Na+/K+ switch of enantioselectivity in G-quadruplex DNA-based catalysis

Article abstract of DOI:10.1039/c3cc45396k

Here we found that the enantioselectivity of G-quadruplex DNA-based Diels-Alder reaction can be switched by just changing Na⁺ to K ⁺, which is ascribed to the structural transformation of the G-quadruplex from antiparallel to hybrid-

Full text of DOI:10.1039/c3cc45396k

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Na+/K+ switch of enantioselectivity in G-quadruplex
DNA-based catalysis†
Changhao Wang,a Guoqing Jia,a Yinghao Li,a Sufang Zhangb and Can Li*ab
Cite this: Chem. Commun., 2013,
49, 11161
Received 17th July 2013,
Accepted 27th August 2013
DOI: 10.1039/c3cc45396k
www.rsc.org/chemcomm
Here we found that the enantioselectivity of G-quadruplex DNA-based recent years, the diversified chiral scaffolds of G-quadruplexes
Diels–Alder reaction can be switched by just changing Na+ to K+, which have attracted much attention in the enantioselective catalysis.
is ascribed to the structural transformation of the G-quadruplex Human telomeric G4DNA alone in the presence of Na+ has
from antiparallel to hybrid-type. By tuning the ratio of Na+/K+, the recently been found to show enantioselective catalytic function
enantioselectivity of the Diels–Alder reaction could be switchable in the Diels–Alder (D–A) reaction11 and Friedel–Crafts reaction.12
and shows much more sensitive to K+ than to Na+.
The reactivity and the enantioselectivity of the above two reactions
can be enhanced when G4DNA binds with copper(II) ions11,12
It is known that alkali metal ions Na+ and K+ play important roles or copper(II) complexes.13,14 Although DNA G-quadruplexes have
in a wide variety of biological processes. In most eukaryotic cells, provided diverse chiral scaffolds in the presence of alkali metal ions
low Na+ and high K+ concentrations are regulated by Na+/K+-ATPase such as Na+ and K+, the enantioselective catalytic functions of
(also known as the Na+/K+ pump) through active ion transport G4DNA in Na+ and K+ media are still largely elusive. Herein we
across the plasma membranes.1 The action potentials for nerve report our recent discovery that the enantioselectivity can be sensi-
impulses are created by the flow of ions across the neuronal tively tuned by changing the alkali metal ions in the enantioselective
membrane through Na+ or K+ channels in nervous systems.2 In D–A reaction catalyzed by a G4DNA-based catalyst. Interestingly, the
nature, Na+ and K+ serve as cofactors and structural roles in enantiomeric excess (ee) of the D–A reaction can be switched
assisting the function of biologically active macromolecules such from about 50% to ꢀ50% by just changing Na+ to K+, which is
as protein enzymes and nucleic acids.3 When binding to DNA, Na+ attributed to the structural transformation of G4DNA from
and K+ are well known for mediating formation and stabilization of antiparallel to hybrid-type.
DNA G-quadruplexes, which are associated with biological roles
In the presence of alkali metal ions, a selected single-stranded
of gene expression4 and potential targets in cancer therapy.5 G-rich DNA sequence from human telomere (ODN, 50-G3(T2AG3)3-30)
One major G-quadruplex from human telomeric DNA in Na+ can fold into various G-quadruplex motifs, so it provides us an
solution, as determined from NMR data, adopts an antiparallel opportunity to study the relationship between the conformation and
structure.6 The other G-quadruplex in parallel conformation the enantioselective catalytic function of the G4DNA. A D–A reaction
was obtained by X-ray diffraction of a K+-containing crystal,7 of (E)-1-(1-methyl-1H-imidazol-2-yl)-3-phenylprop-2-en-1-one (1a)
nevertheless, it displays a hybrid-type G-quadruplex architec- and cyclopentadiene (2) was chosen as a model reaction,15 which
ture in K+ solution although the fine structure is controversial is catalyzed by a G4DNA-based catalyst (ODN-Cu2+) assembled by
to date.8 Very recently, DNA G-quadruplex structures have been G4DNA and Cu2+ ions in a 3-(N-morpholino)propanesulfonic
visualized in human cells during cell-cycle progression,9 suggesting acid (MOPS) buffer (Scheme 1).
