Synthesis of a novel methylene-bridged biscarbazole derivative and evaluation of its DNA and nucleotide binding properties

Article abstract of DOI:10.1016/j.tetlet.2014.10.134

The synthesis of a novel methylene-bridged biscarbazole derivative 1 was described and the possible mechanism for its unexpectedly synthesized intermediate, compound A, was postulated. The binding properties of 1 to both Ct-DNA and nucleotides were investigated via fluorescent and UV-Vis spectra. The spectral investigations illustrated that this binary carbazole exhibited higher binding abilities to both Ct-DNA and nucleotides than its monomeric form, owing to the structurally flexible nature of double carbazole moieties fine-tuned by this non rigid methylene-linkage.

Full text of DOI:10.1016/j.tetlet.2014.10.134

Accepted Manuscript
Synthesis of a novel methylene-bridged biscarbazole derivative and evaluation
of its DNA and nucleotides binding properties
Gang Li, Xue Zhou, Peng Yang, Yong Jian, Tuo Deng, Hongyan Shen, Ying
Bao
PII:
S0040-4039(14)01852-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.134
TETL 45363
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 September 2014
20 October 2014
27 October 2014
Please cite this article as: Li, G., Zhou, X., Yang, P., Jian, Y., Deng, T., Shen, H., Bao, Y., Synthesis of a novel
methylene-bridged biscarbazole derivative and evaluation of its DNA and nucleotides binding properties,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.134
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Synthesis of a novel methylene-bridged biscarbazole derivative and evaluation of its DNA and
nucleotides binding properties
Gang Li, Xue Zhou, Peng Yang, Yong Jian, Tuo Deng and Ying Bao
N
N
N
N
NaBH4
N
OHC
CHO
N
N
Cl
HO
Cl
OH
N
N
Compound A
Compound 1

3
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of a novel methylene-bridged biscarbazole derivative and evaluation of
its DNA and nucleotides binding properties
Gang Li,ab Xue Zhou,ab Peng Yang,*ab Yong Jian,ab Tuo Deng,ab Hongyan Shen,ab and Ying Baoa
a Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, P. R.
China
b Institute of Drug Research in Medicine Capital of China (Shenyang Pharmaceutical University), Benxi, 117004, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
The synthesis of a novel methylene-bridged biscarbazole derivative 1 was described and the
possible mechanism for its unexpectedly synthesized intermediate, compound A, was
postulated. The binding properties of 1 to both Ct-DNA and nucleotides were investigated via
fluorescent and UV-Vis spectra. The spectral investigations illustrated that this binary carbazole
exhibited the higher binding abilities to both Ct-DNA and nucleotides than its monomeric form,
owing to the structurally flexible nature of double carbazole moieties fine-tuned by this non rigid
methylene-linkage.
Received in revised form
Accepted
Available online
Keywords:
Biscarbazole
2014 Elsevier Ltd. All rights reserved.
DNA binding
Nucleotides binding
Fluorescence
UV-Vis spectra
The isolation of naturally occurred diverse binary carbazole
alkaloids strongly inspired chemists and biologists to synthesize
the architecturally novel biscarbazole derivatives and to study
their promising biological activities.1 Biscarbazoles usually
owned distinct properties,2,3 i.e., mahabinine-A, a biscarbazole
alkaloid isolated from Murraya koenigii, could scavenge the
DPPH radicals and induce apoptosis of HL-60 cells; the rigid 7H-
pyrido[4,3-c]carbazole dimers exhibited the higher DNA
bisintercalating properties than their monomers; The
biscarbazoles bridged by methylene-linkage, either naturally or
unnaturally occurred, also received much interests of chemists
and biologists not only for their structural novelties, but also for
their less known biological potentials. Considering this, a few
synthetic approaches have been reported to construct this class of
biscarbazoles. For some examples, Gerhard Bringmann et al.
