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Chiral metallo-supramolecular complexes selectively recognize human telomeric G-quadruplex DNA.

Yu H, Wang X, Fu M, Ren J, Qu X - Nucleic Acids Res. (2008)

Bottom Line: The chiral supramolecular complex has both small molecular chemical features and the large size of a zinc-finger-like DNA-binding motif.The complex is also convenient to synthesize and separate enantiomers.These results provide new insights into the development of chiral anticancer agents for targeting G-quadruplex DNA.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Inorganic Chemistry, Key Laboratory of Rare Earth Chemistry and Physics, Changchun Institute of Applied Chemistry, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Changchun, Jilin 130022, China.

ABSTRACT
Here, we report the first example that one enantiomer of a supramolecular cylinder can selectively stabilize human telomeric G-quadruplex DNA. The P-enantiomer of this cylinder has a strong preference for G-quadruplex over duplex DNA and, in the presence of sodium, can convert G-quadruplexes from an antiparallel to a hybrid structure. The compound's chiral selectivity and its ability to discriminate quadruplex DNA have been studied by DNA melting, circular dichroism, gel electrophoresis, fluorescence spectroscopy and S1 nuclease cleavage. The chiral supramolecular complex has both small molecular chemical features and the large size of a zinc-finger-like DNA-binding motif. The complex is also convenient to synthesize and separate enantiomers. These results provide new insights into the development of chiral anticancer agents for targeting G-quadruplex DNA.

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Variation of the reciprocal melting temperature for G-quadruplex in the absence (black squares) or presence of [Ni2L3]4+-P (red circles) and [Ni2L3]4+-M (blue uptriangles) with the logarithm of NaCl concentration in 10 mM Tris buffer (pH 7.2).
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Figure 4: Variation of the reciprocal melting temperature for G-quadruplex in the absence (black squares) or presence of [Ni2L3]4+-P (red circles) and [Ni2L3]4+-M (blue uptriangles) with the logarithm of NaCl concentration in 10 mM Tris buffer (pH 7.2).

Mentions: To our knowledge, supramolecular [Ni2L3]4+ complex binding to any DNA has not been reported. Hannon and co-workers (26) have shown that both [Fe2L3]4+-M and [Fe2L3]4+-P can increase CT-DNA Tm > 10°C at low-salt concentration (20 mM NaCl, 1 mM cacodylate buffer, pH 6.8) and M-enantiomer has even stronger effect (26,27). Their recent studies compellingly demonstrate that the same helicates recognize specific DNA three-way junctions (28,29), and also show anticancer activity (30). Inspired by these findings, we focus on [Ni2L3]4+ enantiomers binding to DNA and find their chiral selectivity to G-quadruplex. At physiological salt concentration as we used (100 mM NaCl, 10 mM Tris buffer, pH 7.2), M and P can only slightly increase CT-DNA Tm. It should be pointed out that this difference can be due to the different experimental conditions. We use higher ionic strength which can decrease the positively charged complex binding to duplex DNA. This indicates that the electrostatic effect is playing an important role for this complex binding to duplex DNA major groove (26), while the chiral selectivity is essential when the complex binding to G-quadruplex (Figure 2). According to G-quadruplex melting data measured under different ionic strength conditions (Figure 4), and the equation (31): , where the values of ΔH0 are calculated (8) from the melting curves (ΔH0G-DNA, ΔH0G-DNA-M and ΔH0G-DNA-P, are 157.3 ± 0.2, −145.6 ± 0.6 and −135.7 ± 0.5 kJ mol−1 for G-quadruplex DNA alone, G-quadruplex DNA with M- or P-enantiomer, respectively), the number of sodium ion releasing (31) is calculated about 1.8 sodium no matter in the absence or presence of the enantiomer, consistent with G-quadruplex DNA NMR analysis (32). Therefore, M and P binding to G-quadruplex do not lead to more sodium ion release.Figure 4.


