共查询到20条相似文献,搜索用时 0 毫秒
1.
Shangrong Wu Linlin Wang Nan Zhang Ying Liu Dr. Wei Zheng Ang Chang Dr. Fuyi Wang Dr. Songqin Li Dr. Dihua Shangguan 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(17):6037-6047
G‐quadruplex (G4)‐forming sequences are prevalent in the genome and are considered to play important roles in gene regulation, and hence have been viewed as potential therapeutic targets in oncology. However, the structures and functions of most G4s in the genome are poorly understood. Therefore, the development of fluorescent probes and ligands for G4s is important for G4 research and drug discovery. Herein, we report a new G4 ligand, 2,9‐bis[4‐(4‐methylpiperazin‐1‐yl)styryl]‐1,10‐phenanthroline (BMSP), which was synthesized by a simple process. BMSP exhibits almost no fluorescence in aqueous buffer. The interaction of BMSP with G4s greatly enhances its fluorescence with a large Stokes’ shift of 160 nm. Antiparallel human telomeric G4s exhibit the strongest binding affinity (Kd≈0.13 μm ) to BMSP and induce a fluorescence enhancement of up to 150‐fold. BMSP binds to G4s through π–π stacking on the terminal G‐quartets. BMSP can enter live cells, and it strongly inhibits the growth of cancer cells rather than causing cell death. Our results suggest that BMSP has the potential to serve both as a fluorescent probe for some G4s and as a chemotherapeutic agent for cancer treatment. 相似文献
2.
《Angewandte Chemie (International ed. in English)》2017,56(38):11640-11644
The topological diversity of DNA G‐quadruplexes may play a crucial role in its biological function. Reversible control over a specific folding topology was achieved by the synthesis of a chiral, glycol‐based pyridine ligand and its fourfold incorporation into human telomeric DNA by solid‐phase synthesis. Square‐planar coordination to a CuII ion led to the formation of a highly stabilizing intramolecular metal–base tetrad, substituting one G‐tetrad in the parent unimolecular G‐quadruplex. For the Tetrahymena telomeric repeat, CuII‐triggered switching from a hybrid‐dominated conformer mixture to an antiparallel topology was observed. CuII‐dependent control over a protein–G‐quadruplex interaction was shown for the thrombin–tba pair (tba=thrombin‐binding aptamer). 相似文献
3.
Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G‐Quadruplex: a Joint ESI MS and XRD Investigation 下载免费PDF全文
Prof. Carla Bazzicalupi Dr. Marta Ferraroni Francesco Papi Dr. Lara Massai Dr. Benoît Bertrand Prof. Luigi Messori Prof. Paola Gratteri Prof. Angela Casini 《Angewandte Chemie (International ed. in English)》2016,55(13):4256-4259
The dicarbene gold(I) complex [Au(9‐methylcaffein‐8‐ylidene)2]BF4 is an exceptional organometallic compound of profound interest as a prospective anticancer agent. This gold(I) complex was previously reported to be highly cytotoxic toward various cancer cell lines in vitro and behaves as a selective G‐quadruplex stabilizer. Interactions of the gold complex with various telomeric DNA models have been analyzed by a combined ESI MS and X‐ray diffraction (XRD) approach. ESI MS measurements confirmed formation of stable adducts between the intact gold(I) complex and Tel 23 DNA sequence. The crystal structure of the adduct formed between [Au(9‐methylcaffein‐8‐ylidene)2]+ and Tel 23 DNA G‐quadruplex was solved. Tel 23 maintains a characteristic propeller conformation while binding three gold(I) dicarbene moieties at two distinct sites. Stacking interactions appear to drive noncovalent binding of the gold(I) complex. The structural basis for tight gold(I) complex/G‐quadruplex recognition and its selectivity are described. 相似文献
4.
