Amino‐Acid‐Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G‐Quadruplexes

Ongaro, Alberto; Desiderati, Giovanni; Oselladore, Erika; Auricchio, Davide; Memo, Maurizio; Ribaudo, Giovanni; Sissi, Claudia; Gianoncelli, Alessandra

doi:10.1002/cmdc.202100665

Cited by 3 publications

(2 citation statements)

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“…[10] The therapeutic potential of G-quadruplexes was noticed nearly three decades ago and subsequent findings of its role in functional regions of the human genome led to several research endeavors towards the development of small molecules for both drug development [11,12] and diagnostic purposes with implications in live cell imaging. [13,14] A wide variety of compounds have been reported to bind to G-quadruplexes [15][16][17][18][19][20][21][22][23] of different molecularities and conformations. Among these molecules, several planar compounds with extended π-systems and capability towards base stacking interactions have demonstrated preferential binding to Gquadruplexes.…”

Section: Introductionmentioning

confidence: 99%

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Preferential Binding of a Red Emissive Julolidine Derivative to a Promoter G‐Quadruplex

Metangle,

Ranjan

2023

ChemBioChem

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The therapeutic potential of G‐quadruplexes has increased significantly with the growing understanding of their functional roles in pathogens apart from human diseases such as cancer. Here, we report the synthesis of three julolidine‐based molecules and their binding to nucleic acids. Among the synthesized molecules, compound 1 exhibited red emissive fluorescence with a distinct preference for Pu22 G‐quadruplex. The binding of compound 1 to Pu22 G‐quadruplex, initially identified through a fluorescence‐based screening, was further confirmed by UV‐vis, fluorescence spectroscopy, and circular dichroism‐based experiments. Thermal denaturation of compound 1 in the presence of Pu22 G‐quadruplex revealed a concentration‐dependent stabilization (~10.0 °C at 1 : 3 stoichiometry). Fluorescence‐based experiments revealed 1 : 1 stoichiometry of the interaction and an association constant (Ka) of 5.67×106 M−1. CD experiments displayed that the parallel conformation of the G‐quadruplex was retained on compound 1’s binding and signs of higher order binding/complex formation were observed at high compound 1 to DNA ratio. Molecular docking studies revealed the dominance of stacking and van der Waals interactions in the molecular recognition which was aided by some close‐distance interactions involving the quinolinium nitrogen atom.

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Section: Introductionmentioning

confidence: 99%

“…A wide variety of compounds have been reported to bind to G‐quadruplexes [15–23] of different molecularities and conformations. Among these molecules, several planar compounds with extended π‐systems and capability towards base stacking interactions have demonstrated preferential binding to G‐quadruplexes [24,25] .…”

Section: Introductionmentioning

confidence: 99%

Preferential Binding of a Red Emissive Julolidine Derivative to a Promoter G‐Quadruplex

Metangle,

Ranjan

2023

ChemBioChem

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9,10-Bis[(4-(2-hydroxyethyl)piperazine-1-yl)prop2-yne-1-yl]anthracene: G-Quadruplex Selectivity and Anticancer Activity

Anyanwu,

Giannangeli,

Fan

et al. 2024

ACS Med. Chem. Lett.

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G-Quadruplexes (G4s) are appealing targets for anticancer therapy because of their location in the genome and their role in regulating physiological and pathological processes. In this article, we report the characterization of the molecular interaction and selectivity of OAF89, a 9,10-disubstituted G4binding anthracene derivative, with different DNA sequences. Advanced analytical methods, including mass spectrometry and nuclear magnetic resonance, were used to conduct the investigation, together with the use of in silico docking and molecular dynamics. Eventually, the compound was tested in vitro to assess its bioactivity against lung cancer cell lines.

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G-Quadruplex DNA as a Macromolecular Target for Semi-Synthetic Isoflavones Bearing B-Ring Tosylation

Ribaudo,

Anyanwu,

Giannangeli

et al. 2024

Macromol

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Guanine-rich sequences of nucleic acids, including DNA and RNA, are known to fold into non-canonical structures named G-quadruplexes (G4s). Such arrangements of these macromolecular polymers are mainly located in telomeres and in promoter regions of oncogenes and, for this reason, they represent a potential target for compounds with therapeutic applications. In fact, the ligand-mediated stabilization of G4s inhibits telomerase and the activity of transcriptional machinery and counteracts cancer cell immortalization. Flavonoids, along with other classes of small molecules, have been previously tested for their ability to stabilize G4s, but the mechanism of their interaction has not been fully elucidated. In the current work, we report a multi-technique investigation on the binding of tosylated isoflavones obtained by the B-ring modification of compounds from Maclura pomifera to a telomeric DNA sequence. Our study demonstrates that such derivatization leads to compounds showing lower binding affinity but with an increased selectivity toward G4 with respect to double-stranded DNA. The binding mode to the macromolecular target G4 was studied by combining results from electrospray mass spectrometry binding studies, nuclear magnetic resonance experiments and computational simulations. Overall, our findings show that tosylation influences the selectivity toward the macromolecular target by affecting the interaction mode with the nucleic acid.

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Amino‐Acid‐Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G‐Quadruplexes

Cited by 3 publications

References 50 publications

Preferential Binding of a Red Emissive Julolidine Derivative to a Promoter G‐Quadruplex

Preferential Binding of a Red Emissive Julolidine Derivative to a Promoter G‐Quadruplex

9,10-Bis[(4-(2-hydroxyethyl)piperazine-1-yl)prop2-yne-1-yl]anthracene: G-Quadruplex Selectivity and Anticancer Activity

G-Quadruplex DNA as a Macromolecular Target for Semi-Synthetic Isoflavones Bearing B-Ring Tosylation

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