Design, synthesis and characterization of novel chromone based-copper(<scp>ii</scp>) antitumor agents with <i>N</i>,<i>N</i>-donor ligands: comparative DNA/RNA binding profile and cytotoxicity

Arjmand, Farukh; Afsan, Zeenat; Roisnel, Thierry

doi:10.1039/c8ra06722h

Cited by 39 publications

(8 citation statements)

References 94 publications

(94 reference statements)

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“…Keeping in mind the complexity of cancers which show diverse phenotypes and multiple etiologies, a one-size-fits-all drug design strategy for the development of cancer chemotherapeutics does not yield successful results. Lately, Arjmand et al [47] adopted a series of methods, such as the combination of X-ray crystal structures and molecular docking, to design, synthesize, and characterize novel chromone based-copper(II) antitumor inhibitors. In general, after obtaining the structure of the receptor macromolecule by x-crystal single-crystal diffraction technique or multi-dimensional NMR, molecular modeling software can be used to analyze the physicochemical properties of drug binding sites on the receptor, especially including electrostatic field, hydrophobic field, hydrogen bond, and key residues.…”

Section: Structure-based Drug Designmentioning

confidence: 99%

A Review on Applications of Computational Methods in Drug Screening and Design

2020

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Drug development is one of the most significant processes in the pharmaceutical industry. Various computational methods have dramatically reduced the time and cost of drug discovery. In this review, we firstly discussed roles of multiscale biomolecular simulations in identifying drug binding sites on the target macromolecule and elucidating drug action mechanisms. Then, virtual screening methods (e.g., molecular docking, pharmacophore modeling, and QSAR) as well as structure-and ligand-based classical/de novo drug design were introduced and discussed. Last, we explored the development of machine learning methods and their applications in aforementioned computational methods to speed up the drug discovery process. Also, several application examples of combining various methods was discussed. A combination of different methods to jointly solve the tough problem at different scales and dimensions will be an inevitable trend in drug screening and design.Molecules 2020, 25, 1375 2 of 17 Biomolecular Simulations in Drug Screening and DesignThe Nobel Prize in Chemistry 2013 was awarded jointly to Martin Karplus, Michael Levitt, and Arieh Warshel for their pioneering contributions in the development of multiscale models for complex biochemical systems, recognizing the important role that theory and computational methods play as a direct and necessary complement to experiments [12]. Further, applications of biomolecular simulations in identifying drug binding sites and elucidating the molecular mechanisms of diseases have been subject to rapid developments [13][14][15].Depending on the biological problems to be studied, multiscale models will be used in biomolecular simulations. The combination of quantum mechanics (QM) and molecular mechanics (MM) (QM/MM) can be used to study the electronic properties [16], simulate chemical reactions (e.g., the enzyme catalysis mechanism [17]), and calculate spectra [18] in a single simulation, which can be used to elucidate the action mechanism of certain drugs. Another widely used biomolecular method is molecular dynamics (MD) simulation [19][20][21][22][23][24], which applies empirical molecular mechanics (MM) force fields and is based on classical Newtonian mechanics. According to different accuracy requirements, all-atom (AA), united-atom (UA), and coarse-grained (CG) MD simulations as well as explicit/implicit solvent models, which allow simulations of temporal and spatial scales, can be used to facilitate the drug discovery [25,26]. Generally, MD simulations have been used for the identification of potential drug binding sites on target proteins, the calculation of binding free energy between target proteins and drug molecules, the action mechanism of drug molecules, etc. [27,28]. However, it is worth mentioning that MD simulations are also limited to time and length scales. Currently, AAMD simulations can explore time-dependent phenomena of large systems such as viral capsids in atomic detail as long as microseconds or even milliseconds [21,29,30]. Therefore, different types of ...

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Section: Structure-based Drug Designmentioning

confidence: 99%

A Review on Applications of Computational Methods in Drug Screening and Design

2020

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“…The enhancement in the emission intensity arises due to the penetration of complexes into the hydrophobic environment of interior tRNA/ctDNA helixes as has been reported in many research articles describing the interaction studies of small molecules with nucleic acids. [41][42][43] As studies revealed greater binding propensity for tRNA as compared to ctDNA which could be attributed to the conformation of RNA having an L-shaped tertiary structure, where nucleobases are pushed outwards from the helix axis in the minor groove direction and tilted substantially with respect to the helix axis, funneling the complexes to the interior of the narrow grooves of RNA. Furthermore binding strength of 1 and 2 was quantied by employing the Scatchard equation 44 and the evaluated data is shown in Table 1.…”

Section: Interaction Studies With Nucleic Acids (Dna and Rna)mentioning

confidence: 99%

Evaluation of cytotoxic potential of structurally well-characterized RNA targeted ionic non-steroidal anti-inflammatory (NSAID) Cu(ii) & Zn(ii) DACH–mefenamato drug conjugates against human cancer cell lines