have described the synthesis of methylene-bridged binary
carbazole alkaloids as the byproduct of the reduction of
carbazole-3-carboxylic acid esters.4 Knölker group’s work are
very fruitful in this aspect and they have developed a number of
methodologies for the syntheses of naturally occurred methylene-
bridged binary carbazole alkaloids.5 For unnaturally occurred
methylene-bridged binary carbazole, Peter Bruck reported a
synthetic approach by condensation of 6-blocked 9’-
alkylcarbazoles with formaldehyde under acid catalyzed
condition.6 The biological properties about the methylene-
bridged biscarbazoles were also investigated in a limited reports,
i.e, Zheng/Duan and their coworkers recently described that a
methylene-bridged biscarbazole could interact with various DNA
structures and selectively stain the mitochondria in living HeLa
cells as this linkage could appropriately adjust the molecular
orientation of two carbazole units.7 However, both the synthetic
work and biological properties about the methylene-bridged
biscarbazoles are still limited and less investigated.
Scheme 1. Structures of both 1 and 2.
DNA binding ability is one of the most attractive biological
properties of carbazole derivatives, as many small molecules
capable of binding to DNA exhibit anticancer and antimicrobial
activities. The binding patterns of carbazoles to DNA vary
heavily depending on their structurally-modified geometries or

shapes. For examples, the indolo- and pyridocarbazoles are well
known for their capabilities of DNA intercalation and
atom of methylene was then attacked by the nucleophilic 3- (or 6-)
carbon atom of the carbazole ring of another molecule, followed
by losing formaldehyde to restore the carbazole aromaticity. A
postulated mechanism is shown in Scheme 3. These results may
demonstrate a novel pathway of looking for more efficient
approaches to synthesize methylene-bridged biscarbazole.
topoisomerases
vinylpyridinium)-
inhibition.3,8
and
N-methyl-3,6-bis(1-methyl-4-
conjugated
3,6-bisbenzimidazole
carbazoles are capable of thermally stabilizing and fluorescently
recognizing G-quadruplex structure of human telomeric DNA.9
3,6-diamidino-
and
N-pheny-3,6-bis(4-vinylpyridinium)
carbazoles prefer to bind A/T sequences of the DNA minor
groove with the pattern of carbazole nitrogen facing out of the
groove.10
Based on other groups’ findings7,10 and our long-term interests
in DNA binders,11 it occurred to us that a non-rigid linker at its 3-
(or 6- ) position of the biscarbazoles would be able to finely tune
the double crescent-shaped carbazole units and therefore may
offer this class of binary carbazoles more interesting DNA
binding properties.
Herein, we described the synthesis of a novel methylene-
bridged cationic biscarbazole derivative Compound 1, 6,6-bis[1-
(3-methylimidazolium)methyl]-bis(9-butyl-carbazol-3-yl)
Scheme 3 The proposed reaction mechanism.
With this intermediate at hand, we then synthesized the target
compound 1 using the reported method13 and the control
molecule 2 was also obtained facilely in the same way. Both the
intermediate A and the final products were fully characterized
(Fig. S30-S40).
methane dichloride and the spectral investigation of its binding
abilities to both DNA and nucleotides. To better understand this
molecule, its monomeric form compound 2, 3,6-bis[1-(3-
methylimidazolium)methyl]-9-butyl carbazole dichloride, was
also synthesized and investigated as a control (Scheme 1).
The absorption and fluorescent emission spectra of 1 and 2 in
different solvents were recorded (see Fig.S1, S2 and Table 1)
and Fig.1 listed a representative spectra conducted in 10 mM
PBS buffer. These two compounds exhibited featureless UV-Vis
and fluorescent spectra. The absorption bands of 1 at ~304 and
1
~356 nm were assigned to the 1La←1A and Lb←1A transitions,
respectively.14 Absorption spectra of 2 were quite similar to that
of 1, indicating that two carbazole moieties did not electronically
interact with each other in the ground state. The fluorescent
emission spectra of both 1 and 2 are also similar to each other,
the vibrational bands at ~370 nm and ~380 nm of fluorescent
spectra of 1 were clearly ascribed to the carbazole monomer
emission.
Scheme 2 Synthetic routes of 1 and 2; (a) NaBH4, MeOH, CH2Cl2/THF, r.t.,
0.5 h; (b) TsCl, 1-methyl-1H-imidazole, DMF 95 oC, 50 hrs; (c) Amberlite®
IRA402 chloride, MeOH, 3 h.