Solution and Solid‐State Analysis of Binding of 13‐Substituted Berberine Analogues to Human Telomeric G‐quadruplexes 下载免费PDF全文
Dr. Marta Ferraroni Prof. Carla Bazzicalupi Dr. Francesco Papi Dr. Gaetano Fiorillo Dr. Luis Miguel Guamán‐Ortiz Dr. Alessio Nocentini Dr. Anna Ivana Scovassi Dr. Paolo Lombardi Prof. Paola Gratteri 《化学:亚洲杂志》2016,11(7):1107-1115
The interaction between 13‐phenylalkyl and 13‐diphenylalkyl berberine derivatives ( NAX ) and human telomeric DNA G4 structures has been investigated by both spectroscopic and crystallographic methods. NAX042 and NAX053 are the best compounds improving the performance of the natural precursor berberine. This finding is in agreement with the X‐ray diffraction result for the NAX053 ‐Tel12 adduct, showing the ligand which interacts via π‐stacking, sandwiched at the interface of two symmetry‐related quadruplex units, with its benzhydryl group contributing to the overall stability of the adduct by means of additional π‐stacking interactions with the DNA residues. The berberine derivatives were also investigated for their cytotoxic activity towards a panel of human cancer cell lines. Compounds NAX042 and NAX053 affect the viability of cancer cell lines in a dose‐dependent manner. 相似文献
5.
Dr. Petra Galer Dr. Baifan Wang Dr. Primož Šket Prof. Dr. Janez Plavec 《Angewandte Chemie (International ed. in English)》2016,55(6):1993-1997
A four‐repeat human telomere DNA sequence without the 3′‐end guanine, d[TAGGG(TTAGGG)2TTAGG] (htel1‐ΔG23) has been found to adopt two distinct two G‐quartet antiparallel basket‐type G‐quadruplexes, TD and KDH+ in presence of KCl. NMR, CD, and UV spectroscopy have demonstrated that topology of KDH+ form is distinctive with unique protonated T18?A20+?G5 base triple and other capping structural elements that provide novel insight into structural polymorphism and heterogeneity of G‐quadruplexes in general. Specific stacking interactions amongst two G‐quartets flanking base triples and base pairs in TD and KDH+ forms are reflected in 10 K higher thermal stability of KDH+. Populations of TD and KDH+ forms are controlled by pH. The (de)protonation of A20 is the key for pH driven structural transformation of htel1‐ΔG23. Reversibility offers possibilities for its utilization as a conformational switch within different compartments of living cell enabling specific ligand and protein interactions. 相似文献
6.
Novel Oligopyrrole Carboxamide based Nickel(II) and Palladium(II) Salens,Their Targeting of Human G‐Quadruplex DNA,and Selective Cancer Cell Toxicity 下载免费PDF全文
Dr. Asfa Ali Mohini Kamra Soma Roy Prof. K. Muniyappa Prof. Santanu Bhattacharya 《化学:亚洲杂志》2016,11(18):2542-2554
DNA targeting by various metal complexes is a key strategy toward the restriction of cancer cell proliferation. Toward this end, we designed and synthesized novel salen‐based NiII and PdII metal complexes with positively charged flanking side chains comprising N‐methylpyrrole carboxamides of varying lengths. The compounds showed high specificity toward G‐quadruplex DNA over duplex DNA. Sufficient inhibition of the telomerase activity was observed, which was ascertained by the prominent restriction of cancer cell proliferation in the long‐term cell viability and telomerase inhibition assays. The compounds exhibited selective cancer cell death following an apoptotic pathway. Analysis of the binding mode showed partial stacking of the salen moiety over the G‐tetrads and association of the pendant oligopyrrole carboxamide units with the grooves. The conjugation of the tetrad‐binding metal salen core with groove‐oriented flexible oligopyrrole moieties resulted in the high selectivity and stabilization of the human G‐quadruplex DNA structures. 相似文献
7.
