Comparative Studies on DNA-Binding Mechanisms between Enantiomers of a Polypyridyl Ruthenium(II) Complex

Nie, Yanhong; Dai, Zhongming; Fozia, Fozia; Zhao, Guangyao; Jiang, Jianrong; Xu, Xu; Ying, Ming; Wang, Yu; Hu, Zhangli; Xu, Hong

doi:10.1021/acs.jpcb.2c02104

Cited by 12 publications

(6 citation statements)

References 66 publications

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“…Isothermal titration calorimetry (ITC) has emerged as an instrument for precise measurement of thermodynamic profiling in a wide range of biological processes thanks to recent improvements in the sensitivity and reliability of the calorimeter. ITC generates thermodynamic properties from an experiment, including the change in Gibbs free energy (Δ G °), change in enthalpy (Δ H °), change in entropy (Δ S °), binding constant ( K ), and binding sites ( n ). , Knowing about the molecular recognition procedure responsible for complexation and conservation by associating such thermodynamic evidence with a structural description is important. The conventional integrated heat values for the quantification of CT-DNA with YH are displayed in Figure .…”

Section: Resultsmentioning

confidence: 99%

“…ITC generates thermodynamic properties from an experiment, including the change in Gibbs free energy (ΔG°), change in enthalpy (ΔH°), change in entropy (ΔS°), binding constant (K), and binding sites (n). 76,77 Knowing about the molecular recognition procedure responsible for complexation and conservation by associating such thermodynamic evidence with a structural description is important. The conventional integrated heat values for the quantification of CT-DNA with YH are displayed in Figure 13.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

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Structural Insight into Groove Binding of Yohimbine with Calf Thymus DNA: A Spectroscopic, Calorimetric, and Computational Approach

et al. 2023

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A variety of anticancer and antibacterial drugs target DNA as one of their primary intracellular targets. Understanding ligand−DNA interactions and developing new, promising bioactive molecules for clinical use are greatly aided by elucidating the interaction between small molecules and natural polymeric DNAs. Small molecules′ ability to attach to and inhibit DNA replication and transcription provides more information on how drugs impact the expression of genes. Yohimbine has been broadly studied in pharmacological properties, while its binding mode to DNA has not been explicated so far. In this study, an attempt was made to explore the interaction between Yohimbine (YH) and calf thymus (CT-DNA) by using varying thermodynamics and in silico approaches. Minor hypochromic and bathochromic shifts of fluorescence intensity were observed, suggesting the binding of YH to CT-DNA. The Scatchard plot analysis using the McGhee−von Hipple method revealed noncooperative binding and affinities in the range of 10 5 M −1 . The binding stoichiometry value is 2:1 (2 molecules of YH were span by 1 base pair) and was determined by Job's plot. The thermodynamic parameters suggested exothermic binding, which was favored by negative enthalpy and positive entropy changes from both isothermal titration calorimetry and temperature-dependent fluorescence experiment. Salt-dependent fluorescence suggested that the interaction between the ligand and DNA was governed by nonpolyelectrolytic forces. Kinetics experiment confirmed the static type of quenching. The results of iodide quenching, urea denaturation assay, dye displacement, DNA melting, and in silico molecular docking (MD) suggested groove binding of YH to CT-DNA. Circular dichroism spectra confirmed minimal perturbation of CT-DNA with YH binding via groove region. Therefore, the groove binding mechanism of interaction was validated by biophysical techniques and in silico, MD approaches. The findings supported here may contribute to the development of new YH therapeutics possessing better efficacy and lesser side effects.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Materials and Methodsmentioning

confidence: 99%

Structural Insight into Groove Binding of Yohimbine with Calf Thymus DNA: A Spectroscopic, Calorimetric, and Computational Approach

et al. 2023

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“…Obviously, 5b can bind to DNA possibly through intercalation. To further confirm the binding mode of 5b to DNA, we conducted the viscosity measurements because it is sensitive to the length change and thus the most effective experiment to specify the binding mode between the compound and DNA . The viscosity of DNA was increased steadily with an increasing amount of 5b or a classical DNA intercalator EB (Figure C), indicating that 5b was bound to DNA with an intercalative mode.…”

Section: Resultsmentioning

confidence: 99%

Developing a Multitargeted Anticancer Palladium(II) Agent Based on the His-242 Residue in the IIA Subdomain of Human Serum Albumin