that nature has provided the opportunities that G-quadruplex DNA
(G4DNA) might function as a catalytic species such as RNA in
biological processes. Many studies have been devoted to exploring
the possible catalytic functions of G4DNA-based catalysis.10 In
a State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, Dalian 116023, China. E-mail: canli@dicp.ac.cn;
Fax: +86-411-83694447; Tel: +86-411-84379070
b Dalian National Laboratory for Clean Energy, Dalian 116023, China
Scheme 1 The model Diels–Alder reaction used in this work. The absolute
configurations of (2S,3S)-3a (endo) as ‘+’ and (2R,3R)-3a (endo) as ‘ꢀ’ were
assigned from the literature.15
† Electronic supplementary information (ESI) available: Experimental details,
supplementary figures and tables, NMR spectra and HPLC traces. See DOI:
10.1039/c3cc45396k
c
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(Fig. S3b and S3d, ESI†), indicating that the enantioselective
induction is more sensitive to K+ than to Na+. In the range of
1–100 mM K+, the enantioselectivities of the corresponding D–A
reactions cause small changes with the highest ꢀ56% ee at
25 mM K+ (Fig. S3a, ESI†), but the G-quadruplex structure of
ODN-Cu2+ changes from antiparallel to hybrid-type (Fig. S3b, ESI†).
Upon further increasing the K+ concentrations (200–500 mM), the
ee of 3a decreases gradually (Fig. S3a, ESI†) along with a hybrid
G-quadruplex of ODN-Cu2+ (Fig. S3b, ESI†). Taken together, the
enantioselectivity of the D–A reaction can be switched by changing
the alkali metal ion from Na+ to K+, which is possibly attributed to
the G-quadruplex transformation from antiparallel to hybrid-type.
In order to confirm the generality of Na+/K+ switch of
enantioselectivity for the D–A reaction catalyzed by ODN-Cu2+, a
scope of reactants of dienophiles (1a–e) was tested (Table 1). When
tuning the substituent (R1) of the 2-imidazolyl group, the pheno-
Fig. 1 The relationship between the enantioselectivity and the G4DNA conforma-
tion in the presence of alkali metal ions. (a) The enantiomeric excesses of 3a (endo)
for the Diels–Alder reaction catalyzed by ODN-Cu2+ in the presence of alkali metal
ions (50 mM) with reproducibility of ꢁ5%. Conversions are within 5–20% (see
Table S3, ESI† for details). (b) CD spectra of ODN-Cu2+ recorded in the presence of
alkali metal ions (50 mM).
Without alkali metal ions, the D–A product 3a is formed in menon of Na+/K+ switched enantioselectivity is true for a broad
ꢀ10% ee (Fig. 1a) and the structure of ODN-Cu2+ is a labile scope of the dienophiles (Table 1, entries 1–6). By enhancing the
antiparallel G-quadruplex according to the circular dichroism (CD) steric hindrance of the dienophiles (R1 = Me - Et - iPr), the
spectrum (Fig. 1b). In the presence of Li+, the enantioselectivity enantioselectivities of the corresponding reactions increase in
of the D–A reaction is ꢀ11% ee, nearly the same level as that the presence of Na+ (Table 1, entries 1, 3 and 5), but the
without alkali metal ions (Fig. 1a), and the CD spectrum displays enantioselectivities decrease in K+-containing media (Table 1,
a little more stable antiparallel G-quadruplex compared to that entries 2, 4 and 6). The substituent (R2) of the phenyl group in
without alkali metal ions (Fig. 1b). Surprisingly, in the presence the dienophiles was also tested. When the dienophile bears either
of Na+, the ee of 3a is 31% in a reversed configuration compared an electron-donating group (1d) or an electron-withdrawing group
with that in the absence of alkali metal ions or in the presence (1e) in comparison with 1a, the enantioselectivities of the corre-
of Li+ (Fig. 1a), and in this case ODN-Cu2+ folds into a stable sponding D–A products decrease in Na+-containing media (Table 1,
antiparallel6 G-quadruplex (Fig. 1b). When KCl was added to the entries 7 and 9 vs. entry 1), yet comparable enantioselectivities
reaction medium in place of NaCl, the product 3a is obtained in are obtained in K+-containing media (Table 1, entries 8 and 10 vs.
