The crystal structure, self-assembly, DNA-binding and cleavage studies of the [2]pseudorotaxane composed of cucurbit[6]uril

Article abstract of DOI:10.1016/j.bmcl.2006.11.054

The [2]pseudorotaxanes of cucurbit[6]uril with guest molecule 1,6-bis(imidazol-1-yl)hexane (BIMH) were synthesized and characterized by ESI-MS spectrometry, ¹H NMR spectra, and X-ray diffraction crystallography. The influence of different anion

Full text of DOI:10.1016/j.bmcl.2006.11.054

Bioorganic & Medicinal Chemistry Letters 17 (2007) 932–936
The crystal structure, self-assembly, DNA-binding and cleavage
studies of the [2]pseudorotaxane composed of cucurbit[6]uril
Fang-Jun Huo, Cai-Xia Yin and Pin Yang*
Institute of Molecular Science, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education,
Shanxi University, Taiyuan 030006, China
Received 10 September 2006; revised 14 November 2006; accepted 16 November 2006
Available online 19 November 2006
Abstract—The [2]pseudorotaxanes of cucurbit[6]uril with guest molecule 1,6-bis(imidazol-1-yl)hexane (BIMH) were synthesized and
characterized by ESI-MS spectrometry, H NMR spectra, and X-ray diffraction crystallography. The influence of different anions
1
on self-assembly in solid-state was discussed by X-ray diffraction crystallography. However, more interestingly, and to our amaze-
ment, we discovered the CB[6]/BIMH [2]pseudorotaxane exhibiting efficient cleavage of pBR322 DNA in physiological environ-
ment. The cleavage mechanism were studied by fluorescence spectra and the hydrolysis of bis(2,4-dinitrophenyl)-phosphate
(
BDNPP). From DNA-binding mode being electrostatic force and the first-order kinetics equation, we prove indirectly that the
mechanism may be hydrolytic cleavage.
2006 Elsevier Ltd. All rights reserved.
ꢀ
1
1
Cucurbit[n]urils (n = 4–12) family, abbreviated as CB[n]
or Q[n], have attracted more and more attention in re-
assembly, we changed the different anions and got
the two crystal structures with chloride (Cl ), and triflu-
À
1
À
cent years. As an incontrovertible delegate of the fam-
2
oroacetate (CF COO ), respectively. Although phos-
3
ily, cucurbit[6]uril has been well known and widely
3
phate diester is far more kinetically stable than other
common biological functional groups such as amides
studied in various aspects including pseudorotaxane,
5
3
a,c,4
6
12
rotaxane
molecular switch, gene transfection, etc. In these
works published, the guest molecules including mostly
, and polyrotaxane, molecular necklaces,
7
or esters, the backbones of nucleic acids are elegantly
8
hydrolyzed by nucleases to facilitate their synthesis,
manipulation, and repair. Due to potentials in human
medicine and molecular biology, the development of
effective chemical nucleases has attracted much atten-
tion. Hydrolytic cleavage of DNA by small molecule
is far more challenging. Most examples are metal ions
2
d,e,3b,c
alkylammonium ions,
5
pyridylmethyl-ended alky-
, and other organic ammonium
f,g,6
lammonium ions
1
c
13
ions were reported. No guest molecule containing
imidazole group is reported. It is well-known that imid-
azole is the important biological activity molecule and
functional group. And the imidazole residue of histidine
as the active sites of enzymes and proteins is well recog-
1
4
or their complexes, involving transition metal ions
5
1
and their complexes, lanthanide ions and their com-
6
1
plexes, as well as actinides. However, in the above sys-
tems as chemical nucleases sometimes exists limitation in
9
nized. Considering these, we have synthesized the new
1
7
guest molecule, 1,6-bis(imidazole-1-yl)hexane (BIMH),
and have reported the crystal structure and self-assem-
bly of [2]pseudorotaxane composed of CB[6] and 1,6-
bis(imidazole-1-yl)hexane dihydrobromide (BIMH–Br)
special condition. So people suggested a novel strategy
to design and use non-metallic DNA artificial nuclease.
