The application of click chemistry for targeting quadruplex nucleic acids

Saha, Puja; Panda, Deepanjan

doi:10.1039/c8cc07107a

Cited by 36 publications

(26 citation statements)

References 200 publications

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“…As the Cu-catalyzed click reaction between azides and alkynes is a well-established method for the variable functionalization of G4-DNA ligands [52], the berberine-adenine conjugates 4a-e were synthesized by the reaction of 9-propargyladenine (2) [53] with the 9-azidoalkylberberine derivatives 3a-e [54] (Scheme 2). Although the compounds 4a-e formed as the major products in this reaction (>>50%), they were only obtained as isolated products in low to moderate yields (16-38%), mainly because of severe difficulties to completely remove the copper ions that apparently bind tightly to the compounds.…”

Section: Synthesismentioning

confidence: 99%

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

Becher¹,

Berdnikova²,

Ihmels³

et al. 2020

Beilstein J. Org. Chem.

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A small series of five novel berberine derivatives was synthesized by the Cu-catalyzed click reaction of 9-propargyladenine with 9-O-(azidoalkyl)berberine derivatives. The association of the resulting berberine–adenine conjugates with representative quadruplex-forming oligonucleotides 22AG dA(G3TTA)3G3 and a2 d(ACAG4TGTG4)2 was examined with photometric and fluorimetric titrations, thermal DNA denaturation analysis, and CD spectroscopy. The results from the spectrometric titrations indicated the formation of 2:1 or 1:1 complexes (ligand:G4-DNA) with log K b values of 10–11 (2:1) and 5–6 (1:1), which are typical for berberine derivatives. Notably, a clear relationship between the binding affinity of the ligands with the length of the alkyl linker chain, n, was not observed. However, depending on the structure, the ligands exhibited different effects when bound to the G4-DNA, such as fluorescent light-up effects and formation of ICD bands, which are mostly pronounced with a linker length of n = 4 (with a2) and n = 5 (with 22AG), thus indicating that each ligand–G4-DNA complex has a specific structure with respect to relative alignment and conformational flexibility of the ligand in the binding site. It was shown exemplarily with one representative ligand from the series that such berberine–adenine conjugates exhibit a selective binding, specifically a selectivity to quadruplex DNA in competition with duplex DNA, and a preferential thermal stabilization of the G4-DNA forms 22AG and KRAS. Notably, the experimental data do not provide evidence for a significant effect of the adenine unit on the binding affinity of the ligands, for example, by additional association with the loops, presumably because the adenine residue is sterically shielded by the neighboring triazole unit.

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Section: Synthesismentioning

confidence: 99%

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

Becher¹,

Berdnikova²,

Ihmels³

et al. 2020

Beilstein J. Org. Chem.

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“…Recently, we used 5-ethynyl-2′-deoxyuridine and direct visualization of the chromosome behavior in cell division through the azide–alkyne click reaction [ 23 ]. The click reaction has also been applied in the labeling of myoglobin, bovine serum albumin, and other proteins [ 23 , 32 , 33 , 34 ]. Next, we checked the fluorescence spectra of the click reaction product to investigate whether the 8 et dG would be used for imaging application.…”

Section: Resultsmentioning

confidence: 99%

Conformation of G-quadruplex Controlled by Click Reaction

Xiao

Guo

et al. 2020

Molecules

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G-quadruplexes are non-canonical four stranded secondary structures possessing great biological importance. Controlling G-quadruplex conformation for further regulating biological processes is both exciting and challenging. In this study, we described a method for regulating G-quadruplex conformation by click chemistry for the first time. 8-ethynyl-2′-deoxyguanosine was synthesized and incorporated into a 12-nt telomere DNA sequence. Such a sequence, at first, formed mixed parallel/anti-parallel G-quadruplexes, while it changed to anti-parallel after reaction with azidobenzene. Meanwhile, the click reaction can give the sequence intense fluorescence.

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“…Computational biological studies suggested the distribution of G4s across the genome and their prevalence in oncogene promoters . Therefore, G4s are harnessed as potential therapeutic targets by small molecules . Various small molecules have been reported to stabilize different G4 structures.…”

Section: Figurementioning

confidence: 99%

“…[2] Therefore, G4s are harnessed as potential therapeutic targets by small molecules. [3,4] Various small molecules have been reported to stabilize different G4 structures. Small molecules capable of stabilizing G4 can trigger DNA double-strand breaks and induce DNA damage response (DDR) and cell death.…”

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confidence: 99%

G‐Quadruplex‐Binding Small Molecule Induces Synthetic Lethality in Breast Cancer Cells by Inhibiting c‐MYC and BCL2 Expression

et al. 2019

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Herein, a prolinamide‐derived peptidomimetic that preferentially binds to c‐MYC and BCL2 G‐quadruplexes present in the promoter regions of apoptosis‐related genes (c‐MYC and BCL2) over other DNA quadruplexes are described. Biological assays, such as real‐time quantitative reverse transcription, western blot, dual luciferase, and small interfering RNA knockdown assays, indicate that the ligand triggers a synthetic lethal interaction by simultaneously inhibiting the expression of c‐MYC and BCL2 genes through their promoter G‐quadruplexes. The ligand shows antiproliferative activity in MCF‐7 cells that overexpress both MYC and BCL2 genes, in comparison to cells that overexpress either of the two. Moreover, the ligand induces S‐phase cell‐cycle arrest, DNA damage, and apoptosis in MCF‐7 cells.

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The application of click chemistry for targeting quadruplex nucleic acids

Abstract: The Cu(i)-catalyzed azide and alkyne 1,3-dipolar cycloaddition (CuAAC), commonly known as the “click reaction”, has emerged as a versatile synthetic tool for targeting quadruplex nucleic acids.

Cited by 36 publications

References 200 publications

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

Conformation of G-quadruplex Controlled by Click Reaction

G‐Quadruplex‐Binding Small Molecule Induces Synthetic Lethality in Breast Cancer Cells by Inhibiting c‐MYC and BCL2 Expression

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