Molecular Recognition of the Hybrid‐2 Human Telomeric G‐Quadruplex by Epiberberine: Insights into Conversion of Telomeric G‐Quadruplex Structures 下载免费PDF全文
Dr. Clement Lin Guanhui Wu Dr. Kaibo Wang Dr. Buket Onel Dr. Saburo Sakai Prof. Yong Shao Prof. Danzhou Yang 《Angewandte Chemie (International ed. in English)》2018,57(34):10888-10893
Human telomeres can form DNA G‐quadruplex (G4), an attractive target for anticancer drugs. Human telomeric G4s bear inherent structure polymorphism, challenging for understanding specific recognition by ligands or proteins. Protoberberines are medicinal natural‐products known to stabilize telomeric G4s and inhibit telomerase. Here we report epiberberine (EPI) specifically recognizes the hybrid‐2 telomeric G4 predominant in physiologically relevant K+ solution and converts other telomeric G4 forms to hybrid‐2, the first such example reported. Our NMR structure in K+ solution shows EPI binding induces extensive rearrangement of the previously disordered 5′‐flanking and loop segments to form an unprecedented four‐layer binding pocket specific to the hybrid‐2 telomeric G4; EPI recruits the (?1) adenine to form a “quasi‐triad” intercalated between the external tetrad and a T:T:A triad, capped by a T:T base pair. Our study provides structural basis for small‐molecule drug design targeting the human telomeric G4. 相似文献
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DNA Triplexes‐Guided Assembly of G‐Quadruplexes for Constructing Label‐free Fluorescent Logic Gates 下载免费PDF全文
Lijun Xu Shanni Hong Xiaoqiang Shen Lu Zhou Jine Wang Jianye Zhang Prof. Dr. Renjun Pei 《化学:亚洲杂志》2016,11(13):1892-1895
Assembly of G‐quadruplexes guided by DNA triplexes in a controlled manner is achieved for the first time. The folding of triplex sequences in acidic conditions brings two separated guanine‐rich sequences together and subsequently a G‐quadruplex structure is formed in the presence of K+. Based on this novel platform, label‐free fluorescent logic gates, such as AND, INHIBIT, and NOR, are constructed with ions as input and the fluorescence of a G‐quadruplex‐specific fluorescent probe NMM as output. 相似文献
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Methyl Substitution Regulates the Enantioselectivity of Supramolecular Complex Binding to Human Telomeric G‐Quadruplex DNA 下载免费PDF全文
Bailu Xu Dr. Chuanqi Zhao Dr. Yong Chen Prof. Hisae Tateishi‐Karimata Prof. Jinsong Ren Prof. Naoki Sugimoto Prof. Xiaogang Qu 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(50):16467-16472
Chiral supramolecular compounds with substituents at different positions show different binding properties with human telomeric G‐quadruplex DNA. These different positions of methyl substitution in chiral supramolecular compounds can modulate their enantioselectivity and structural preference when binding with human telomeric G‐quadruplex DNA. 相似文献
12.
Templated Formation of Discrete RNA and DNA:RNA Hybrid G‐Quadruplexes and Their Interactions with Targeting Ligands 下载免费PDF全文
Laureen Bonnat Dr. Jérôme Dejeu Hugues Bonnet Béatrice Génnaro Dr. Olivier Jarjayes Prof. Fabrice Thomas Dr. Thomas Lavergne Prof. Eric Defrancq 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(9):3139-3147
G‐rich RNA and DNA oligonucleotides derived from the human telomeric sequence were assembled onto addressable cyclopeptide platforms through oxime ligations and copper‐catalyzed azide‐alkyne cycloaddition (CuAAc) reactions. The resulting conjugates were able to fold into highly stable RNA and DNA:RNA hybrid G‐quadruplex (G4) architectures as demonstrated by UV, circular dichroism (CD), and NMR spectroscopic analysis. Whereas rationally designed parallel RNA and DNA:RNA hybrid G4 topologies could be obtained, we could not force the formation of an antiparallel RNA G4 structure, thus supporting the idea that this topology is strongly disfavored. The binding affinities of four representative G4 ligands toward the discrete RNA and DNA:RNA hybrid G4 topologies were compared to the one obtained with the corresponding DNA G4 structure. Surface plasmon resonance (SPR) binding analysis suggests that the accessibility to G4 recognition elements is different among the three structures and supports the idea that G4 ligands might be shaped to achieve structure selectivity in a biological context. 相似文献
13.
Towards the Development of Structure‐Selective G‐Quadruplex‐Binding Indolo[3,2‐b]quinolines 下载免费PDF全文
Andrea Funke Jonathan Dickerhoff Prof. Dr. Klaus Weisz 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(9):3170-3181
The interaction of phenyl‐substituted indolo[3,2‐b]quinolines with DNA G‐quadruplexes of different topology were studied by using a combination of spectroscopic and calorimetric methodologies. N5‐Methylated indoloquinoline derivatives (MePIQ) with an aminoalkyl side chain exhibit high affinities for the parallel‐stranded MYC quadruplex and a (3+1)‐hybrid structure combined with an excellent discrimination against the antiparallel thrombin‐binding aptamer (TBA) and the human telomeric (HT) quadruplexes. Dissociation constants for the binding of the ligand to the MYC quadruplex are in the submicromolar range, being below the corresponding dissociation constants for the antiparallel‐stranded quadruplexes by about one order of magnitude. Competition experiments with double‐helical DNA reveal the impact of indoloquinoline structural features on the selectivity for the parallel quadruplex relative to duplex DNA. Based on a calorimetric analysis binding to MYC is shown to be equally driven by favorable enthalpic and entropic contributions with no significant impact on the type of cation present. 相似文献
14.