The synthetic routes of both 1 and 2 were presented in
2 and the detailed synthetic procedures and
Scheme
characterization data were given in the Supplementary
Information. Compound A, the intermediate of 1, was actually
an unexpected byproduct of the reduction of 9-butylcarbazole-
3,6-carbaldehyde with NaBH4. The optimization of reactions
conditions could increase the isolated yield of this product up to
24% from the initial 5% (ESI, see Table S1). The formation of
this intermediate seemed to be independent on its concentration,
but dependent on the factors like proportions of both NaBH4 and
methanol. Without the addition of methanol, the reaction could
not occur at all, which may indicate that the preliminary
generation of the hydroxymethyl-carbazole was required.
Fig.1 The absorption (15 µM) and fluorescent emission (5 µM) spectra of 1
and 2 in 10 mM PBS.
Table 1 The absorption and fluorescence spectral characteristics of 1 and 2
in different solvents.
Stokes'
shift
(nm)
Compds. Solvents
methanol
λ
max ( nm )
ε (M-1cm-1)
λem ( nm )
φ
353
356
356
6.8 × 103
9.1 × 103
7.5 × 103
364, 375
370, 382
371, 382
0.235
0.192
0.168
11
27
27
It is likely that the reduction may experience an ipso-
substitution (or ipso-alkylation) process to give A. In the limited
reports about such ipso-alkylations,12 however, acid catalysts are
generally required to produce either a radical cation or carbonium
ion first. But the existence of excess NaBH4 in our experimental
conditions excluded the possibility of acid-catalysed ipso-
substitution. We assumed that the nucleophilic addition of
hydride (H-) of NaBH4 to the carbonyl of the aldehyde would
produce a transitory Lewis acid borane (BH3), thereby activating
the methylene of hydroxymethyl group. This activated carbon
1
water
PBS buffer
methanol
349
350
4.7 × 103
3.6 × 103
359, 375
362, 377
0.472
0.383
10
25
water
2
PBS buffer
350
5.0 × 103
362, 378
0.322
27

5
The binding abilities of 1 to calf thymus (Ct) DNA were
firstly investigated by UV-Vis spectra at different ionic strength
(0.5, 5, 10, 50 mM ) buffered by 0.5 mM PBS (ESI, see Fig.S3-
S5) and Fig.2 listed the representative UV-Vis titration spectra
recorded at 50 mM ionic strength.
electrostatic binding pattern to the DNA-grooves-binding one
as more binding sites offered, which could be reflected from the
hypochromic and bathochromic effects of UV-Vis spectra of 1 at
the stage of [DNA]/[1] > ~1.0.
Qualitatively speaking, the extent of hypochromism in the
absorption spectrum is usually consistent with the strength of the
interactions. Table 2 listed their calculated Hypo%: the data were
38.80% for 1 (calculated after the region of [DNA]/[1] > ~1.0)
and 13.20 % for 2 at 10 mM ionic strength; the values are 32.40
% and 14.10 % at 50 mM ionic strength, respectively. It could be
seen that 1 exhibited higher extent of hypochromic effect than 2,
which indicated that it owned higher DNA binding ability.
Fig.3 Fluorescence spectra of 1 (A) and 2 (B) (5 µM) upon addition of Ct-
DNA (0.5 mM PBS, 5% methanol, 10 mM NaCl, pH = 7.4).
Fig.2 UV-Vis spectra of 1 (15 µM) upon addition of Ct-DNA at 50 mM NaCl
(0.5 mM PBS, 5% methanol, pH = 7.4), inset: (A) expanded spectra from 290
nm to 310 nm, (B) expanded spectra from 300 nm to 400 nm.