2020

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New RNA targeted ionic [Cu(DACH) 2 (H 2 O) 2 ](mef) 2 , 1 and [Zn(DACH) 2 (H 2 O) 2 ](mef) 2 , 2 drug conjugates were synthesized and characterized by spectroscopic techniques FT-IR, UV-vis, EPR in case of 1 and 1 H and 13 C NMR in case of 2, ESI-MS, thermogravimetric analysis and single-crystal X-ray structure determination in case of 1. The interaction studies of 1 & 2 with most likely drug targets like ctDNA and tRNA were performed which demonstrated that the complexes 1 and 2 exhibited strong preferential binding to tRNA as compared to ctDNA, K b ¼ 2.52(AE0.04) Â 10 5 M À1 , 7.85(AE0.02) Â 10 4 M À1 , respectively. Scanning electron microscopy analyses of complex-ctDNA/tRNA condensates suggested the interaction of complexes with ctDNA/tRNA had occurred, followed by lengthening of DNA double helix and bulge region of tRNA. Cytotoxic activity of 1 and 2 against human cancer cell lines namely; MCF-7 (breast), HeLa (cervical), MIA-PA-CA 2 (pancreatic), A-498 (kidney), Hep-G2 (hepatoma) was evaluated by SRB assay. The obtained results showed that copper complex 1 was an outstanding cytotoxic agent with remarkably good GI 50 value (<10 mg ml À1 ) against the tested cancer cell lines except for MIA-PA-CA 2, while zinc complex 2 revealed moderate cytotoxicity against all the tested cancer cell lines.

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“…[6,7] Moreover, chromone-based metallodrugs are known to inhibit various types of cancer targets viz., DNA, tRNAs, kinase inhibitor enzymes and topoisomerases. [8][9][10] Zn(II) in chromone-appended ligand framework can be explored as an antitumor agent due to its capability to mediate cleavage of the phosphate diester backbone, redox inertness, Lewis acidity, and rapid ligand exchange. [11] Chelation of Zn(II) to naturally occurring chromone improves the complex's planar functionality thereby, allowing the complex to insert and stack between base pairs of double-helical DNA more readily than the free ligand.…”

Section: Introductionmentioning

confidence: 99%

Chromone‐Appended Zn(II) tRNA‐Targeted Potential Anticancer Chemotherapeutic Agent: Structural Details, in vitro ct‐DNA/tRNA Binding, Cytotoxicity Studies And Antioxidant Activity

et al. 2022

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A 3-formyl-chromone-appended zinc(II) intercalator drug candidate of the formulation [bis(chromone)(H 2 O) 2 Zn(II)] was prepared as a potent anticancer agent and thoroughly characterized by multi-spectroscopic and single X-ray crystallographic studies. Preliminary binding studies of complex 1 with ct-DNA/tRNA were carried out employing various complementary biophysical techniques and the corroborative results of these experiments suggested strong binding propensity via intercalation binding mode towards ct-DNA/tRNA therapeutic targets, with higher preference for tRNA as quantified by binding constant { K b , K and K sv } parameters. The cleavage studies with pBR322 DNA were performed which implied that 1 cleaved the DNA by hydrolytic cleavage pathway which was further validated by T4 religation assay. Moreover, 1 was found to exhibit the tRNA cleavage behavior in a concentration and time-dependent manner. The cytotoxicity of complex 1 was evaluated against Huh-7, DU-145 and the PNT2 cell lines by MTT assay. A dose-dependent growth inhibition of the Huh-7 and DU-145 cells at low micromolar concentrations was observed and in another set of experiments, lipid peroxidation & glutathione (GSH) depletion were induced in the presence of the tested drug candidate. Interestingly, drug candidate 1 demonstrated selective cytotoxic activity for the DU-145 cancer cell line with LC 50 value of 3.2 μM which was further visualized by confocal microscopy.

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Design, synthesis and characterization of novel chromone based-copper(ii) antitumor agents with N,N-donor ligands: comparative DNA/RNA binding profile and cytotoxicity

Abstract: New chromone-based Cu(ii) tRNA targeted complexes 1–3 as potential anticancer agents have been synthesized and thoroughly characterized.

Cited by 39 publications

References 94 publications

A Review on Applications of Computational Methods in Drug Screening and Design

A Review on Applications of Computational Methods in Drug Screening and Design

Evaluation of cytotoxic potential of structurally well-characterized RNA targeted ionic non-steroidal anti-inflammatory (NSAID) Cu(ii) & Zn(ii) DACH–mefenamato drug conjugates against human cancer cell lines

Chromone‐Appended Zn(II) tRNA‐Targeted Potential Anticancer Chemotherapeutic Agent: Structural Details, in vitro ct‐DNA/tRNA Binding, Cytotoxicity Studies And Antioxidant Activity

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