Xiu‐Cai Chen Dr. Shuo‐Bin Chen Jing Dai Jia‐Hao Yuan Prof. Tian‐Miao Ou Prof. Zhi‐Shu Huang Prof. Jia‐Heng Tan 《Angewandte Chemie (International ed. in English)》2018,57(17):4702-4706
Because of the absence of methods for tracking RNA G‐quadruplex dynamics, especially the folding and unfolding of this attractive structure in live cells, understanding of the biological roles of RNA G‐quadruplexes is so far limited. Herein, we report a new red‐emitting fluorescent probe, QUMA‐1 , for the selective, continuous, and real‐time visualization of RNA G‐quadruplexes in live cells. The applications of QUMA‐1 in several previously intractable applications, including live‐cell imaging of the dynamic folding, unfolding, and movement of RNA G‐quadruplexes and the visualization of the unwinding of RNA G‐quadruplexes by RNA helicase have been demonstrated. Notably, our real‐time results revealed the complexity of the dynamics of RNA G‐quadruplexes in live cells. We anticipate that the further application of QUMA‐1 in combination with appropriate biological and imaging methods to explore the dynamics of RNA G‐quadruplexes will uncover more information about the biological roles of RNA G‐quadruplexes. 相似文献
15.
Yongdong Su Hirofumi Fujii Ekaterina A. Burakova Boris P. Chelobanov Masayuki Fujii Dmitry A. Stetsenko Vyacheslav V. Filichev 《化学:亚洲杂志》2019,14(8):1212-1220
The effect of phosphate group modifications on formation and properties of G‐quadruplexes (G4s) has not been investigated in detail. Here, we evaluated the structural, thermodynamic and kinetic properties of the parallel G‐quadruplexes formed by oligodeoxynucleotides d(G4T), d(TG4T) and d(TG5T), in which all phosphates were replaced with N‐methanesulfonyl (mesyl) phosphoramidate or phosphoryl guanidine groups resulting in either negatively charged or neutral DNA sequences, respectively. We established that all modified sequences were able to form G‐quadruplexes of parallel topology; however, the presence of modifications led to a decrease in thermal stability relative to unmodified G4s. In contrast to negatively charged G4s, assembly of neutral G4 DNA species was faster in the presence of sodium ions than potassium ions, and was independent of the salt concentration used. Formation of mixed G4s composed of both native and neutral G‐rich strands has been detected using native gel electrophoresis, size‐exclusion chromatography and ESI‐MS. In summary, our results indicate that the phosphate modifications studied are compatible with G‐quadruplex formation, which could be used for the design of biologically active compounds. 相似文献
16.