To give the overall DNA binding constants of both 1 and 2
and quantitatively compare their differences of DNA binding
affinities, the fluorescent spectra upon binding to Ct-DNA were
firstly investigated in the presence of 10 mM NaCl buffered by
0.5 mM PBS (Fig.3). It could be seen that the addition of DNA
quenched the fluorescence of both 1 and 2 and besides, the
saturation of the former being reached more rapidly than that of
the latter, indicative of its stronger DNA binding character. But
such steep curve could not be accurately fitted, therefore, the
fluorescence titration spectra of 1 were repeated by decreasing
the concentration of 1 lower to 500 nM as well as increasing the
ionic strength up to 200 mM, thus giving a more reliable fitting
curve (Fig.S8).
Generally speaking, in the UV-Vis spectra profiles of 1 at
different ionic strength, when [DNA]/[1] < ~1.0, hyperchromic
and light scattering effects occurred; when [DNA]/[1] > ~1.0, the
slight hypochromic and bathochromic effects were observed at
~304 and ~356 nm. In the regions of [DNA]/[1] ratio > ~1.0, no
clear isosbestic points were observed in the spectra at lower ionic
strengths (0.5, 5 and 10 mM), indicative of the existence of
multiple binding equilibria caused by nonspecfic binding. At 50
mM ionic strength (Fig.2, insert A), however, the spectra showed
a single isosbestic point at ca. 301 nm, which indicated that the
minimization of nonspecific electrostatic interactions enabled 1
to select the highest-affinity sites.
Hill equation16 was used to fit the fluorescent titration data in
Fig.3B and Fig.S8 and both fitting give a good R-square values
(Fig.S8, S9 and Table 2). It could be seen that the binding
constant of 1 is 2.1 × 108 M-1 even at the ionic strength of 200
mM, whereas the value of 2 is 1.3 × 106 M-1at the ionic strength
of 10 mM.
UV-Vis spectra of 2 upon binding to DNA, measured at two
different ionic strengths (see Fig.S6, S7), was a little bit different
from those of 1 and it showed the slight hypochromic and
bathochromic effects at ~298 and ~350 nm and no hyperchromic
and light scattering effects were observed at the initial stage of
the addition of DNA.
Table 2 The binding constants of 1 and 2 with Ct-DNA.
Ionic strength
10 mM
Compound 1 Compound 2
It is generally accepted that hypochromism in the absorption
spectrum refers to the groove binding pattern whereas
hyperchromic effect may be attributed to many reasons, i.e, the
thermally-denatured DNA, the dissociation of the aggregated
ligands, or structurally contracted DNA caused by the binding
between its external negatively-charged phosphate group and
positively-charged cationic ligands.15
Hypo %
(calculated from
UV-Vis)
38.80%
32.40%
13.20%
14.10%
50 mM
Ka, M-1
200 mM for
10 mM for
2.1 × 108
R2 = 99.1%
1.3 × 106
R2 = 97.1%
1
(calculated from
FL)
2
For both
1 and 2, the observed hypochromic and
Taken together, it could safely say that 1 exhibits higher DNA
binding ability than 2 and it is assumed that the higher DNA
binding ability of 1 may come from its structurally flexible nature
of two carbazole units adjusted by this non-rigid methylene
linkage. On the other hand, although UV-Vis titration spectra of
these two compounds exhibited different extent of hypochromic
and bathochromic effects, these observed spectral changes are
still smaller than those exhibited by conventional DNA major
groove binders, which means that their bindings to DNA most
possibly happen to the minor grooves. Actually, a number of
references10 revealed that the crescent-shape scaffold of
bathochromic effects in their UV-Vis titration spectra indicated
the characteristics of their DNA-grooves binding. Their major
differences lie in the initial stage of the addition of DNA and the
extent of hypochromic effects. Compared to 2, 1 owns a
geometrically larger size and may require more DNA sites to
bind, and if no sufficient binding sites to offer, 2 simply interacts
with DNA by external electrostatic binding, thus causing a
relatively large size species, which could account for the
observed light scattering at the stage of [DNA]/[1] < ~1.0; when
more DNA was added, however, 1 switched its solely

dicationic 3,6-substituted carbazoles favored their interaction
with AT sequences within DNA minor grooves, with a pattern of
3,6-substituents swing into the mionor groove while N-
substituent of the carbazole ring pointing out of the groove.
