Selective RNA Versus DNA G‐Quadruplex Targeting by In Situ Click Chemistry

Antonio, Marco Di; Biffi, Giulia; Mariani, Angelica; Raiber, Eun‐Ang; Rodriguez, Raphaël; Balasubramanian, Shankar

doi:10.1002/anie.201206281

Cited by 152 publications

(120 citation statements)

References 59 publications

(23 reference statements)

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“…41 Recently reported pyridostatin based ligand is able to discriminate telomeric RNA quadruplex from its DNA counterpart. 42 Ligands having few fold binding preferences for promoter quadruplexes over telomeric DNA are also reported. [43][44][45][46][47] So far, to the best of our knowledge, there is no report on ligands, which specifically bind to and stabilize the promoter quadruplex DNAs over all the known topologies of human telomeric DNA.…”

Section: Introductionmentioning

confidence: 99%

Topology Specific Stabilization of Promoter over Telomeric G-Quadruplex DNAs by Bisbenzimidazole Carboxamide Derivatives

et al. 2014

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Various potential G-quadruplex forming sequences present in the genome offer a platform to modulate their function by means of stabilizing molecules. Though G-quadruplex structures exhibit diverse structural topologies, the presence of G-quartets as a common structural element makes the design of topology specific ligands a daunting task. To address this, the subtle structural variations of loops and grooves present in the quadruplex structures can be exploited. To this end, we report the design and synthesis of quadruplex stabilizing agents based on bisbenzimidazole carboxamide derivatives of pyridine, 1,8-naphthyridine, and 1,10-phenanthroline. The designed ligands specifically bind to and stabilize promoter quadruplexes having parallel topology over any of the human telomeric quadruplex topologies (parallel, hybrid, or antiparallel) and duplex DNAs. CD melting studies indicate that ligands could impart higher stabilization to c-MYC and c-KIT promoter quadruplexes (up to 21 °C increment in Tm) than telomeric and duplex DNAs (ΔTm ≤ 2.5 °C). Consistent with a CD melting study, ligands bind strongly (Kb = ∼10(4) to 10(5) M(-1)) to c-MYC quadruplex DNA. Molecular modeling and dynamics studies provide insight into how the specificity is achieved and underscore the importance of flexible N-alkyl side chains attached to the benzimidazole-scaffold in recognizing propeller loops of promoter quadruplexes. Overall, the results reported here demonstrate that the benzimidazole scaffold represents a potent and powerful side chain, which could judiciously be assembled with a suitable central core to achieve specific binding to a particular quadruplex topology.

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Section: Introductionmentioning

confidence: 99%

Topology Specific Stabilization of Promoter over Telomeric G-Quadruplex DNAs by Bisbenzimidazole Carboxamide Derivatives

et al. 2014

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“…[2] Recently, G4 s were visualized using G4-specific antibodies in human cells and tissues, and G4 ligands can stabilize such structures in cells. [3] Approaches for RNA G4 identification in cellular RNA have been largely limited to computational predictions, using algorithms such as Quadparser and QGRS.…”

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confidence: 99%

Targeted Detection of G‐Quadruplexes in Cellular RNAs

Kwok

Balasubramanian

2015

Angew Chem Int Ed

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The G-quadruplex (G4) is a non-canonical nucleic acid structure which regulates important cellular processes. RNA G4s have recently been shown to exist in human cells and be biologically significant. Described herein is a new approach to detect and map RNA G4s in cellular transcripts. This method exploits the specific control of RNA G4–cation and RNA G4–ligand interactions during reverse transcription, by using a selective reverse transcriptase to monitor RNA G4-mediated reverse transcriptase stalling (RTS) events. Importantly, a ligation-amplification strategy is coupled with RTS, and enables detection and mapping of G4s in important, low-abundance cellular RNAs. Strong evidence is provided for G4 formation in full-length cellular human telomerase RNA, offering important insights into its cellular function.

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“…142 In their study, they selected G4 formed by the human telomeric DNA (H-Telo). 143 No adduct was formed when the reaction mixture was incubated in the absence of DNA, in the presence of double-stranded DNA, or in the presence of telomeric oligonucleotides pre-annealed to prevent G4 formation, thus confirming that H-Telo serves as a reaction pot.…”

Section: Dna Minor Groove Templation Rolementioning

confidence: 99%

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Maraković

Šinko

2017

ACSi

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Modern drug discovery is mainly based on the de novo synthesis of a large number of compounds with a diversity of chemical functionalities. Though the introduction of combinatorial chemistry enabled the preparation of large libraries of compounds from so-called building blocks, the problem of successfully identifying leads remains. The introduction of a dynamic combinatorial chemistry method served as a step forward due to the involvement of biological macromolecular targets (receptors) in the synthesis of high affinity products. The major breakthrough was a synthetic method in which building blocks are irreversibly combined due to the presence of a receptor. Here we present various receptor-based combinatorial chemistry approaches. Huisgen's cycloaddition (1,3-dipolar cycloaddition of azides and alkynes) forms stabile 1,2,3-triazoles with very high receptor affinity that can reach femtomolar levels, as the case with acetylcholinesterase inhibitors shows. Huisgen's cycloaddition can be applied to various receptors including acetylcholinesterase, acetylcholine binding protein, carbonic anhydrase-II, serine/threonine-protein kinase and minor groove of DNA.

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Selective RNA Versus DNA G‐Quadruplex Targeting by In Situ Click Chemistry

Cited by 152 publications

References 59 publications

Topology Specific Stabilization of Promoter over Telomeric G-Quadruplex DNAs by Bisbenzimidazole Carboxamide Derivatives

Topology Specific Stabilization of Promoter over Telomeric G-Quadruplex DNAs by Bisbenzimidazole Carboxamide Derivatives

Targeted Detection of G‐Quadruplexes in Cellular RNAs

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

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