Chloroquine Binding to Nucleic Acids: Characteristics, Biological Consequences, and a Proposed Binding Model for the Interaction

Yielding, K. Lemone; Blodgett, Lerena Wade; Sternglanz, Helene; Gaudin, D.

doi:10.1007/978-3-642-65141-0_8

Cited by 14 publications

(4 citation statements)

References 38 publications

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“…Such constant is considerably higher than the result found for the second mode (∼6.25 × 10 4 M –1 from averaging the results found from the persistence and contour length analyses). Cohen et al and Yielding et al have previously reported two binding constants for the interaction of the analog chloroquine (CLQ) with DNA, in agreement with our results. Kwakye-Berko et al report that the equilibrium association constant of DNA–CLQ interaction decreases for high ionic strengths, achieving ∼382 M –1 at 100 mM [Na] .…”

supporting

confidence: 93%

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Hydroxychloroquine Exhibits a Strong Complex Interaction with DNA: Unraveling the Mechanism of Action

Bazoni

Moura

Rocha

2020

J. Phys. Chem. Lett.

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supporting

confidence: 93%

“…Such type of study is important since it may bring clues on the molecular mechanism of action of the drug, as well as on possible side effects related to its indiscriminate use. The analog drug chloroquine (CLQ), on the other hand, is more studied in its interaction with nucleic acids, although many controversial results persist. − …”

mentioning

confidence: 99%

Hydroxychloroquine Exhibits a Strong Complex Interaction with DNA: Unraveling the Mechanism of Action

Bazoni

Moura

Rocha

2020

J. Phys. Chem. Lett.

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“…Norfloxacin, amsacrine, and etoposide, the DNA topo inhibitors were effective against asexual but not sexual stages of the malaria parasite (Chavalitshewinkoon et al, 2000). Chloroquine, quinine, and related 4-aminoquinolines are effective drugs against malarial infection, and the ability of chloroquine to form complexes with DNA is well documented (Blodgett and Yielding, 1968;Yielding et al, 1971). Chloroquine, mepacrine, and other quinoline derivatives are potent inhibitors of DNA and RNA polymerase (O'Brien et al, 1966;Whichard et al, 1972), as well as DNA and RNA synthesis in P. knowlesi (Gutteridge et al, 1972).…”

Section: Resultsmentioning

confidence: 99%

Oxygenated chalcones and bischalcones as a new class of inhibitors of DNA topoisomerase II of malarial parasites

et al. 2007

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The DNA topoisomerase (topo) II of chloroquine-sensitive and chloroquine-resistant strains of the rodent malaria parasite P. berghei were utilized as a target for testing of antimalarial compounds. Compounds belonging to the bischalcone and chalcone series significantly inhibited enzyme activity and percentage parasitaemia of chloroquine-sensitive and chloroquine-resistant strains of P. berghei. Compounds 1a, 1b, 2a, 2b, and 2c showed 100% inhibition while compounds 2h and 2i showed 60% and 63% inhibition of topoisomerase II activity of the chloroquinesensitive strain, respectively. Compounds 2a, 2b, and 2d significantly inhibited the topo II activity of chloroquine-resistant strain. Compounds 2g and 2e specifically inhibited the topo II activity of the chloroquine-resistant strain of P. berghei with no effect on the chloroquine-sensitive strain. The in vitro topo II inhibition by chalcone and bischalcone analogs can be correlated with their in vivo antimalarial activity, as compounds 2c and 2h inhibited both in vitro activity of topo II and in vivo parasitaemia of the chloroquine-sensitive strain of P. berghei. In the chloroquine-resistant strain, compounds 2c, 2e, 2g, and 2i inhibited activity against both in vitro topo II and parasitaemia in vivo. The significant inhibition of topo II in the chloroquine-resistant strain by some of the analogs suggests the utilization of these structures for the synthesis of compounds active against chloroquine-resistant malarial parasites.

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“…In fact, CLQ and its derivative HCLQ, which was synthesized with the purpose to reduce the cytotoxicity of the former, present a wide range of side effects that can be explained by their action upon neural and cardiac cells, where low concentrations of these molecules cause the inhibition of important ionic channels. − In addition, previous studies have shown that both CLQ and HCLQ can directly interact with DNA molecules, thus being potentially cytotoxic to many types of cells. − …”

Section: Introductionmentioning

confidence: 99%

New Insights into the Mechanism of Action of the Drug Chloroquine: Direct Interaction with DNA and Cytotoxicity

Rocha

2022

J. Phys. Chem. B

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Chloroquine (CLQ) and hydroxychloroquine (HCLQ) are compounds largely employed in the treatment of various human diseases for decades. Nevertheless, a number of intrinsic details concerning their mechanisms of action, especially at the molecular level, are still unknown or have presented controversial results in the literature. Using optical tweezers, here, we investigate at the single-molecule level the molecular mechanism of action of the drug CLQ in its intrinsic interaction with the double-stranded (ds)DNA molecule, one of its targets inside cells, determining the binding modes and the physicochemical (binding) parameters of the interaction. In particular, we show that the ionic strength of the surrounding medium strongly influences such interaction, changing even the main binding mode. In addition, the cytotoxicity of CLQ against three different cell lines was also investigated here, allowing one to evaluate and compare the effect of the drug on the cell viability. In particular, we show that CLQ is highly cytotoxic at a very low (a few micromolar) concentration range for all cell lines tested. These results were rigorously compared to the equivalent ones obtained for the closely related compound hydroxychloroquine (HCLQ), allowing a critical comparison between the action of these drugs at the molecular and cellular levels.

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Chloroquine Binding to Nucleic Acids: Characteristics, Biological Consequences, and a Proposed Binding Model for the Interaction

Cited by 14 publications

References 38 publications

Hydroxychloroquine Exhibits a Strong Complex Interaction with DNA: Unraveling the Mechanism of Action

Hydroxychloroquine Exhibits a Strong Complex Interaction with DNA: Unraveling the Mechanism of Action

Oxygenated chalcones and bischalcones as a new class of inhibitors of DNA topoisomerase II of malarial parasites

New Insights into the Mechanism of Action of the Drug Chloroquine: Direct Interaction with DNA and Cytotoxicity

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