Most recently, Kim’s and Nakamura’s groups have pub-
lished the outcome that the CB[6] could affect the activ-
1
0
18
as a short communication. In this study, to investigate
the influence of the anions on the self-assembly, which is
important as well as metal-coordinated to direct self-
ity of spermine on DNA. Therefore, we wonder
whether the complex CB[6]/BIMH can exhibit the simi-
lar property of hydrolyzing pBR322 DNA. The experi-
ment outcome is positive, the experiments show that
the complex CB[6]/BIMH can cleave circular plasmid
pBR322 DNA at pH 7.2 and 37 ꢁC. Furthermore, the
cleavage mechanism was deduced by available methods
including fluorescence spectra and the hydrolysis of
bis(2,4-dinitrophenyl)-phosphate (BDNPP).
Keywords: Cucurbituril; Self-assembly; DNA-cleavage; Pseudorotaxane.
*
Corresponding author. Tel.: +86 351 7011022; fax: +86 351
011022; e-mail: yangpin@sxu.edu.cn
7
0
960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.11.054

F.-J. Huo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 932–936
933
We have reported a similar crystal structure (CB[6]/
1
along p Á Á Á p orient. However, the self-assembly of
0
À
BIMH–Br) and its self-assembly, where the formation
9
of superstructure was named as a pseudopolyrotaxane.
CB[6]/BIMH–CF COO complex exhibited the zig-zag
3
1
À
chain formation due to CF COO anions’ influence.
3
To explore the influence of the different anions on the
self-assembly, we gained another two crystals by chang-
ing different anions (Cl : CCDC 601457 and CF COO :
CCDC 601456). The structures and self-assembly of
them are shown in Figures 1 and 2, respectively. Figure
The superstructure formation is mainly oriented via
the other p Á Á Á p between the guest imidazole rings from
one [2]pseudorotaxane and the semi-glycoluril-ring of
the host CB[6] from the other [2]pseudorotaxane with
À
À
3
2
0
˚
a centroid–centroid 3.454 A (0.7ꢁ). The packings of the
1
gives the representative crystal structure. The hexane
two crystals are shown in Figures 1S and 2S (ESI). In
addition, it is made out that the packing of [2]pseudoro-
taxane with halide anions was more close than the one
chain moieties are located fully inside the cavity and
the protonated imidazole rings resided outside the
portal.
À
À10
of [2]pseudorotaxane with CF COO , which was reflect-
3
À
and 1.659 for Cl
ed in lattice density (1.747 for Br
versus 1.629 for CF COO ).
À
As shown in Figure 2, the self-assembly of [2]pseudoro-
taxane with Cl anion is consistent with the one we
3
À
1
0
1
reported. The highly ordered linear pseudopolyrotax-
ane formation was aggregated by intermolecular
p Á Á Á p (face-to-face) stacking between neighboring imid-
The H NMR spectrum (D O, 25 ꢁC, TMSP as an inte-
2
rior criterion) characterized the structure of the 1:1 com-
plex by only one set of signals (ESI, Fig. 3S). The signals
of the methylene protons located inside CB[6] shifted
upfield to (d 3.99, 1.18, 0.57) from their original reso-
nances (d 4.23, 1.89, 1.33, respectively). The outside pro-
tons (for hydrogen atoms on imidazole group H1, H2,
H3), the changes in chemical shifts are different. For
H1 and H2, the resonances were downfield (to d 9.16,
˚
azole rings with a centroid–centroid 3.961 A (0.0ꢁ),
+
interpseudorotaxane C–H Á Á Á O and N –H Á Á Á O hydro-
gen bond interactions (Table S1). The separation be-
˚
tween neighboring CB[6] molecules is 12.578 A (c axis)
7.92) from their original positions (d 8.71, 7.50) due to
the deshielding effect of the portal carbonyl groups.
The signal of H3, however, showed a slightly upshift
field from original 7.46 to 7.37. The smaller upshift
(
was reported by Mock being about 6 A or 4.5 methylene
Dd = À0.09 ppm) change, though the shielding region
˚
2
d
groups, should be also a result of shielding region of
CB[6] due to less volume imidazole group relative to
3
f
the portal of CB[6].