Considering the structural flexibility of biscarbazole 1 as well as
the butyl substituent on its N-atoms, it is less likely for it to
intercalate the GC rich sequences of DNA major groove, but
rather it is more possible for it to bind minor groove of DNA.
(Fig.S14-S18). All the tested nucleotides quenched the
fluorescence of 1 and Fig.5 gave a representative titration spectra
for its ATP binding. Assuming a 1:2 stoichiometry of host-guest
complexes, confirmed by Job plots of 1-ATP complexes (Fig.S25,
S26), a nonlinear least-squares equation19 was used to fit the data
of the fluorescent titrations. The calculated binding constants for
all the tested nucleotides were listed in Table 3, it could be seen
that 1 exhibited remarkable selectivity toward triphosphate
nucleotides over di- and mono- ones and slight selectivity toward
nucleobase in an order A > U > C > G. As the structure of 1
showed in Scheme 1, methylene-linkage was not only used to
bridge the two cabazole cores, but to connect terminal
imidazolium and carbazole core. As such, the above results
indicated that the non-rigid connection also offered the
imidazolium more flexible nature to find the more favorable
binding position of phosphate anions of nucleotides.
To support this postulation, DNA thermal denaturation study,
Circular Dichroism (CD) spectral titrations and the fluorescent
competitive experiments with the complexes of EB/DNA and
Hoescht 33258/DNA (Fig.S10-S13) were further conducted as
these techniques are usually used to determine the mode of
binding and the mechanism of action.17 These results indicated
that 1 slightly increased ∆Tm of DNA denaturation (Fig.S10);
produced a slight positive ICD signal in the wavelength
1
1
corresponding to its La←1A and Lb←1A transitions (Fig.S11);
quenched the fluorescence of the complex of Hoescht
33258/DNA much easier than that of the complexes of EB/DNA
(Fig.S12 and S13), all of which illustrated that the minor groove
of DNA is more favorable binding site for 1.
As a comparison, 2 showed negligible fluorescent change
upon binding to ATP (Fig.S19), and no changes to ADP and
AMP (data were not shown).
Table 3 The binding constants of 1 and 2 with different nucleotides.
Moreover, David Wilson and his coworkers has observed that
carbazole ring exhibited very different behaviors upon binding to
the bases of denatured d(G-C)7 and to those of denatured d(A-T)7
oligomer,10c which indicated that carbazole derivatives may have
different binding properties to nucleotides. We then investigated
the binding abilities of 1 with nucleotides to further illustrate the
potential of this methylene-linked biscarbazole derivative.
Nucleotides
Compound 1
Compound 2
Ka,,M-2 (FL)
Hypo% (UV)
Ka , M-1 (FL)
ATP
ADP
AMP
UTP
GTP
CTP
2.2 × 108
7.4 × 102
1.3 × 103
8.2 × 107
1.8 × 107
7.7 × 107
17.0 %
5.8 %
3.3 %
8.0 %
*
5.8 × 102
*
*
*
*
*
The UV-Vis spectra of 1 upon binding to different nucleotides
were firstly conducted (Fig.S20-S24) and Fig.4 listed the
representative spectra of 1 binding with ATP. It could be seen
that the addition of ATP decreased the absorption intensities at
302 nm accompanying with slight bathochromic shift (2 nm).
Hypochromic and bathochromic effects were actually observed
for most of the tested nucleotides with the exception of GTP,
which exhibited the hyperchromic effect instead. As some
references in respect to the supramolecular binding of nucleotides
revealed,18 the hypochromic effects were usually ascribed to π-π
stacking between the chromophores of the host and the
nucleobases of the guest. As such, the binding of 1 with GTP was
possibly driven mainly by electrostatic binding between cationic
imidazolium of 1 and phosphate anions of GTP and less by π-π
interactions of their chromophores.
*
* Too weak to calculate
Fig.5 Fluorescence spectra of 1 (5 µM) upon addition of ATP at pH 7.4 (10
mM PBS, 5% methanol), inset: the corresponding binding isotherm.