Chiral metallo-supramolecular complexes selectively recognize human telomeric G-quadruplex DNA.

Yu H, Wang X, Fu M, Ren J, Qu X - Nucleic Acids Res. (2008)

Variation of the reciprocal melting temperature for G-quadruplex in the absence (black squares) or presence of [Ni2L3]4+-P (red circles) and [Ni2L3]4+-M (blue uptriangles) with the logarithm of NaCl concentration in 10 mM Tris buffer (pH 7.2).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
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Figure 4: Variation of the reciprocal melting temperature for G-quadruplex in the absence (black squares) or presence of [Ni2L3]4+-P (red circles) and [Ni2L3]4+-M (blue uptriangles) with the logarithm of NaCl concentration in 10 mM Tris buffer (pH 7.2).
Mentions: To our knowledge, supramolecular [Ni2L3]4+ complex binding to any DNA has not been reported. Hannon and co-workers (26) have shown that both [Fe2L3]4+-M and [Fe2L3]4+-P can increase CT-DNA Tm > 10°C at low-salt concentration (20 mM NaCl, 1 mM cacodylate buffer, pH 6.8) and M-enantiomer has even stronger effect (26,27). Their recent studies compellingly demonstrate that the same helicates recognize specific DNA three-way junctions (28,29), and also show anticancer activity (30). Inspired by these findings, we focus on [Ni2L3]4+ enantiomers binding to DNA and find their chiral selectivity to G-quadruplex. At physiological salt concentration as we used (100 mM NaCl, 10 mM Tris buffer, pH 7.2), M and P can only slightly increase CT-DNA Tm. It should be pointed out that this difference can be due to the different experimental conditions. We use higher ionic strength which can decrease the positively charged complex binding to duplex DNA. This indicates that the electrostatic effect is playing an important role for this complex binding to duplex DNA major groove (26), while the chiral selectivity is essential when the complex binding to G-quadruplex (Figure 2). According to G-quadruplex melting data measured under different ionic strength conditions (Figure 4), and the equation (31): , where the values of ΔH0 are calculated (8) from the melting curves (ΔH0G-DNA, ΔH0G-DNA-M and ΔH0G-DNA-P, are 157.3 ± 0.2, −145.6 ± 0.6 and −135.7 ± 0.5 kJ mol−1 for G-quadruplex DNA alone, G-quadruplex DNA with M- or P-enantiomer, respectively), the number of sodium ion releasing (31) is calculated about 1.8 sodium no matter in the absence or presence of the enantiomer, consistent with G-quadruplex DNA NMR analysis (32). Therefore, M and P binding to G-quadruplex do not lead to more sodium ion release.Figure 4.

Bottom Line: The chiral supramolecular complex has both small molecular chemical features and the large size of a zinc-finger-like DNA-binding motif.The complex is also convenient to synthesize and separate enantiomers.These results provide new insights into the development of chiral anticancer agents for targeting G-quadruplex DNA.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Inorganic Chemistry, Key Laboratory of Rare Earth Chemistry and Physics, Changchun Institute of Applied Chemistry, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Changchun, Jilin 130022, China.

ABSTRACT
Here, we report the first example that one enantiomer of a supramolecular cylinder can selectively stabilize human telomeric G-quadruplex DNA. The P-enantiomer of this cylinder has a strong preference for G-quadruplex over duplex DNA and, in the presence of sodium, can convert G-quadruplexes from an antiparallel to a hybrid structure. The compound's chiral selectivity and its ability to discriminate quadruplex DNA have been studied by DNA melting, circular dichroism, gel electrophoresis, fluorescence spectroscopy and S1 nuclease cleavage. The chiral supramolecular complex has both small molecular chemical features and the large size of a zinc-finger-like DNA-binding motif. The complex is also convenient to synthesize and separate enantiomers. These results provide new insights into the development of chiral anticancer agents for targeting G-quadruplex DNA.

Show MeSH
Related in: MedlinePlus