Chiral Metallo–Supramolecular Complexes Selectively Induce Human Telomeric G‐Quadruplex Formation under Salt‐Deficient Conditions

Zhao, Chuanqi; Geng, Jie; Feng, Lingyan; Ren, Jinsong; Qu, Xiaogang

doi:10.1002/chem.201100272

Cited by 59 publications

(31 citation statements)

References 51 publications

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“…Table S4). chiral induction, [15] indicating that it is likely the enantioselective catalysis predominantly occurs in the loop region. We also investigated the rate acceleration (k app ODN-1-Cu 2+/k app Cu 2+) for complexes of ODN-1-4 (Table 4).…”

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confidence: 99%

Enantioselective Diels–Alder Reactions with G‐Quadruplex DNA‐Based Catalysts

et al. 2012

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Deoxyribonucleic acid (DNA) is the genetic material of living organisms. In the past, double-stranded DNA (dsDNA) with its ubiquitous architecture has not been regarded as a catalytic species, since the duplex structure precludes the formation of catalytically competent tertiary structures.[1] To date, although no naturally occurring catalytic DNA has been reported, DNA for nonbiological applications has aroused much interest in chemists for applications in areas such as catalysis, encoding, and stereocontrol.[2] Among these applications, a series of DNA-based asymmetric catalysis have been developed, which use a hybrid catalyst composed of dsDNA and a copper(II) complex.[3] This same strategy was later applied to G-quadruplex DNA (G4DNA) and modest enantioselectivities in the Diels-Alder (D-A) reaction were obtained.[4] Very recently, a G4DNA metalloenzyme composed of G4DNA and copper(II) ions has been reported to be able to catalyze an enantioselective Friedel-Crafts reaction. [5] This biology/chemistry interface is an attractive area of research and awaits further extensive exploration. Herein, we report an enantioselective D-A reaction achieved through the use of human telomeric G4DNA-based catalysts. We show that the absolute configuration of the products can be reversed when the conformation of the G4DNA is switched from antiparallel to parallel. Furthermore, both the reaction rate and the enantioselectivity of the reaction were found to be dependent on the DNA sequence.The D-A reaction is an important carbon-carbon bond forming reaction in organic synthesis. In the past few decades, it has received much attention in the development of innovative catalytic strategies to control the creation of the new carbon-carbon bonds and stereocenters. Among those strategies, biological molecules have been viewed as interesting and promising catalysts.[6] Herein, human telomeric G4DNA (ODN-1, 5'-G 3 (T 2 AG 3 ) 3 -3') was selected owing to its tunable conformation. As an initial attempt, a model D-A reaction [7] between aza-chalcone (1 a) and cyclopentadiene (2) was chosen to probe the catalytic performance of ODN-1. We found that ODN-1 alone in its antiparallel conformation [8] could promote the D-A reaction and the enantiomeric excess of the endo isomer of product 3 a is 17 % (Table 1, entry 2).The enantioselectivity of the ODN-1 promoted D-A reaction is significantly higher than that of the uncatalyzed reaction (Table 1, entry 2 vs. entry 1), which suggests that ODN-1 might function as an enantioselective catalyst for the D-A reaction.We assembled a complex between Cu(NO 3 ) 2 and ODN-1 (ODN-1-Cu 2+ ) and tested its ability to enantioselectively catalyze the D-A reaction. ODN-1-Cu 2+ provides a significant enhancement in the reaction rate ( entry 3). We also observed an excellent diastereoselectivity for product 3 a (endo/exo of 98:2) and a good enantioselectivity (74 % ee). These results suggest that ODN-1-Cu 2+ can serve as a potent catalyst, providing stereoselectivity and enhancement in reaction rates. To furthe...