An attempt of studying the superstructure assembly for-
mation (pseudopolyrotaxane) in solution of the
[
2]pseudorotaxane was not successful by electrospray
ionization mass (ESI-MS), which is a quite soft ioniza-
tion progress that can reflect the state of molecules in
2
1
solution. Though Osaka reported that the technique
only detected the doubly charged CB[6] or CB[7] com-
Figure 1. The represented crystal structure of CB[6]/BIMH [2]pseud-
orotaxanes. C atoms, gray; N atoms, light blue; O atoms, red. Side
view of the structure, all H atoms, except for H atoms involved in
2
2
plex, our result (Fig. 4S) shows that not only doubly
charged ions (m/z 608.7, CB[6] + BIMH + 2H ) but also
+
+
singly charged ions (m/z 1215.4, CB[6] + BIMH + H ;
hydrogen bonding. The minor disorder, anions, and solvent (H
2
O) are
omitted for clarity. Only atoms involving hydrogen bonds are labeled.
about a half intensity) were detected. These indicate that
the new CB[6]/BIMH [2]pseudorotaxane can exist stably
in gas-phase as a doubly charged complex and singly
charged complex.
The cleavage reaction on plasmid DNA was monitored
by agarose gel electrophoresis. When circular plasmid
DNA is subject to electrophoresis, relatively fast migra-
tion will be observed for the intact supercoil form (S,
CCC form). If scission occurs on one strand (nicking),
the supercoil will relax to generate a slower-moving
open circular form (C, OC form). If both strands are
cleaved, a linear form (L) that migrates between Form
2
3
C and Form S will be generated. Figure 3 (left) shows
the results of cleaving superhelical pBR322 DNA in the
presence of varying concentrations of the CB[6]/BIMH
complex. The results indicate that the S form of
pBR322 DNA diminishes gradually, whereas the C form
increases with the increase of concentration of the
Figure 2. The self-assembly of [2]pseudorotaxane was effected by
À
different anions. Top (Cl ): the linear superstructure formation, may
À
3
been named pseudopolyrotaxane; bottom (CF COO ): zig-zag chain
formation.

934
F.-J. Huo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 932–936
(assigned to those of 2,4-dinitrophenolate and -nitro-
phenolate, respectively; Fig. 6S) at 37(±0.5) ꢁC on a
diode-array spectrophotometer with a thermostated cell
holder. All the reactions were carried out under sec-
ond-order conditions. The rate constants were obtained
by fitting the initial (<3%) concentration changes
according to the first-order kinetics equation (correlation
coefficient >0.99). Figure 6S is the kinetics linear spectra
of reaction of complex and BDNPP. The pH of the
solution was maintained by 10 mM Tris–HCl buffer
Figure 3. Results of electrophoresis of pBR322 DNA (Reagents and
conditions: 10 mM Tris–HCl buffer, 6.2 mM NaCl, pH 7.18, at 37 ꢁC
for 4 h); Left: the presence of varying concentrations of CB[6]/BIMH:
lanes l–5, [CB[6]/BIMH] = 0, 10, 25, 50, and 150 lM, respectively. S is
supercoiled DNA (CCC form), C is nicked circular form DNA (OC
form) and L is linear DNA, The amount distribute for each lane: lane 1
(
pH: 7.18). In experiment, [BDNPP] = [complex]
=
(
impact pBR322: S = 64%, C = 36%, L = 0%); lane 2 (S = 58%,
C = 40%, L = 2%); lane 3 (S = 51%, C = 43%, L = 6%); lane 4
S = 32%, C = 55%, L = 13%); lane 5 (S = 7%, C = 69%, L = 24%);
int
int
À1
À5
À1
À1
7.5 · 10 mol L , measured 11994 (mol/L) cm of
2,4-dinitrophenolate at 37 ꢁC. The observed second-
order rate constant is k = 11.6 (mol/L) min
t1/2 = 1139 min.