Insight into How Telomeric G‐Quadruplexes Enhance the Peroxidase Activity of Cellular Hemin 下载免费PDF全文
Tingting Ai Qiufang Yang You Lv Yuqin Huang Yuzhi Li Jia Geng Dan Xiao Cuisong Zhou 《化学:亚洲杂志》2018,13(14):1805-1810
The toxic oxidative damage of G‐quadruplexes (G4), linked to neurodegenerative diseases, may arise from their ability to bind and oxidatively activate cellular hemin. However, there have been no precise studies on how telomeric G4 enhances the low intrinsic peroxidase activity of hemin. Herein, a label‐free and nanopore‐based strategy was developed to explore the enhancement mechanism of peroxidase activity of hemin induced by telomeric G4 (d(TTAGGG)n). The nanopore‐based strategy demonstrated that there were simultaneously two different binding modes of telomere G4 to hemin. At the single‐molecule level, it was found that the hybrid structural telomeric G4 directly binds to hemin (the affinity constant (Ka)≈106 m ?1) to form a tight complex, and some of them underwent a topological change to a parallel structure with an enhancement of Ka to approximately 107 m ?1. Through detailed analysis of the topology and peroxidase activity and molecular modeling investigations, the parallel telomere G4/hemin DNAzyme structure was proven to be preferable for high peroxidase activity. Upon strong π–π stacking, the parallel structural telomere G4 supplied a key axial ligand to the hemin iron, which accelerated the intermediate compound formation with H2O2 in the catalytic cycle. Our studies developed a label‐free and single‐molecule strategy to fundamentally understand the catalytic activity and mechanism of telomeric DNAzyme, which provides some support for utilizing the toxic, oxidative‐damage property in cellular oxidative disease and anticancer therapeutics. 相似文献
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Dr. Tianjun Chang Dr. Hongmei Gong Pi Ding Dr. Xiangjun Liu Dr. Weiguo Li Dr. Tao Bing Dr. Zehui Cao Prof. Dr. Dihua Shangguan 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(12):4015-4021
G‐quadruplex (G4)/hemin DNAzymes have been extensively applied in bioanalysis and molecular devices. However, their catalytic activity is still much lower than that of proteinous enzymes. The G4/hemin DNAzyme activity is correlated with the G4 conformations and the solution conditions. However, little is known about the effect of the flanking sequences on the activity, though they are important parts of G4s. Here, we report sequences containing d(CCC), flanked on both ends of the G4‐core sequences remarkably enhance their DNAzyme activity. By using circular dichroism and UV‐visible spectroscopy, the d(CCC) flanking sequences were demonstrated to improve the hemin binding affinity to G4s instead of increasing the parallel G4 formation, which might explain the enhanced DNAzyme activity. Meanwhile, the increased hemin binding ability promoted the degradation of hemin within the DNAzyme by H2O2. Furthermore, the DNAzyme with d(CCC) flanking sequences showed strong tolerance to pH value changes, which makes it more suitable for applications requiring wide pH conditions. The results highlight the influence of the flanking sequences on the DNAzyme activity and provide insightful information for the design of highly active DNAzymes. 相似文献
19.
A Nitroxide‐Tagged Platinum(II) Complex Enables the Identification of a DNA G‐Quadruplex Binding Mode 下载免费PDF全文
Dr. Cui‐Xia Xu Dr. Xiaojun Zhang Yi‐Wei Zhou Hanqiang Wang Dr. Qian Cao Dr. Yong Shen Prof. Dr. Liang‐Nian Ji Prof. Dr. Zong‐Wan Mao Prof. Dr. Peter Z. Qin 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(10):3405-3413
We reported a novel strategy for investigating small molecule binding to G‐quadruplexes (GQs). A newly synthesized dinuclear platinum(II) complex (Pt2L) containing a nitroxide radical was shown to selectively bind a GQ‐forming sequence derived from human telomere (hTel). Using the nitroxide moiety as a spin label, electron paramagnetic resonance (EPR) spectroscopy was carried out to investigate binding between Pt2L and hTel GQ. Measurements indicated that two molecules of Pt2L bind with one molecule of hTel GQ. The inter‐spin distance measured between the two bound Pt2L, together with molecular docking analyses, revealed that Pt2L predominately binds to the neighboring narrow and wide grooves of the G‐tetrads as hTel adopts the antiparallel conformation. The design and synthesis of nitroxide tagged GQ binders, and the use of spin‐labeling/EPR to investigate their interactions with GQs, will aid the development of small molecules for manipulating GQs involved in crucial biological processes. 相似文献
20.
G‐quadruplex (G4) structures are of general importance in chemistry and biology, such as in biosensing, gene regulation, and cancers. Although a large repertoire of G4‐binding tools has been developed, no aptamer has been developed to interact with G4. Moreover, the G4 selectivity of current toolkits is very limited. Herein, we report the first l ‐RNA aptamer that targets a d ‐RNA G‐quadruplex (rG4). Using TERRA rG4 as an example, our results reveal that this l ‐RNA aptamer, Ap3‐7, folds into a unique secondary structure, exhibits high G4 selectivity and effectively interferes with TERRA‐rG4–RHAU53 binding. Our approach and findings open a new door in further developing G4‐specific tools for diverse applications. 相似文献