Octahedral copper(<scp>ii</scp>)-diimine complexes of triethylenetetramine: effect of stereochemical fluxionality and ligand hydrophobicity on Cu<sup>II</sup>/Cu<sup>I</sup>redox, DNA binding and cleavage, cytotoxicity and apoptosis-inducing ability

Sharma, Mitu; Ganeshpandian, Mani; Majumder, Munmi; Ajaykamal, Tamilarasan; Sharma, Mukesh; Mukhopadhyay, Rupak; Islam, Nashreen S.; Palaniandavar, Mallayan

doi:10.1039/d0dt00928h

Cited by 42 publications

(37 citation statements)

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“…Reactive oxygen species, including superoxide anion radical, hydrogen peroxide and hydroxyl radical, are produced within cells under normal aerobic growth conditions, but their production is increased under the influence of external stresses. Several recent reports suggest a role for ROS in drug-induced apoptosis through engagement of downstream proteins involved in the execution of apoptosis [ 25 , 68 ]. Modulation of oxidative stress is an important strategy in anticancer drug development.…”

Section: Discussionmentioning

confidence: 99%

“…Aiming at these desired pharmacodynamic profiles, diimines, tetradentate ligands and substituted derivatives as ligands are currently attractive in the discovery of metal-based drugs for different cancers [ 25 , 26 ]. These coordinated or transition metal complexes have been found to be potent as cell cycle inhibitors [ 27 , 28 , 29 ], DNA topoisomerase inhibitors [ 30 , 31 ], pro- and anti-apoptotic protein modulators (p53, Bax and Bcl-2) [ 32 , 33 , 34 ], etc.…”

Section: Introductionmentioning

confidence: 99%

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Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study

et al. 2020

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This research was aimed at finding the cytotoxic potential of the mixed ligand copper(II) complex [Cu(tdp)(phen)](ClO4)—where H(tdp) is the tetradentate ligand 2-[(2-(2-hydroxyethylamino)-ethylimino)methyl]phenol, and phen is 1,10-phenanthroline—to two genotypically different breast cancer cells, MCF-7 (p53+ and ER+) and MDA-MB-231 (p53- and ER-). The complex has been already shown to be cytotoxic to ME180 cervical carcinoma cells. The special focus in this study was the induction of cell death by apoptosis and necrosis, and its link with ROS. The treatment brought about nuclear fragmentation, phosphatidylserine externalization, disruption of mitochondrial trans-membrane potential, DNA damage, cell cycle arrest at sub-G1 phase, and increase of ROS generation, followed by apoptotic death of cells during early hours and a late onset of necrosis in the cells surviving the apoptosis. The efficacy of the complex against genotypically different breast cancer cells is attributed to a strong association through p53-mitochondrial redox—cell cycle junction. The ADMET properties and docking of the complex at the active site of Top1 are desirable attributes of a lead molecule for development into a therapeutic. Thus, it is shown that the copper(II)–phenolate complex[Cu(tdp)(phen)]+ offers potential to be developed into a therapeutic for breast cancers in general and ER-negative ones in particular.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study

et al. 2020

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“…Electronic spectra of complexes 1-3 were recorded in DMSO at room temperature which revealed two well resolved absorption maxima in the range 260 to 290 nm and 300-315 nm attributed to ππ* and n-π* electronic transitions, respectively. Broad d-d bands observed in the visible part of spectra in the range 400-642 nm are typical for tetragonally distorted octahedral environment around the Cu (II) center [30].…”

Section: Spectroscopic Characterizationmentioning

confidence: 95%

Copper (II)-based halogen-substituted chromone antitumor drug entities: Studying biomolecular interactions with ct-DNA mediated by sigma hole formation and cytotoxicity activity

Arjmand¹,

Khursheed²,

Roisnel³

et al. 2020

Bioorganic Chemistry

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Copper-based antitumor drug entities 1-3 derived from substituted (F -, Br -, -CH 3 ) 3formylchromone pharmacophore were synthesized and thoroughly characterized by spectroscopic and single X-ray crystallographic studies. These complexes show structural novelty due to presence of the X-bonds in chromone scaffold which could facilitate higher propensity for nucleic acids via sigma σ-hole interactions. Therefore, structure-activity relationship of 1-3 was studied by performing ct-DNA binding, pBR322 cleavage and cytotoxicity activity to validate their potential to act as chemotherapeutic drug entities. The binding studies of 1-3 with ct-DNA were carried out employing many biophysical techniques and the corroborative results of these experiments showed intercalation mode of binding and the order of binding was found to be 2 > 1 >3. The structure of drug entities could facilitated strong halogen bonding interaction(in case of 1 &2) and stability of X bond was rationalized by sigma hole region of positive electrostatic potential on the surface of C-X covalent bond, as determined by gas phase B3LYP computational DFT studies. Interestingly, 2 exhibited most avid binding affinity due to presence of Brelectron withdrawing and polarizable group. Further, cleavage studies of 1-3 with pBR322 plasmid DNA were performed which demonstrated significant cleavage activity , the supercoiled form (Form I) of plasmid DNA was converted to nicked form (Form II) with the appearance of linearized form(Form III) in between two, implicating lethal double strand breaks of DNA. 2 showed predominantly higher cleavage activity following the similar trend as observed for binding studies.The cytotoxicity of the complexes 1-3 was evaluated by MTT assay against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines; complex 2 exhibited specific and selective cytotoxicity for the DU-145 cancer cell line with LC 50 value of 1.6μM. Highlights Substituted chromone Copper (II) complexes were synthesized and characterized.  DFT computational studies were also performed.  Electrophoretic studies revealed an oxidative cleavage pathway.  Cytotoxicity was evaluated against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines.  Copper (II) complex 2 exhibited selective cytotoxicity against DU-145 cell line at GI 50 =1.6μM.