(
À1
À1
,
Right: only BIMH–Cl, lanes l–5, [BIMH] = 0, 10, 25, 50, and 150 lM,
respectively, scarce hydrolysis.
obs
According to these experiment results above, we sup-
pose simply that the DNA-cleavage mechanism for the
[2]pseudorotaxane CB[6]/BIMH should be a coopera-
tion process of the host CB[6] and the guest BIMH mol-
CB[6]/BIMH complex and the linear form (L) is also
produced. When the concentration of CB[6] goes up to
150 lM (lane 5), the pBR322 DNA gave a mixture of
24% linear form (L), 69% open circular form (C), and
7% supercoil form (S). However, single BIMH cleaves
2
7
ecules. Based on the previous reports, the fact that the
glycoluril carbonyl O atoms acted as the hydrogen
2
8
scarcely the DNA (Fig. 3right) in the same physiological
conditions. Here, it is needed to be pointed that we only
studied the CB[6]/BIMH complex having the function of
incising pBR322 DNA in this text. About pH effect, ion
intensity and so on, are our future work.
acceptor
and the crystal structure information
(Fig. 7S), the proposed hydrolysis mechanism is depict-
ed in Figure 4. The protonated imidazole affords the
proton to the phosphate anion of DNA, and synchro-
nously the CB[6] glycoluril carbonyl O atom, acting as
Lewis base on, pulls a proton from water molecule to
promote its attack the phosphorus atom. The mecha-
nism can be applicable for the CB[6]/spermidine hydro-
We know EB (ethidium bromide) was the most frequent
probe of often used as probes for DNA structure detec-
2
4
18
tion. EB emits intense fluorescent light in the presence
of DNA due to its strong intercalation between the adja-
cent DNA base pairs. In fact, if fluorescence quenching
or not for EB bound to DNA is used to determine the
binding mode between another molecule and DNA. In
order to investigate the mode of the CB[6]/BIMH com-
plex binding to DNA, the fluorescence spectra experi-
lyzing DNA molecule. However, the real hydrolysis
mechanism needs to be confirmed through the further
detailed research.
In summary, the new [2]pseudorotaxanes of cucur-
bit[6]uril with new guest molecule 1,6-bis(imidazol-1-
yl)hexane were synthesized and fully characterized by
À5
1
ment (ESI, Fig. 5S) of EB–DNA (1:1, 8 · 10 M)
ESI-MS spectrometry, H NMR spectra, and X-ray
system was carried out in the absence and the presence
of complex. The results suggest that the emission band
at 600 nm of the EB–DNA system was increased in
intensity with increasing the CB[6]/BIMH complex con-
diffraction crystallography. The influence of different
anions on supramolecular self-assembly in solid-state
was discussed by X-ray diffraction crystallography.
À4
centration until up to 1.25 · 10 mol/L (Rt = CCB[6]/
/
C
= 1.55). The CB[6]/BIMH complex itself
BIMH DNA
does not show appreciable fluorescence in the spectral
region studied. The observed fluorescence increase indi-
cates that EB intercalated, the only fluorescent species,
was bound to DNA more tightly, which indicates there
exist electrostatic interactions between CB[6]/BIMH
complex and DNA. This may be due to the fact that
CB[6]/BIMH with positive charge, like metal cation
2
5
ions, can bind to the phosphate group of DNA by
electrostatic forces to make a contraction in the helix
axis of DNA.
From above DNA-binding mode being electrostatic
force, we deduce that complex incising pBR322 DNA
may be hydrolysis mechanism. To give an evidence, the
model substrate BDNPP [bis(2,4-dinitrophenyl)-phos-
phate] was employed because its hydrolysis can reflect
2
6
the incising mechanism of pBR322 DNA. CB[6]/BIMH
complex-promoted hydrolysis of BDNPP was monitored
by following the visible absorbance change at 400 nm
Figure 4. The proposed DNA-cleavage mechanism for CB[6]/BIMH
[2]pseudorotaxane.

F.-J. Huo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 932–936
935
Significantly, the CB[6]/BIMH [2]pseudorotaxane exhib-
it efficient cleavage of pBR322 DNA in physiological
environment. The cleavage mechanism was studied by
fluorescence spectra and the hydrolysis experiment of
bis(2,4-dinitrophenyl)-phosphate (BDNPP). These re-
sults can introduce the new developments for new
supermolecular material and supramolecular biochemis-
Whang, D.; Heo, J.; Kim, C.-A.; Kim, K. Chem. Comm.