50% ee (Fig. 1a) and the corresponding CD spectrum displays a entry 2). Although the enantioselectivities obtained are somewhat
hybrid-type of DNA G-quadruplex (Fig. 1b) as described in the different by varying the steric and electronic factors, the general
literature.8b However, ODN-Cu2+ with Rb+ or Cs+ shows decreased trend of Na+/K+ switched enantioselectivity is always the same.
enantioselectivity of the D–A reaction as compared with K+
The enantioselectivity can be switched when the D–A
(Fig. 1a). It is obviously seen that the alkali metal ions play reaction is catalyzed by ODN-Cu2+ in the presence of Na+ or K+.
important roles in the enantioselective induction of the G4DNA-
based catalysis, which might be ascribed to the structural changes
Table 1 Substrate scope of the G-quadruplex DNA-based Diels–Alder reactions
of G4DNA as previously mentioned in double-stranded DNA-
based catalysis.16
In view of chiral inversion in the case of Na+ and K+ (Fig. 1a)
together with their biological significances, we further studied
the effect of Na+ and K+ on the enantioselective induction of the
D–A reaction (Fig. S2 and S3, ESI†). Compared with the those of
Entrya Dienophile 1 Additiveb Conversionc (%) Endo : exod eed (%)
no alkali metal ions, the continuous addition of Na+ can change
1
2
3
4
5
6
7
8
9
10
1a: R1 = Me, NaCl
17
36
32
88
80
39
40
81
30
93
96 : 4
96 : 4
95 : 5
95 : 5
92 : 8
86 : 14
91 : 9
97 : 3
93 : 7
94 : 6
49e
ꢀ56e
55
the antiparallel G-quadruplex of ODN-Cu2+ from a labile state to
a compact one (Fig. S2b, ESI†), and the absolute configuration of
3a can be switched from ‘‘ꢀ’’ to ‘‘+’’ and up to 49% ee was
obtained at 100 mM Na+ (Fig. S2a, ESI†). Upon further increasing
the amount of Na+ (200–500 mM), the enantioselectivities
decrease (Fig. S2a, ESI†) and the corresponding CD spectra show
compact antiparallel G-quadruplexes but with slightly declined
intensities (Fig. S2b, ESI†). Compared with Na+, a distinct
phenomenon was observed in the case of K+ (Fig. S3, ESI†).
Without K+, ODN-Cu2+ is a labile antiparallel G-quadruplex and
R2 = H
1b: R1=Et,
R2 = H
KCl
NaCl
KCl
ꢀ20
1c: R1 = iPr, NaCl
R2 = H KCl
1d: R1 = Me, NaCl
R2 = 4-Me KCl
1e: R1 = Me, NaCl
R2 = 2-Br KCl
67
ꢀ2
5
ꢀ50
13
ꢀ58
a
Reaction conditions: 1 (1 mmol), 2 (15 mL, 180 mmol), ODN (5 mol%),
Cu(NO3)2 (15 mol%), MOPS buffer (20 mM, pH 6.5), 4 1C, 3 d. All data
b
are averaged over two separated experiments. NaCl (100 mM) or KCl
gives the D–A product 3a in ꢀ10% ee (Fig. S3a, ESI†). When only (25 mM). Determined by the crude 1H NMR spectroscopy (HPLC for
c
d
a trace amount of K+ ions (1 mM) is added, the ee value of 3a
sharply increased to ꢀ50% (Fig. S3a and S3c, ESI†) and the
antiparallel structure of ODN-Cu2+ gradually becomes stable
3a) with reproducibility of ꢁ10%. Determined by chiral-phase HPLC.
Enantiomeric excesses are obtained only for the endo isomers of the
corresponding Diels–Alder products with reproducibility of ꢁ5%.
e
(2S,3S)-3a (endo) as ‘+’ and (2R,3R)-3a (endo) as ‘ꢀ’.
c
11162 Chem. Commun., 2013, 49, 11161--11163
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of the chiral compounds (possibly drug molecules) to the potential
G-quadruplex targets for cancer therapy and may shed light on the
chemical behaviours of DNA in the life process.
This research was financially supported by the National Science
Foundation of China (Grant Number 31000392). We thank
Dr Y. Liu, Dr S.M. Lu, Dr J. Li and Dr Z.K. Zhao of the Dalian
Institute of Chemical Physics for their valuable discussions.