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“…While the electronic absorption spectra of Cu(II) (B 2 and A 2 ) before and after irradiation exhibited bands at 308, 398 and 653 nm in DMF refer to L→M charge transfer and d→d transitions, respectively in octahedral geometry [28]. Diamagnetic behavior of complex (B 1 ) and the magnetic suitability value of complex (B2) is 1.78 B.M., which is an indicative of tetrahedral and octahedral geometry [27,29].…”

Section: Uv-vis Spectra and Magnetic Moment Propertiesmentioning

confidence: 99%

Synthesis, Quantum Chemical Calculations, Molecular Docking and Studying the Effect of High Energetic Gamma Irradiation on Cu(I, II), Zn(II) and Cd(II) Complexes with their Antibacterial Activity.

Elganzory

2021

Preprint

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New complexes of Cu(I,II), Zn(II) and Cd(II) of thiosemicarbazide ligand 1-(p-(methylanilinocetyl-4-phenyl-thiosemicarbazide)(H2LB) have been prepared and characterized by 1HNMR, Mass spectra, FT-IR, elemental analyses, molar conductance, UV-visible spectra, magnetic susceptibility measurements, thermogravimetric analysis (TGA/DTG) and X-ray diffraction pattern before and after irradiation. The results confirmed that gamma ray enhanced the stability of irradiated compounds as compared to non-irradiated compounds. XRD patterns proved that increasing the crystallinity of the samples and the particles in nano range after gamma irradiation. The obtained data indicated that the Cu(I) and Cd(II) ions coordinated to the ligand through the (C = O), N(2)H and (C = S), the ligand behaves as neutral tridentate. While in complexes Cu(II) and Zn(II)complexes (B2 and B3) the ligand behave as neutral tetradentate and coordination take place via (C = O) and two N(2)H. These studies revealed that, two kinds of stereochemical geometries; Cu(II) and Zn(II) complexes were predicted to be octahedral, Cu(I) and Cd(II)complexes were found to be tetrahedral. The theoretical conformational structure analyses were performed using density functional theory for ligand and complexes at B3LYP functional with 6-31G(++)d,p basis set for ligand and LANL2DZ basis set for complexes. The ligand and its metal complexes have been tested for their inhibitory effect on the growth of bacteria against gram-positive (Streptococcus pyogenes) and gram-negative (Escherichia coli). Results suggested that in case of 1µg/ml and 5µg/ml for Cu(II) and Zn(II) complexes have higher activity than other complexes. The chelation could facilitate the ability to cross the cell membrane of E. coli and can be explained by Tweedy’s chelation theory. Molecular docking investigation proved that; the Zn(II) complex had interesting interactions with active site amino acids of topoisomerase II DNA gyrase enzymes (code: 2XCT).

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Octahedral copper(ii)-diimine complexes of triethylenetetramine: effect of stereochemical fluxionality and ligand hydrophobicity on Cu^II/Cu^Iredox, DNA binding and cleavage, cytotoxicity and apoptosis-inducing ability

Abstract: Stereochemical fluxionality of octahedral [Cu(trien)(diimine)]2+ complexes determines the CuII/CuI redox potential, DNA binding affinity, ROS generation, cytotoxicity and apoptosis-inducing ability.

Cited by 42 publications

References 84 publications

Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study

Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study

Copper (II)-based halogen-substituted chromone antitumor drug entities: Studying biomolecular interactions with ct-DNA mediated by sigma hole formation and cytotoxicity activity

Synthesis, Quantum Chemical Calculations, Molecular Docking and Studying the Effect of High Energetic Gamma Irradiation on Cu(I, II), Zn(II) and Cd(II) Complexes with their Antibacterial Activity.

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Octahedral copper(ii)-diimine complexes of triethylenetetramine: effect of stereochemical fluxionality and ligand hydrophobicity on CuII/CuIredox, DNA binding and cleavage, cytotoxicity and apoptosis-inducing ability

Abstract: Stereochemical fluxionality of octahedral [Cu(trien)(diimine)]2+ complexes determines the CuII/CuI redox potential, DNA binding affinity, ROS generation, cytotoxicity and apoptosis-inducing ability.

Cited by 42 publications

References 84 publications

Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study

Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study

Copper (II)-based halogen-substituted chromone antitumor drug entities: Studying biomolecular interactions with ct-DNA mediated by sigma hole formation and cytotoxicity activity

Synthesis, Quantum Chemical Calculations, Molecular Docking and Studying the Effect of High Energetic Gamma Irradiation on Cu(I, II), Zn(II) and Cd(II) Complexes with their Antibacterial Activity.

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Octahedral copper(ii)-diimine complexes of triethylenetetramine: effect of stereochemical fluxionality and ligand hydrophobicity on Cu^II/Cu^Iredox, DNA binding and cleavage, cytotoxicity and apoptosis-inducing ability