Thiazole orange – Spermine conjugate: A potent human telomerase inhibitor comparable to BRACO-19

Wang, Siwen; Yang, Dazhou; Singh, Mandeep; Joo, Hyun; Rangel, Vanessa M.; Tran, Aaron; Phan, Erich; Xue, Liang

doi:10.1016/j.ejmech.2019.04.041

Cited by 13 publications

(7 citation statements)

References 45 publications

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“…The large stacking surface of TMPyP4 could intercalate into duplex DNA at this high concentration (50 μM) and thus block polymerase activity. These results were consistent with previously reported data (Liu et al, 2017;Wang et al, 2019). As shown in Figure 6, compound 7 selectively inhibits the telomerase activity while it has no effect on the polymerase activity in the concentration range of 1.6 to 12.5 µM.…”

Section: Inhibition Of Human Telomerase Activity By Compoundsupporting

confidence: 93%

“…On the other hand, amino-containing side chains (piperidine, pyrrolidine) showed enhanced binding affinity but decreased binding selectivity for G4 over duplex DNA. Similar results have also been reported in our study of thiazole orange derivatives as G4 ligands ( Wang et al, 2019) and by others (Funke & Weisz, 2019;Lavrado et al, 2015). The decreased selectivity could result from non-specific interactions between positively charged amino groups and DNA backbones.…”

supporting

confidence: 92%

“…Initial surveys suggested that over 300,000 putative G-quadruplex forming sequences are present in the human genome (Huppert & Balasubramanian, 2005;Todd, Johnston, & Neidle, 2005), and recent studies predicted an even higher G4 prevalence when considering G4s with long loops (Bedrat, Lacroix, & Mergny, 2016) and G4s in some large genes (Chambers et al, 2015), implying that a structure-function relationship may exist. In recent years, G4s have emerged as a target of considerable interest because they are not native substrates for binding of nucleic acid processing enzymes (e.g., telomerase and polymerase); therefore, inducing G4 formation has been recognized as a promising approach to regulate enzymatic functions (Neidle, 2017;Rhodes & Lipps, 2015;Tian, Chen, Wang, & Zhou, 2018), for instance, inhibition of human telomerase activity (De Cian et al, 2008;Liu, Wang, Dotsenko, Samoshin, & Xue, 2017;Wang et al, 2019) and regulation of oncogene expression (Balasubramanian, Hurley, & Neidle, 2011;Nishikawa, Kuwano, Takahara, Nishida, & Rokutan, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors

et al. 2020

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In this paper, we report the synthesis of a phenanthroline and neomycin conjugate (7). Compound 7 binds to a human telomeric G‐quadruplex (G1) with a higher affinity compared with its parent compounds (phenanthroline and neomycin), which is determined by several biophysical studies. Compound 7 shows good selectivity for G‐quadruplex (G4) DNA over duplex DNA. The binding of 7 with G1 is predominantly enthalpy‐driven, and the binding stoichiometry of 7 with G1 is one for the tight‐binding event as determined by ESI mass spectrometry. A plausible binding mode is a synergistic effect of end‐stacking and groove interactions, as indicated by docking studies. Compound 7 can inhibit human telomerase activity at low micromolar concentrations, which is more potent than previously reported 5‐substituted phenanthroline derivatives.

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Section: Inhibition Of Human Telomerase Activity By Compoundsupporting

confidence: 93%

supporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors

et al. 2020

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“…For example, the aminohexyl-substituted derivative 1b 6 and the phenylpropyl-substituted compound 1d 3 have the highest affinity to G-quadruplex DNA, whereas the deriva-tives with other alkyl chain lengths have a lower affinity [38]. Along the same line, the influence of the length and substituents of the side chains at the G4-DNA ligands have been assessed for quinolinium [43], indoloquinoline [44,45], phenanthroline [46], phenothiazine [47], and thiazole orange [48] derivatives. In these studies, the delicate balance between the hydrophobic effects of the alkyl chain and the thermodynamically favorable interactions on the association of ammonium or pyridinium groups in the grooves and loops was assessed.…”

Section: Introductionmentioning

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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“…dU-containing DNA (10 μM, 100 μL in typical condition) was hybridized with Spcontaining DNA in the UDG buffer (× 1), annealed at 80°C for 10 min and then slowly cooled to room temperature. UDG (1 unit) was then added and incubated at 37°C for 1 h and 1.5 eq of TO containing amino group (TOÀ NH 2 ) [25,67] to the AP sites was added to the solution. The pH of the reaction mixture was adjusted to~5 by adding 0.2 M citrate buffer (pH 5.0) and NaBH 3 CN was added up to the concentration of 100 mM.…”

Section: Methodsmentioning

confidence: 99%

Stacked Thiazole Orange Dyes in DNA Capable of Switching Emissive Behavior in Response to Structural Transitions

et al. 2021

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Functional nucleic acids with the capability of generating fluorescence in response to hybridization events, microenvironment or structural changes are valuable as structural probes and chemical sensors. We now demonstrate the enzymeassisted preparation of nucleic acids possessing multiple thiazole orange (TO) dyes and their fluorescent behavior, that show a spectral change from the typical monomer emission to the excimer-type red-shifted emission. We found that the fluorescent response and emission wavelength of the TO dyes were dependent on both the state of the DNA structure (singleor double-stranded DNA) and the arrangement of the TO dyes. We showed that the fluorescent behavior of the TO dyes can be applied for the detection of RNA molecules, suggesting that our approach for preparing the fluorescent nucleic acids functionalized with multiple TO dyes could be useful to design a fluorescence bioimaging and detection technique of biomolecules.

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Thiazole orange – Spermine conjugate: A potent human telomerase inhibitor comparable to BRACO-19

Cited by 13 publications

References 45 publications

Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors

Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors

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

Stacked Thiazole Orange Dyes in DNA Capable of Switching Emissive Behavior in Response to Structural Transitions

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