker
SMART APEX CCD diffractometer ([Ag2(2)2](ClO4)2). The
structures were solved by direct methods and were refined by full-
matrix, least-squares on F2 by using the SHELXTL PLUS and
SHELXL-97 programs.31 All non-hydrogen atoms were refined
anisotropically, while hydrogen atoms were calculated in ideal
positions. Relevant crystallographic data are listed in Table 3.
1
explosive. H NMR (500 MHz, DMSO-d6): δ (ppm) = 8.85 (s, 1 H,
H2), 8.52 (s, 1 H, H8), 5.62 (s, 1 H, exocyclic H), 5.02 (s, 1 H,
exocyclic H), 4.79 (s, 2 H, N−CH2), 4.24 (t, 2 H, N−CH2), 1.80 (m,
2 H, CH2), 0.84 (t, 3 H, CH3). 13C NMR (125 MHz, DMSO-d6): δ
(ppm) = 152.5, 145.8, 143.5, 141.8, 141.3, 117.7, 90.1, 58.9, 46.3, 23.4,
11.2. ESI-MS m/z: 322.0227 [Ag(2)]+ (calcd 322.0222).
Synthesis of [Cu(1)2(HCO2)2(OH2)2](NO3)2·2H2O. 9-Ethyl-1,N6-
ethenoadenine9 (1) (61 mg, 0.32 mmol) was dissolved in methanol (5
mL). Triethylamine (500 μL) was added and the suspension stirred
until complete dissolution of 1. To this solution, Cu(NO3)2·3H2O (79
mg, 0.32 mmol) in methanol (3 mL) was added dropwise. The final
dark green solution was stirred for 12 h at 60 °C and then evaporated
to dryness. The residue was washed with acetonitrile (3 × 10 mL) and
diethyl ether (3 × 10 mL) and dried at room temperature to yield the
title compound. Single crystals suitable for X-ray diffraction analysis
were obtained by slow evaporation from a methanol/water solution
(2:1). The yield was almost quantitative. ESI-MS m/z: 250.0148 [M]2+
(calcd for [Cu2(1)2]2+, 250.0154; the Cu(II) ions have been reduced
to Cu(I) under the ESI conditions). The elemental analysis suggests
the possibility of a partial substitution of one formate by nitrate with a
concomitant loss of water in the bulk compound. Elemental analysis
(%): found, C 33.9, H 3.8, N 26.6; calcd for [Cu2(1)2(HCO2)
(NO3)](NO3)2·2CH3CN, C 33.9, H 3.1, N 25.8.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.6b00927.
Synthesis and characterization of the 1,N6-ethenoadenine
deoxyribonucleoside phosphoramidite, Ag(I)-mediated
cyclization of 9-propyl-N6-propargyladenine, character-
ization of the Ag(I)-binding behavior of the parallel-
stranded duplex under near-neutral conditions, control
experiment ruling out the inadvertent formation of
Ag(I)-mediated base pairs from A:T or G:C base pairs
within the Hoogsteen duplex, control experiment ruling
out the inadvertent formation of C−Ag(I)−C base pairs
from within the pyrimidine-rich sequence, determination
of the pKa value of 1,N6-ethenoadenine deoxyribonucleo-
side, investigation of the Cu(II)-binding behavior of a
DNA duplex with an εA:εA mispair, characterization of
the Cu(II)-binding behavior of the parallel-stranded
duplex under acidic conditions, surface characterization
by XPS, molecular structure of 9-octadecyl-1,N6-
ethenoadenine (4), NMR spectra (PDF)
Synthesis of 9-Icosyl-1,N6-ethenoadenine (3). 1,N6-Etheno-
adenine9 (0.49 g, 3.1 mmol), n-bromoicosane (1.11 g, 3.07 mmol),
and potassium carbonate (0.426 g, 3.08 mmol) were suspended in a
mixture of dimethylformamide (150 mL) and tetrahydrofuran (20
mL). The mixture was stirred under reflux at 80 °C for 72 h. The
reaction mixture was allowed to cool to room temperature and
subsequently poured into ice-cold distilled water (150 mL) to obtain a
flocculent white-yellow precipitate. The water layer was pipetted out,
and the residue was washed with distilled water (2 × 50 mL) and n-
pentane (3 × 40 mL) and dried. The crude product was purified by
column chromatography [SiO2, ethyl acetate/methanol (15:0.5 to
15:1)], to obtain 3 as a white solid. Rf: 0.24 in ethyl acetate/methanol
(15:2). Yield: 0.37 g (0.84 mmol, 27%). 1H NMR (400 MHz, THF-d8,
300 K): δ (ppm) = 8.97 (s, 1H, H2), 7.98 (s, 1H, H8), 7.83 (d, J = 1.6
Hz, 1H, H11), 7.46 (d, J = 1.5 Hz, 1H, H10), 4.30 (m, J = 7.1 Hz, 2H,
NCH2), 1.92 (m, J = 7.2 Hz, 2H, NCH2CH2), 1.33−1.26 (m, ∼34 H,
CH2), 0.88 (t, J = 6.6 Hz, 3H, CH3). 13C NMR (100 MHz, THF-d8,
300 K): δ (ppm) = 142.7 (C6), 141.1 (C8), 140.0 (C4), 136.6 (C2),
133.9 (C10), 124.9 (C5), 111.5 (C11), 44.7 (NCH2), 31.2
(NCH2CH2), 32.9, 30.6 (10 × C), 30.5, 30.4, 30.3, 30.1, 27.5, 23.6
(CH2), 14.4 (CH3). ESI-MS m/z: 440.3737 [M + H]+ (calcd
440.3748). Elemental analysis (%): found, C 73.5, H 10.4, N 15.7;
calcd for C27H45N5, C 73.8, H 10.3, N 15.9.