Notes and references
1 (a) P. L. Jorgensen, Biochim. Biophys. Acta, 1982, 694, 27–68;
(b) J. D. Horisberger, V. Lemas, J. P. Kraehenbuhl and B. C. Rossier,
Annu. Rev. Physiol., 1991, 53, 565–584; (c) J. B. Lingrel and T. Kuntzweiler,
J. Biol. Chem., 1994, 269, 19659–19662; (d) J. H. Kaplan, Annu. Rev.
Biochem., 2002, 71, 511–535.
2 (a) W. L. Stahl, Neurochem. Int., 1986, 8, 449–476; (b) D. C. Gadsby,
R. F. Rakowski and P. Deweer, Science, 1993, 260, 100–103;
(c) C. M. Colbert and E. H. Pan, Nat. Neurosci., 2002, 5, 533–538;
(d) S. Dai, D. D. Hall and J. W. Hell, Physiol. Rev., 2009, 89, 411–452.
3 (a) E. U. Woehl and M. F. Dunn, Coord. Chem. Rev., 1995, 144,
147–197; (b) S. Prasad, K. J. Wright, D. B. Roy, L. A. Bush,
A. M. Cantwell and E. Di Cera, Proc. Natl. Acad. Sci. U. S. A., 2003,
100, 13785–13790; (c) M. J. Page and E. Di Cera, Physiol. Rev., 2006,
86, 1049–1092.
4 (a) A. Siddiqui-Jain, C. L. Grand, D. J. Bearss and L. H. Hurley, Proc.
Natl. Acad. Sci. U. S. A., 2002, 99, 11593–11598; (b) J. L. Huppert and
S. Balasubramanian, Nucleic Acids Res., 2005, 33, 2908–2916;
(c) Z. A. E. Waller, S. A. Sewitz, S.-T. D. Hsu and S. Balasubramanian,
J. Am. Chem. Soc., 2009, 131, 12628–12633; (d) R. Rodriguez,
K. M. Miller, J. V. Forment, C. R. Bradshaw, M. Nikan, S. Britton,
T. Oelschlaegel, B. Xhemalce, S. Balasubramanian and S. P. Jackson,
Nat. Chem. Biol., 2012, 8, 301–310.
5 (a) J. L. Mergny and C. Helene, Nat. Med., 1998, 4, 1366–1367;
(b) H. Y. Han and L. H. Hurley, Trends Pharmacol. Sci., 2000, 21,
136–142; (c) S. Balasubramanian and S. Neidle, Curr. Opin. Chem.
Biol., 2009, 13, 345–353; (d) S. Balasubramanian, L. H. Hurley and
S. Neidle, Nat. Rev. Drug Discovery, 2011, 10, 261–275; (e) A. Siddiqui-Jain
and L. H. Hurley, Nat. Chem., 2013, 5, 153–155.
6 Y. Wang and D. J. Patel, Structure, 1993, 1, 263–282.
7 G. N. Parkinson, M. P. H. Lee and S. Neidle, Nature, 2002, 417, 876–880.
8 (a) J. Li, J. J. Correia, L. Wang, J. O. Trent and J. B. Chaires, Nucleic
Acids Res., 2005, 33, 4649–4659; (b) K. N. Luu, A. T. Phan, V. Kuryavyi,
L. Lacroix and D. J. Patel, J. Am. Chem. Soc., 2006, 128, 9963–9970;
(c) Y. Xu, Y. Noguchi and H. Sugiyama, Bioorg. Med. Chem., 2006, 14,
5584–5591; (d) J. Dai, M. Carver, C. Punchihewa, R. A. Jones and
D. Yang, Nucleic Acids Res., 2007, 35, 4927–4940; (e) A. T. Phan,
V. Kuryavyi, K. N. Luu and D. J. Patel, Nucleic Acids Res., 2007, 35,
6517–6525; ( f ) K. W. Lim, S. Amrane, S. Bouaziz, W. Xu, Y. Mu,
D. J. Patel, K. N. Luu and A. T. Phan, J. Am. Chem. Soc., 2009, 131,
4301–4309.
Fig. 2 The enantioselectivity of the Diels–Alder reaction catalyzed by ODN-Cu2+
of 1a and 2 by varying the Na+/K+ ratios. Solid circles (from left to right): the ee of
3a (endo) in 100 mM Na+-containing media with increasing concentration of KCl
(0–25 mM). Empty circles (from right to left): the ee of 3a (endo) in reaction
media containing 25 mM K+ with increasing concentration of NaCl (0–100 mM).