Zhang

et al. 2023

J. Med. Chem.

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To obtain next-generation metal drugs that can overcome the deficiencies of platinum (Pt) drugs and treat cancer more effectively, we proposed to develop a multitargeted palladium (Pd) agent to the tumor microenvironment (TME) based on the specific residue(s) of human serum albumin (HSA). To this end, we optimized a series of Pd(II) 2-benzoylpyridine thiosemicarbazone compounds to obtain a Pd agent (5b) with significant cytotoxicity. The HSA-5b complex structure revealed that 5b bound to the hydrophobic cavity in the HSA IIA subdomain and then His-242 replaced a leaving group (Cl) of 5b, coordinating with the Pd center. The in vivo results showed that the 5b/HSA-5b complex had significant capacity of inhibiting tumor growth, and HSA optimized the therapeutic behavior of 5b. In addition, we confirmed that the 5b/HSA-5b complex inhibited tumor growth through multiple actions on different components of TME: killing cancer cells, inhibiting tumor angiogenesis, and activating T cells.

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“…The outcomes are collected in Tables S6 and S7 and Figure S10. As already reported in the literature, the intercalation of the drug between two base pairs should entail a bathochromic shift and hypochromicity of the band in the UV–visible region. ,,, This can be due to the effect of base pairs that could act like electrons donors in the interaction with the intercalated drug and to the decreasing in the energy gap between molecular orbitals (HOMO and LUMO) after DNA binding of the intercalative agent. Analyzing the data reported in Table S6 and Figure S10 it can be noted a hypochromicity of the lowest energy band in all the considered models Ru-1 to Ru-IV .…”

Section: Resultsmentioning

confidence: 99%

“…Many anticancer drugs in clinical use possess a structure suitable for reversible interaction with DNA, as well as many chromophores, such as merocyanines, have been shown to possess intercalative properties and can thus be exploited in designing multi-functional cancer drugs . While many platinum complexes have been already proposed and computationally explored for DNA distortion by intercalation, − only few octahedral ruthenium complexes have been suggested for this purpose, ,− most probably because of their steric hindrance that do not facilitate the entrance of one of the coordinated ligands between base pairs to distort the DNA structure. In recent years, a merocyanine-based chromophore, the 5-chloro-7-(2-(1,3,3-trimethyl-3 H -indol-1-ium-2-yl)vinyl)quinolin-8-olate, has been included in the scaffold of Ru(II) polypyridyl complexes for an efficient •OH-mediated DNA photocleavage upon red-light irradiation of low intensity .…”

Section: Introductionmentioning

confidence: 99%

Computational Assessment of a Dual-Action Ru(II)-Based Complex: Photosensitizer in Photodynamic Therapy and Intercalating Agent for Inducing DNA Damage

et al. 2023

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A combined quantum-mechanical and classical molecular dynamics study of a recent Ru(II) complex with potential dual anticancer action is reported here. The main basis for the multiple action relies on the merocyanine ligand, whose electronic structure allows the drug to be able to absorb within the therapeutic window and in turn efficiently generate 1 O 2 for photodynamic therapy application and to intercalate within two nucleobases couples establishing reversible electrostatic interactions with DNA. TDDFT outcomes, which include the absorption spectrum, triplet states energy, and spin−orbit matrix elements, evidence that the photosensitizing activity is ensured by an MLCT state at around 660 nm, involving the merocyanine-based ligand, and by an efficient ISC from such state to triplet states with different characters. On the other hand, the MD exploration of all the possible intercalation sites within the dodecamer B-DNA evidences the ability of the complex to establish several electrostatic interactions with the nucleobases, thus potentially inducing DNA damage, though the simulation of the absorption spectra for models extracted by each MD trajectory shows that the photosensitizing properties of the complex remain unaltered. The computational results support that the anti-tumor effect may be related to multiple mechanisms of action.

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Comparative Studies on DNA-Binding Mechanisms between Enantiomers of a Polypyridyl Ruthenium(II) Complex

Cited by 12 publications

References 66 publications

Structural Insight into Groove Binding of Yohimbine with Calf Thymus DNA: A Spectroscopic, Calorimetric, and Computational Approach

Structural Insight into Groove Binding of Yohimbine with Calf Thymus DNA: A Spectroscopic, Calorimetric, and Computational Approach

Developing a Multitargeted Anticancer Palladium(II) Agent Based on the His-242 Residue in the IIA Subdomain of Human Serum Albumin

Computational Assessment of a Dual-Action Ru(II)-Based Complex: Photosensitizer in Photodynamic Therapy and Intercalating Agent for Inducing DNA Damage

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