X-ray crystallographic data in CIF format (CIF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: sverma@iitk.ac.in.
*E-mail: chilf@suda.edu.cn.
*E-mail: mueller.j@uni-muenster.de.
H
DOI: 10.1021/acs.inorgchem.6b00927
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Saneyoshi, H.; Urata, H.; Torigoe, H.; Ono, A. Chem. Commun. 2015,
51, 17343−17360.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
(11) (a) Muller, J. Eur. J. Inorg. Chem. 2008, 2008, 3749−3763.
̈
(b) Takezawa, Y.; Shionoya, M. Acc. Chem. Res. 2012, 45, 2066−2076.
(c) Clever, G. H.; Shionoya, M. Coord. Chem. Rev. 2010, 254, 2391−
2402. (d) Ono, A.; Torigoe, H.; Tanaka, Y.; Okamoto, I. Chem. Soc.
Rev. 2011, 40, 5855−5866. (e) Clever, G. H.; Kaul, C.; Carell, T.
Angew. Chem., Int. Ed. 2007, 46, 6226−6236.
Funding
Deutsche Forschungsgemeinschaft, NRW Graduate School of
Chemistry, China Scholarship Council, COST Action CM1105.
(12) (a) Kumbhar, S.; Johannsen, S.; Sigel, R. K. O.; Waller, M. P.;
Notes
Muller, J. J. Inorg. Biochem. 2013, 127, 203−210. (b) Johannsen, S.;
̈
The authors declare no competing financial interest.
Megger, N.; Bohme, D.; Sigel, R. K. O.; Muller, J. Nat. Chem. 2010, 2,
̈
̈
̌
229−234. (c) Yamaguchi, H.; Sebera, J.; Kondo, J.; Oda, S.; Komuro,
T.; Kawamura, T.; Dairaku, T.; Kondo, Y.; Okamoto, I.; Ono, A.;
ACKNOWLEDGMENTS
■
Financial support from the DFG (SFB 858, J.M., L.C.; TRR 61,
L.C.), the NRW Graduate School of Chemistry (S.M.), and
COST Action CM1105 (S.M.) is gratefully acknowledged. We
thank the single-crystal CCD X-ray facility at IIT−Kanpur and
CSIR for a Senior Research Fellowship (R.K.P.). We thank the
Chinese Ministry of Education for a CSC scholarship (C.W.).
This work was supported by an Outstanding Investigator
Award, DAE-SRC, and J. C. Bose Fellowship, SERB, India
(S.V.).
Burda, J. V.; Kojima, C.; Sychrovsky, V.; Tanaka, Y. Nucleic Acids Res.
́
2014, 42, 4094−4099. (d) Kondo, J.; Yamada, T.; Hirose, C.;
Okamoto, I.; Tanaka, Y.; Ono, A. Angew. Chem., Int. Ed. 2014, 53,
2385−2388. (e) Kondo, J.; Tada, Y.; Dairaku, T.; Saneyoshi, H.;
Okamoto, I.; Tanaka, Y.; Ono, A. Angew. Chem., Int. Ed. 2015, 54,
13323−13326.
(13) (a) Megger, D. A.; Fonseca Guerra, C.; Hoffmann, J.; Brutschy,
B.; Bickelhaupt, F. M.; Muller, J. Chem. - Eur. J. 2011, 17, 6533−6544.
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(b) Okamoto, I.; Iwamoto, K.; Watanabe, Y.; Miyake, Y.; Ono, A.
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