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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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The melting profiles of human telomeric G-quadruplex (1 µM/strand) in the absence (black) or presence of 1 µM M (red) or P-enantiomer (blue) of [Ni2L3]4+ (A) and [Fe2L3]4+ (B) in 10 mM KCl, 10 mM Tris buffer, pH 7.2.
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Figure 8: The melting profiles of human telomeric G-quadruplex (1 µM/strand) in the absence (black) or presence of 1 µM M (red) or P-enantiomer (blue) of [Ni2L3]4+ (A) and [Fe2L3]4+ (B) in 10 mM KCl, 10 mM Tris buffer, pH 7.2.

Mentions: Human telomeric G-quadruplex DNA is polymorphic, which can form an antiparallel structure (7,36) in the presence of sodium or adopt a hybrid structure in the presence of potassium. With addition of DNA equimolar M- or P-enantiomer in sodium, unexpectedly, P-enantiomer binding can induce DNA positive CD band intensity significantly increased and shifted from 295 to 290 nm. The negative band intensity simultaneously decreased and shifted from 265 to 256 nm (Figure 7, red line). This phenomenon is similar to the structural transition of quadruplex alone occurred in Na+ buffer titrated (23) by K+ (Figure 7, cyan line). Besides, similar G-quadruplex CD spectra were observed upon P-enantiomer binding no matter in Na+ or in K+ buffer (Figure S3). It should be pointed out that the CD band of the enantiomers at longer wavelength does not change when binding to G-quadruplex. As for M-enantiomer, its binding can just decrease the negative band intensity at 265 nm without band shift and cannot increase the positive band intensity (Figure 7, green line). However, the 1:1 mixture (13) of M and P (Figure 7, blue line) shows the same effect as P-enantiomer does. These results indicate that only P-enantiomer can convert G-quadruplex (Scheme 1) from antiparallel to hybrid structure (42), similar to previous reports that Se2SAP and TMPYP4 prefer antiparallel/parallel hybrid structure (3), but in contrast with telomestatin and macrocylic and helical oligoamides (23), which favor the antiparallel structure. DNA UV melting studies in K+ buffer (Figure 8) further support that P-enantiomer prefers the hybrid structure over M because P-enantiomer can increase Tm 20°C and M-enantiomer can only increase Tm 12°C. The difference in Tm increase shows P-enantiomer chiral preference even in K+ buffer. This can be the reason why P-enantiomer binding can drive G-quadruplex from antiparallel to hybrid structural transition in Na+ while M binding cannot. Gel electrophoresis (Figure 3B) and 2-Ap fluorescence titration data (Figure S4) obtained in K+ buffer further demonstrate that P-enantiomer prefers hybrid structure over M no matter in Na+ or in K+ buffer. Our preliminary data in cancer cells indicate that the two enantiomers show telomerase inhibition (Figure S5), and influence telomere shortening, β-galactosidase activity and upregulation of cyclin-dependent kinase (CDK) inhibitors p16 and p21 (data not shown), further studies are undergoing and will be reported in due course.Figure 7.


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)

The melting profiles of human telomeric G-quadruplex (1 µM/strand) in the absence (black) or presence of 1 µM M (red) or P-enantiomer (blue) of [Ni2L3]4+ (A) and [Fe2L3]4+ (B) in 10 mM KCl, 10 mM Tris buffer, pH 7.2.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2553577&req=5

Figure 8: The melting profiles of human telomeric G-quadruplex (1 µM/strand) in the absence (black) or presence of 1 µM M (red) or P-enantiomer (blue) of [Ni2L3]4+ (A) and [Fe2L3]4+ (B) in 10 mM KCl, 10 mM Tris buffer, pH 7.2.
Mentions: Human telomeric G-quadruplex DNA is polymorphic, which can form an antiparallel structure (7,36) in the presence of sodium or adopt a hybrid structure in the presence of potassium. With addition of DNA equimolar M- or P-enantiomer in sodium, unexpectedly, P-enantiomer binding can induce DNA positive CD band intensity significantly increased and shifted from 295 to 290 nm. The negative band intensity simultaneously decreased and shifted from 265 to 256 nm (Figure 7, red line). This phenomenon is similar to the structural transition of quadruplex alone occurred in Na+ buffer titrated (23) by K+ (Figure 7, cyan line). Besides, similar G-quadruplex CD spectra were observed upon P-enantiomer binding no matter in Na+ or in K+ buffer (Figure S3). It should be pointed out that the CD band of the enantiomers at longer wavelength does not change when binding to G-quadruplex. As for M-enantiomer, its binding can just decrease the negative band intensity at 265 nm without band shift and cannot increase the positive band intensity (Figure 7, green line). However, the 1:1 mixture (13) of M and P (Figure 7, blue line) shows the same effect as P-enantiomer does. These results indicate that only P-enantiomer can convert G-quadruplex (Scheme 1) from antiparallel to hybrid structure (42), similar to previous reports that Se2SAP and TMPYP4 prefer antiparallel/parallel hybrid structure (3), but in contrast with telomestatin and macrocylic and helical oligoamides (23), which favor the antiparallel structure. DNA UV melting studies in K+ buffer (Figure 8) further support that P-enantiomer prefers the hybrid structure over M because P-enantiomer can increase Tm 20°C and M-enantiomer can only increase Tm 12°C. The difference in Tm increase shows P-enantiomer chiral preference even in K+ buffer. This can be the reason why P-enantiomer binding can drive G-quadruplex from antiparallel to hybrid structural transition in Na+ while M binding cannot. Gel electrophoresis (Figure 3B) and 2-Ap fluorescence titration data (Figure S4) obtained in K+ buffer further demonstrate that P-enantiomer prefers hybrid structure over M no matter in Na+ or in K+ buffer. Our preliminary data in cancer cells indicate that the two enantiomers show telomerase inhibition (Figure S5), and influence telomere shortening, β-galactosidase activity and upregulation of cyclin-dependent kinase (CDK) inhibitors p16 and p21 (data not shown), further studies are undergoing and will be reported in due course.Figure 7.

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