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confidence: 99%

Enantioselective Diels–Alder Reactions with G‐Quadruplex DNA‐Based Catalysts

et al. 2012

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“…After titration with Δ1a , the intensity of the CD band at 256 nm decreased gradually from positive to negative, and at the same time, a distinct increase at 288 nm and an emergence of a shoulder peak at 270 nm were observed. This induced CD spectrum was similar to that of the hybrid G-quadruplex in K + buffer, indicating that Δ1a can induce the formation of hybrid G-quadruplex under Na + or K + -deficient conditions (37). In contrast, no inducing process was observed after adding of Λ1a (Figure 2D).…”

Section: Resultsmentioning

confidence: 64%

Chiral metallohelices enantioselectively target hybrid human telomeric G-quadruplex DNA

Zhao

Howson

Zhao

et al. 2017

Nucleic Acids Research

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The design and synthesis of metal complexes that can specifically target DNA secondary structure has attracted considerable attention. Chiral metallosupramolecular complexes (e.g. helicates) in particular display unique DNA-binding behavior, however until recently few examples which are both water-compatible and enantiomerically pure have been reported. Herein we report that one metallohelix enantiomer Δ1a, available from a diastereoselective synthesis with no need for resolution, can enantioselectively stabilize human telomeric hybrid G-quadruplex and strongly inhibit telomerase activity with IC50 of 600 nM. In contrast, no such a preference is observed for the mirror image complex Λ1a. More intriguingly, neither of the two enantiomers binds specifically to human telomeric antiparallel G-quadruplex. To the best of our knowledge, this is the first example of one pair of enantiomers with contrasting selectivity for human telomeric hybrid G-quadruplex. Further studies show that Δ1a can discriminate human telomeric G-quadruplex from other telomeric G-quadruplexes.

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“…一些小分子化合物如: 吖啶类、离子卟啉类、EB 类、蒽醌类、二萘嵌苯类、telomestatin [4] 等已经被证实了具有显著的稳定 G-四链体 DNA 的能力. 除了上述的有机小分子外, 一些金属配合物也表现出了与 G-四链体 DNA 相互作用以及抑制端粒酶的活性能力 [5,6] . Rick-…”

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Stabilization of Telomere DNA, and Mechanism of Apoptosis of Tumor Cells Induced by Ruthenium Complexes

Liu¹,

Chen²,

Zhang³

et al. 2014

Acta Chim. Sinica

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Telomerase is highly expressed in tumor cells, which has become an important target of anticancer drugs. Since many tumor cells were rich in G4-DNA, we investigated the capabilities of these two ruthenium complexes to stabilize G4-DNA. Two ruthenium(II) complexes were synthesized and characterized via electrospray ionization-mass spectrometry. Since many tumor cells were rich in G4-DNA, we investigated the capabilities of these two ruthenium complexes to stabilize G4-DNA. The interactions of these compounds with G-quadruplex DNA have been studied by fluorescence spectroscopy and circular dichroism (CD) spectroscopy. The stabilization of quadruplex DNA to complex 2 was better than complex 1, and complex 2 can induce telomeric G-quadruplex to occur conformation transformation, while complex 1 cannot. The results showed that the interaction of ruthenium complexes with G-quadruplex DNA was related with the plane of ligand. A novel visual method has been developed for making a distinction between ct-DNA and HTG21 by our Ru complexes binding hemin to form the hemin-G-quadruplex DNAzyme. The results showed that in the presence of complex 1 or 2, HTG21 can fold into a G-quadruplex, but CT-DNA cannot form the G-quadruplex structure. The anticancer activities of these complexes were evaluated by using the MTT assay. Interestingly, the anti-tumor activity of complex 2 exhibited greater inhibition to HepG2 cells, suggesting the ruthenium complexes were much less toxic towards normal cells, and speculated that it targeted the telomeric G-quadruplex was play a role on anti-tumor effect. To further evaluate the characteristics of the death induced by complexes 1 and 2-treated cells staining with Hoechst is analyzed by fluorescence microscopy. These results indicated that complex 2 revealed antiproliferative activities by apoptosis. We also used PI staining and flow cytometry to assess whether the ruthenium complex 2 affected cell cycle progression in HepG2 cells. Complex 2 is a potential antitumor drugs that can induce cancer cell death by acting on cell cycle arrest in G1 phase and the formation of DNA fragments (apoptosis characteristics).

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Chiral Metallo–Supramolecular Complexes Selectively Induce Human Telomeric G‐Quadruplex Formation under Salt‐Deficient Conditions

Cited by 59 publications

References 51 publications

Enantioselective Diels–Alder Reactions with G‐Quadruplex DNA‐Based Catalysts

Enantioselective Diels–Alder Reactions with G‐Quadruplex DNA‐Based Catalysts

Chiral metallohelices enantioselectively target hybrid human telomeric G-quadruplex DNA

Stabilization of Telomere DNA, and Mechanism of Apoptosis of Tumor Cells Induced by Ruthenium Complexes

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