1H-NMR titration of 1 with ATP was also investigated
(Fig.S27) and the most remarkably observed changes of chemical
shift was the downfield-shifting (0.029 ppm) and broadening of
H9 of imidazolium of 1, indicating the interaction of imidazolium
with the phosphate anions of ATP. No cross peaks between the
protons of nucleobase of ATP and those of carbazole moiety of 1
were observed from the 2D NOESY (Fig.S28, S29), excluding
the possibility of their H-π binding pattern, which was reported in
some cases of the supramolecular binding of nucleotides.18
Taken together, the findings of the studies of nucleotides
binding further illustrated that this methylene-bridged
biscarbazole derivative 1 exhibited the higher binding abilities
than 2. And besides, the non-rigid methylene-linkage between the
terminal imidazolium and carbazole core also offered the
imidazolium more flexible nature to find more favorable binding
Fig.4 UV-Vis spectra of 1 (15 µM) upon addition of ATP at pH = 7.4 (10
mM PBS, 5% methanol).
The fluorescent spectra of 1 binding with various nucleotides
were carried out to evaluate quantitatively their binding constants

7
(c) Somphol, K,; Chen, R.; Bhadbhade, M.; Kumar, N.; Black, D.
StC. Synlett, 2013, 24, 24.
position of phosphate anions of nucleotides, which may also
account for its ability of seeking favorable sites of DNA to bind,
i.e, the phosphate anions of DNA backbone, aside from the AT
sites.
13. Banerjee, S.; Kitchen, J. A.; Gunnlaugsson, T.; Kelly, J. M. Org.
Biomol. Chem., 2012, 10, 3033.
14. (a) Johnson, G. E. J. Phys. Chem. 1974, 78, 1512; (b) Ohkita, H.;
Ito, S.; Yamamoto, M.; Tohda, Y.; Tani, K. J. Phys. Chem. A
2002, 106, 2140.
In conclusion,
a
novel cationic methylene-bridged
biscarbazole derivative 1 was synthesized and the possible
mechanism for compound A, its unexpectedly synthesized
intermediate, was postulated. This binary carbazole exhibited the
higher binding abilities to both Ct-DNA and nucleotides than its
monomer. The remarkable selectivity of 1 toward triphosphate
nucleotides and the slight selectivity toward adenine base
illustrated that the non rigid methylene-linkage, which bridged
both the carbazole cores and the terminal imidazoliums with the
core, contributed to its higher DNA binding ability of this novel
biscarbazole.
15. Muhammad Sirajuddin, Saqib Ali, Amin Badshah, Journal of
Photochemistry and Photobiology B: Biology 2013,124, 1.
16. (a) Friefelder D., Principles of Physical Chemistry
with
Application to the Biological Sciences (Second edition), 1985,
Jones and Bartlett, Boston; (b) Liu, J; Morikawa, M.; Kimizuka,
N. J. Am. Chem. Soc. 2011, 133, 17370.
17. (a) Palchaudhuri, R.; Hergenrother, P. J. Curr. Opin. Biotechnol.
2007, 18, 497; (b) Ren, J.; Jenkins, T. C.; Chaires, J. B.
Biochemistry 2000, 39, 8439; (c) Jia, T.; Xiang J.; Wang, J.; Guo,
P.; Yu, J. Org. Biomol. Chem. 2013, 11, 5512; (d) Garbett, N. C.;
Ragazzon P. A.; Chaires, J. B. Nat. Protoc. 2007, 2, 3166; (e) Haj,
H. T.-B.; Salerno, M.; Priebe, W.; Kozlowski, H.; Garnier-
Suillerot, A. Chem. Biol Interact 2003, 145, 349; (f) Wu, Y.-S.;
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Acknowledgments
18. Z. Xu, S. K. Kim and J. Yoon, Chem. Soc. Rev., 2010, 39, 1457.
19. Connors, A. Binding Constants, Wiley, New York, 1987.
We gratefully acknowledge financial supports from National
Natural Science Foundation of China (21102095), Liaoning
Provincial Natural Science Foundation (201102209), Program of
Liaoning Excellent Talents in University (LJQ2012090),
Liaoning Provincial
Postdoctoral Converging Project
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(2011921013) and Programs for innovative research team of the
Ministry of Education and Programs for Liaoning innovative
research team in university.
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