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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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(A) Structures of the M-enantiomer (left) and P-enantiomer (right) of [Ni2L3]4+ cation. Nickel: gray; nitrogen: yellow; carbon atoms in three ligand L are shown in red, green and blue, respectively. Hydrogen atoms are omitted for clarity. The crystal data of [Ni2L3]4+ are from the Cambridge Crystallographic Data Centre CCDC 182/570 (15). (B) Structures of the M-enantiomer (left) and P-enantiomer (right) of [Fe2L3]4+ cation. Iron atoms are in purple, other atoms are the same as in [Ni2L3]4+. The crystal data of [Fe2L3]4+ are from the Cambridge Crystallographic Data Centre CCDC 622770 (16). (C) CD spectra of the M-enantiomer (black) and P-enantiomer (red) of [Ni2L3]4+; (D) CD spectra of the M-enantiomer (black) and P-enantiomer (red) of [Fe2L3]4+. The CD spectra are measured at the concentration of 10 µM for each enantiomer in 100 mM NaCl, 10 mM Tris buffer (pH 7.2).
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Figure 1: (A) Structures of the M-enantiomer (left) and P-enantiomer (right) of [Ni2L3]4+ cation. Nickel: gray; nitrogen: yellow; carbon atoms in three ligand L are shown in red, green and blue, respectively. Hydrogen atoms are omitted for clarity. The crystal data of [Ni2L3]4+ are from the Cambridge Crystallographic Data Centre CCDC 182/570 (15). (B) Structures of the M-enantiomer (left) and P-enantiomer (right) of [Fe2L3]4+ cation. Iron atoms are in purple, other atoms are the same as in [Ni2L3]4+. The crystal data of [Fe2L3]4+ are from the Cambridge Crystallographic Data Centre CCDC 622770 (16). (C) CD spectra of the M-enantiomer (black) and P-enantiomer (red) of [Ni2L3]4+; (D) CD spectra of the M-enantiomer (black) and P-enantiomer (red) of [Fe2L3]4+. The CD spectra are measured at the concentration of 10 µM for each enantiomer in 100 mM NaCl, 10 mM Tris buffer (pH 7.2).

Mentions: Supramolecular chemistry has been described as an information science (18,19). It provides an excellent methodology for designing large synthetic compounds targeting DNA major groove (20,21), because the compound can have similar size like DNA-binding protein recognition motifs (such as zinc fingers or α-helices) and multiple cationic charges favoring the noncovalent binding to anionic DNA. The chiral compound we used, [M2L3]4+ (M = Ni2+ or Fe2+), has a bimetallo triple helicate structure (15–17). Structures and CD spectra of the two pairs of enantiomers, M and P, are shown in Figure 1. Each enantiomer has a hydrophobic surface and a size (15–17) (length ∼18 Å, diameter ∼8 Å) compatible with G-quartet [length ∼14 Å, width (22) ∼11 Å], and the positive charged triple helical structure has the potential to interact with the loops and grooves of G-quadruplex, which has been proposed for zinc-finger protein and macrocyclic and helical oligoamides binding (6,23).Figure 1.


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)

(A) Structures of the M-enantiomer (left) and P-enantiomer (right) of [Ni2L3]4+ cation. Nickel: gray; nitrogen: yellow; carbon atoms in three ligand L are shown in red, green and blue, respectively. Hydrogen atoms are omitted for clarity. The crystal data of [Ni2L3]4+ are from the Cambridge Crystallographic Data Centre CCDC 182/570 (15). (B) Structures of the M-enantiomer (left) and P-enantiomer (right) of [Fe2L3]4+ cation. Iron atoms are in purple, other atoms are the same as in [Ni2L3]4+. The crystal data of [Fe2L3]4+ are from the Cambridge Crystallographic Data Centre CCDC 622770 (16). (C) CD spectra of the M-enantiomer (black) and P-enantiomer (red) of [Ni2L3]4+; (D) CD spectra of the M-enantiomer (black) and P-enantiomer (red) of [Fe2L3]4+. The CD spectra are measured at the concentration of 10 µM for each enantiomer in 100 mM NaCl, 10 mM Tris buffer (pH 7.2).
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Figure 1: (A) Structures of the M-enantiomer (left) and P-enantiomer (right) of [Ni2L3]4+ cation. Nickel: gray; nitrogen: yellow; carbon atoms in three ligand L are shown in red, green and blue, respectively. Hydrogen atoms are omitted for clarity. The crystal data of [Ni2L3]4+ are from the Cambridge Crystallographic Data Centre CCDC 182/570 (15). (B) Structures of the M-enantiomer (left) and P-enantiomer (right) of [Fe2L3]4+ cation. Iron atoms are in purple, other atoms are the same as in [Ni2L3]4+. The crystal data of [Fe2L3]4+ are from the Cambridge Crystallographic Data Centre CCDC 622770 (16). (C) CD spectra of the M-enantiomer (black) and P-enantiomer (red) of [Ni2L3]4+; (D) CD spectra of the M-enantiomer (black) and P-enantiomer (red) of [Fe2L3]4+. The CD spectra are measured at the concentration of 10 µM for each enantiomer in 100 mM NaCl, 10 mM Tris buffer (pH 7.2).
Mentions: Supramolecular chemistry has been described as an information science (18,19). It provides an excellent methodology for designing large synthetic compounds targeting DNA major groove (20,21), because the compound can have similar size like DNA-binding protein recognition motifs (such as zinc fingers or α-helices) and multiple cationic charges favoring the noncovalent binding to anionic DNA. The chiral compound we used, [M2L3]4+ (M = Ni2+ or Fe2+), has a bimetallo triple helicate structure (15–17). Structures and CD spectra of the two pairs of enantiomers, M and P, are shown in Figure 1. Each enantiomer has a hydrophobic surface and a size (15–17) (length ∼18 Å, diameter ∼8 Å) compatible with G-quartet [length ∼14 Å, width (22) ∼11 Å], and the positive charged triple helical structure has the potential to interact with the loops and grooves of G-quadruplex, which has been proposed for zinc-finger protein and macrocyclic and helical oligoamides binding (6,23).Figure 1.

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