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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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Representative illustration of chiral supramolecular complex selective recognition of human telomeric G-quadruplex DNA.
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Figure 9: Representative illustration of chiral supramolecular complex selective recognition of human telomeric G-quadruplex DNA.

Mentions: We also studied another two distinct telomeric G-quadruplex DNA: tetrahymena G4(T2G4)3, a monomeric hybrid structure (37) and oxytricha telomeric DNA (T4G4)4, a monomeric antiparallel structure (38), and compared with human telomeric G-quadruplex DNA in sodium and in potassium (39,40) buffer (Table 3). Clearly, no matter in the presence of sodium or potassium, both M- and P-enantiomers destabilize these two telomeric DNA without chiral selectivity. The results of gel electrophoresis (Figure S1) show that there are no new bands emerged in the case of tetrahymena or oxytricha telomeric DNA with either M- or P-enantiomer indicating that the two enantiomers bind weakly to the two DNA. These results demonstrate that P-enantiomer is capable of discriminating between quadruplexes (Figure S1). We also examined the interactions of M- and P-enantiomer with a parallel-stranded tetramolecular quadruplex TG4T (41) by means of CD melting and gel electrophoresis. Both M- and P-enantiomer binding destabilized the quadruplex stability (Figure S2A), and no new band was observed in the gel (Figure S2B). The enantiomer binding to unfolded quadruplexes and the detailed destabilization mechanism are not clear yet and we are undertaking further studies. The results presented here indicate that the chiral selective stabilization of human telomeric G-quadruplex is not only related to G-quadruplex topology, but also related to the sequence and the loop constitution. Furthermore, we extend our work by investigating the effect of the 5′- or 3′-flanking sequence of human telomeric G-quadruplex (42) on the chiral selectivity of the enantiomers. As shown in Table 3, for DNA alone, its stability is decreased with longer flanking sequence. However, flanking sequence does not influence P-enantiomer chiral selectivity either in sodium or in potassium buffer (Table 3). This demonstrates that the 5′- or 3′-end capping sequence (42) does not influence P-enantiomer binding to the end of G-quartet (Scheme 1) by external stacking further supporting the 2-Ap fluorescence results (8,33) and S1 nuclease cleavage data.Scheme 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)

Representative illustration of chiral supramolecular complex selective recognition of human telomeric G-quadruplex DNA.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 9: Representative illustration of chiral supramolecular complex selective recognition of human telomeric G-quadruplex DNA.
Mentions: We also studied another two distinct telomeric G-quadruplex DNA: tetrahymena G4(T2G4)3, a monomeric hybrid structure (37) and oxytricha telomeric DNA (T4G4)4, a monomeric antiparallel structure (38), and compared with human telomeric G-quadruplex DNA in sodium and in potassium (39,40) buffer (Table 3). Clearly, no matter in the presence of sodium or potassium, both M- and P-enantiomers destabilize these two telomeric DNA without chiral selectivity. The results of gel electrophoresis (Figure S1) show that there are no new bands emerged in the case of tetrahymena or oxytricha telomeric DNA with either M- or P-enantiomer indicating that the two enantiomers bind weakly to the two DNA. These results demonstrate that P-enantiomer is capable of discriminating between quadruplexes (Figure S1). We also examined the interactions of M- and P-enantiomer with a parallel-stranded tetramolecular quadruplex TG4T (41) by means of CD melting and gel electrophoresis. Both M- and P-enantiomer binding destabilized the quadruplex stability (Figure S2A), and no new band was observed in the gel (Figure S2B). The enantiomer binding to unfolded quadruplexes and the detailed destabilization mechanism are not clear yet and we are undertaking further studies. The results presented here indicate that the chiral selective stabilization of human telomeric G-quadruplex is not only related to G-quadruplex topology, but also related to the sequence and the loop constitution. Furthermore, we extend our work by investigating the effect of the 5′- or 3′-flanking sequence of human telomeric G-quadruplex (42) on the chiral selectivity of the enantiomers. As shown in Table 3, for DNA alone, its stability is decreased with longer flanking sequence. However, flanking sequence does not influence P-enantiomer chiral selectivity either in sodium or in potassium buffer (Table 3). This demonstrates that the 5′- or 3′-end capping sequence (42) does not influence P-enantiomer binding to the end of G-quartet (Scheme 1) by external stacking further supporting the 2-Ap fluorescence results (8,33) and S1 nuclease cleavage data.Scheme 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