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Acknowledgment
Financial support from the National Natural Science
Foundation of China (Nos: 30470408 and 20601018,
P. Yang) is greatly appreciated.
9
Supplementary data
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Supplementary data associated with this article can be
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0. The guest molecule 1,6-bis(imidazol-1-yl)hexane (BIMH
2
À
1
with Cl ): Yield 85%. H NMR (300 MHz, 25 ꢁC, D O,
TMSP): d 8.71 (s, 2H), 7.50 (s, 1H), 7.46 (s, 1H), 4.23
2
23, 1347; (f) Xiao, X.; Tao, Z.; Ge, J.-Y.; Ma, P.-H.; Xue,
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(
t, 4H, a-CH
2
), 1.89 (m, 4H, b-CH
2
), 1.33 (m, 4H, c-
1
3
4
. He, X. Y.; Li, G.; Chen, H. L. Inorg. Chem. Commun.
002, 5, 633.
CH2); C NMR (300 MHz, D O): d 134.13, 121.56,
1
2
2
19.48, 49.05, 28.94, 24.75; Elemental analysis (calcd %):
5
. (a) Meschke, C.; Buschmann, H. J.; Schollmeyer, E.
Macromol. Rapid Commun. 1998, 19, 59; (b) Choi, S. W.;
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C, 49.48; N, 19.24; H, 6.87. Found: C, 49.86; N, 19.44;
H, 6.53. The procedure for preparation of the [2]pseud-
orotaxane CB[6]/BIMH is same as the one we report-
1
0
1
3
526; (c) Hou, Z.-S.; Tan, Y. B.; Kim, K.; Zhou, Q.-F.
ed. For CB[6]/BIMH–Cl: H NMR (300 MHz, 25 ꢁC,
O, TMSP): d 9.16 (s, 2H), 7.92(s, 2H), 7.37 (s, 2H),
.78 (d, 12H), 5.58 (s, 12H), 4.32 (d, 12H), 3.99 (t, 4H),
Polymer 2006, 47, 742; (d) Park, K. M.; Whang, D.; Lee,
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D
2
5

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F.-J. Huo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 932–936
1
.18(m, 4H), 0.57 (m, 4H); C NMR (300 MHz, D
d 155.8, 135.2, 123.3, 116.8, 71.1, 51.2, 48.6, 28.6, 27.3;
ESI-MS: 608.7 for doubly charged cations, 1215.4 for
single-charged cations. Elemental analysis (calcd %) for
3
1
2
O):
23. (a) Selvakumar, B.; Rajendiran, V.; Maheswari, P. U.;
Evans, H. S.; Palaniandavar, M. J. Inorg. Biochem. 2006,
100, 316; (b) Yang, P.; Ren, R.; Guo, M. L.; Song, A. X.;
Meng, X. L.; Yuan, C. X.; Zhou, Q. H.; Chen, H. L.; Xiong,
Z. H.; Gao, X. L. J. Biol. Inorg. Chem. 2004, 9, 495.
24. Yang, J.; Ma, J. F.; Liu, Y. C.; Zheng, G. L.; Li, L.; Liu, J.
F. J. Mol. Struct. 2003, 646, 55.
36 36 24 18 4 2
C H N O12ÆC12H N Æ2HClÆ8H O: C, 40.22; N, 27.37;
H, 5.03. Found: C, 39.99; N, 27.12; H, 4.97. Crystal-
lographic data for CB[6]/BIMH–Cl: C H Cl N O ,
4
8
72
2
28 20
Mr = 1432.24, monoclinic, space group P2 /c(No.14),
1
25. Li, Q. S.; Yang, P.; Wang, H. F.; Guo, M. L. J. Inorg.
Biochem. 1996, 64, 181.
26. Rossi, L. M.; Neves, A.; Bortoluzzi, A. J.; H o¨ rner, R.;
Szpoganicz, B.; Terenzi, H.; Mangrich, A. S.; Pereira-
Maia, E.; Castellano, E. E.; Haase, W. Inorg. Chim. Acta.
2005, 358, 1807.