This interesting phenomenon leads us to examine the catalytic
performances of ODN-Cu2+ when both Na+ and K+ are present
in the benchmark D–A reaction.
On one hand, in the presence of 100 mM Na+, different
amounts of KCl (0–25 mM) were added to test the enantio-
selectivity of the D–A reaction catalyzed by ODN-Cu2+ (solid
circles in Fig. 2, from left to right). When only a trace amount of
K+ (0.01 mM) was added to the Na+-containing (100 mM)
medium (Na+/K+ = 10 000), the ee of 3a decreases from 49%
to 41% (Fig. 2), indicating that the enantioselective induction is
more sensitive to K+ in comparison with Na+ as discussed above.
Upon increasing the amount of K+ to 0.1–1 mM (Na+/K+ = 1000–100),
the enantioselectivities of the D–A reactions gradually decrease
(Fig. 2). Upon further increasing the K+ concentrations (1–25 mM),
the enantioselectivities of the corresponding D–A reactions
decrease sharply and product 3a becomes nearly racemic when
100 mM Na+ and 25 mM K+ coexist (Fig. 2). On the other hand, in
the presence of 25 mM K+, different amounts of NaCl (0–100 mM)
were added to investigate the enantioselectivity of the D–A reaction
catalyzed by ODN-Cu2+ (empty circles in Fig. 2, from right to left).
With only 25 mM K+, the enantioselectivity of the D–A reaction
is ꢀ56% ee. When Na+ is added in the range of 0–25 mM,
the ees of 3a do not evidently change (Fig. 2). Upon further
increasing the Na+ concentration from 25 mM to 100 mM, the
ees of 3a decrease sharply (Fig. 2). The above results suggest
that ODN-Cu2+ can act as a switchable catalyst for the enantio-
selective D–A reaction by tuning the Na+/K+ ratio.
9 G. Biffi, D. Tannahill, J. McCafferty and S. Balasubramanian, Nat.
Chem., 2013, 5, 182–186.
10 (a) P. Travascio, A. J. Bennet, D. Y. Wang and D. Sen, Chem. Biol.,
1999, 6, 779–787; (b) Z. Tang, D. P. N. Goncalves, M. Wieland,
A. Marx and J. S. Hartig, ChemBioChem, 2008, 9, 1061–1064;
(c) D.-M. Kong, L.-L. Cai, J.-H. Guo, J. Wu and H.-X. Shen, Biopolymers,
2009, 91, 331–339; (d) S. Nakayama, J. Wang and H. O. Sintim, Chem.–
Eur. J., 2011, 17, 5691–5698; (e) C. Li, L. Zhu, Z. Zhu, H. Fu, G. Jenkins,
C. Wang, Y. Zou, X. Lu and C. J. Yang, Chem. Commun., 2012, 48,
8347–8349.
11 C. Wang, G. Jia, J. Zhou, Y. Li, Y. Liu, S. Lu and C. Li, Angew. Chem.,
Int. Ed., 2012, 51, 9352–9355.
12 C. Wang, Y. Li, G. Jia, Y. Liu, S. Lu and C. Li, Chem. Commun., 2012,
48, 6232–6234.
13 S. Roe, D. J. Ritson, T. Garner, M. Searle and J. E. Moses, Chem.
Commun., 2010, 46, 4309–4311.
14 S. Park, K. Ikehata, R. Watabe, Y. Hidaka, A. Rajendran and
H. Sugiyama, Chem. Commun., 2012, 48, 10398–10400.
15 A. J. Boersma, B. L. Feringa and G. Roelfes, Org. Lett., 2007, 9,
3647–3650.
In summary, we have reported that the enantioselectivity is
highly sensitive to alkali metal ions in the enantioselective D–A
reaction catalyzed by a G4DNA-based catalyst. Interestingly, the
enantioselectivity of D–A reaction can be switched from about
50% ee to ꢀ50% ee by just changing the alkali metal ion from
Na+ to K+, which is ascribed to the structural transformation of
G-quadruplex motifs from an antiparallel to a hybrid type. By tuning
the ratio of Na+/K+, the enantioselectivity of the D–A reaction could
be switchable and shows much more sensitive to K+ than to Na+.
These results could be helpful for understanding the recognition
16 A. J. Boersma, J. E. Klijn, B. L. Feringa and G. Roelfes, J. Am. Chem.
Soc., 2008, 130, 11783–11790.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 11161--11163 11163