˚
˚
˚
a = 12.369(4) A, b = 20.115(6) A, c = 12.578(4) A, b =
˚
3
1
13.664(3)ꢁ, V = 2866.3(15) A , Z = 2, q
= 1.659 g/
calcd
3
À1
cm , l(Moka) = 0.220 mm , F(000) = 1500, T = 203 K,
h
max = 25.01ꢁ, 13538 reflections measured, 4969 unique
(R
int = 0.0223). Final residual for 452 parameters and
4
0
969 reflections with I > 2r(I): R = 0.0671, wR =
.1922, and GOF = 1.057. CCDC 601457 contains the
27. (a) Asaad, N.; Kirby, A. J. J. Chem. Soc., Perkin Trans.
2002, 2, 1708; (b) Yang, Q.; Xu, J. Q.; Sun, Y. S.; Li, Z.
G.; Li, Y. G.; Qian, X. H. Bioorg. Med. Chem. Lett. 2006,
16, 803; (c) Piatek, A. M.; Gray, M.; Anslyn, E. V. J. Am.
Chem. Soc. 2004, 126, 9878.
1
2
supplementary crystallographic data for this paper.
These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by contacting
The Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; Fax: +44
28. Huo, F. J.; Yin, C. X.; Yang, P. Acta. Crystallorgr., Sect.
C 2005, 61, o500.
1223/336 033; E-mail: data_request@ccdc.cam.ac.uk.
Crystallagrophic data for CB[6]/BIMH–CF COO:
29. Liu, S. M.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc
2005, 127, 16798.
3
C
52
H
80
F
P2 /c(No.14), a = 14.456(2) A, b = 19.016(3) A, c =
6
N
28
O
28, Mr = 1659.44, monoclinic, space group
˚ ˚
30. (a) Zhao, J. Z.; Kim, H. J.; Oh, J.; Kim, S. Y.; Lee, J. W.;
Sakamoto, S.; Yamaguchi, K.; Kim, K. Angew. Chem.,
Int. Ed. Engl. 2001, 40, 4233; (b) Jon, S. Y.; Selvapalam,
N.; Oh, D. H.; Kang, J.-K.; Kim, S.-Y.; Jeon, Y. J.; Lee, J.
W.; Kim, K. J. Am. Chem. Soc. 2003, 125, 10186; (c)
Zhao, Y. J.; Xue, S. F.; Zhu, Q. J.; Tao, Z.; Zhang, J. X.;
Wei, Z. B.; Long, L. S.; Hu, M. L.; Xiao, H. P. Chin. Sci.
Bull. 2004, 49, 1046; (d) Zheng, L. M.; Zhu, Q. J.; Zhu, J.
N.; Zhang, Y. Q.; Tao, Z.; Xue, S. F.; Wei, Z. B.; Long, L.
S. Chin. J. Inorg. Chem. 2005, 21, 1583; (e) Day, A. I.;
Arnold, A. P.; Blanch, R. J. Molecules 2003, 8, 74.
31. Isaacs, L.; Park, S.-K.; Liu, S.; Ko, Y. H.; Selvapalam, N.;
Kim, Y.; Kim, H.; Zavalij, P. Y.; Kim, G.-H.; Lee, H.-S.;
Kim, K. J. Am. Chem. Soc. 2005, 127, 18000.
1
˚
˚
3
1
q
3.285(2) A, b = 112.138(2)ꢁ, V = 3382.7(10) A , Z = 2,
3
À1
,
calcd = 1.629 g/cm , l(Moka) = 0.143 mm
F(000) =
1
732, T = 203 K, hmax = 25.01ꢁ, 16109 reflections mea-
sured, 5913 unique (Rint = 0.0325). Final residual for 523
parameters and 5913 reflections with I > 2r(I):
R
1
= 0.0990, wR
01456 contains the supplementary crystallographic data
for this paper.
1. Ishihara, S.; Takeoka, S. Tetrahedron Lett. 2006, 47, 181.
2
= 0.2524, and GOF = 1.084. CCDC
6
2
2
2. Osaka, I.; Kondou, M.; Selvapalam, N.; Samal, S.; Kim,
K.; Rekharsky, M. V.; Ionue, Y.; Arakawa, R. J. Mass.
Specrom. 2006, 41, 202.