In situ reactivity of electrochemically generated nitro radical anion on Ornidazole and its monomeric Cu(II) complex with nucleic acid bases and calf thymus DNA

Nandy, Promita; Das, Saurabh

doi:10.1016/j.ica.2019.119267

Cited by 8 publications

(25 citation statements)

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“…Earlier, we demonstrated that formation of RNO 2 •– on Onz and Cu(Onz) 2 Cl 2 in an electrochemical pathway was responsible for modification of nucleobases and calf thymus DNA under anaerobic (Ar-saturated) conditions, indicating the importance of RNO 2 •– in causing damage to a nucleobase. 31 , 45 Since radiation-induced chemical reactions also generate RNO 2 •– , one can expect that besides radiation-induced base damage by • OH in solution, a substantial part of the damage could be due to RNO 2 •– , making such compounds effective hypoxic cytotoxins as well, and that it could be used on hypoxic tumors. Table 1 summarizes the results of radiation-induced base damage on the three nucleobases used as targets.…”

Section: Results and Discussionmentioning

confidence: 99%

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Radio-Sensitizing Effects of Cu^II and Zn^II Complexes of Ornidazole: Role of Nitro Radical Anion

et al. 2020

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The treatment of malignant cells that are deficient in oxygen due to the insufficient flow of blood is often seen as a major hindrance in radiotherapy. Such cells become radio-resistant because molecular oxygen, the natural and best radio-sensitizer, is depleted. Hence, to compensate this deficiency in oxygen, there is a need for agents that enhance radiation-induced damage of cells (radio-sensitizers) in a manner that normal cells are least affected. Simultaneously, agents capable of showing activity under hypoxic conditions are known as hypoxic cytotoxins that selectively and preferably destroy cells under hypoxic environments. 5-Nitroimidazoles fit both definitions. Their efficiency is based on their ability to generate the nitro radical anion that interacts with the strands of DNA within cells, either damaging or modifying them, leading to cell death. 5-Nitroimidazoles are important radio-pharmaceuticals (radio-sensitizers) in cancer-related treatments where the nitro radical anion has an important role. Since its generation leads to neurotoxic side effects that may be controlled through metal complex formation, this study looks at the possibility of two monomeric complexes of Ornidazole [1-chloro-3-(2-methyl-5-nitro-1 H -imidazole-1-yl)propan-2-ol] with Cu II and Zn II to be better radio-sensitizers and/or hypoxic cytotoxins than Ornidazole. The study reveals that although there is a decrease in nitro radical anion formation by complexes, such a decrease does not hamper their radio-sensitizing ability. Nucleic acid bases (thymine, cytosine, and adenine) or calf thymus DNA used as targets were irradiated with 60 Co γ rays either in the absence or presence of Ornidazole and its monomeric complexes. Radiation-induced damage of nucleic acid bases was followed by high-performance liquid chromatography (HPLC), and modification of calf thymus DNA was followed by ethidium bromide fluorescence. Studies indicate that the complexes were better in performance than Ornidazole. Cu II -ornidazole was significantly better than either Ornidazole or Zn II -ornidazole, which is attributed to certain special features of the Cu II complex; aspects like having a stable lower oxidation state enable it to participate in Fenton reactions that actively influence radio-sensitization and the ability of the complex to bind effectively to DNA.

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Section: Results and Discussionmentioning

confidence: 99%

“… 26 − 28 Worth mentioning here is that the complexes are either better DNA-binding agents or DNA-damaging agents or both, following interaction of in situ generated RNO 2 •– with nucleobases and calf thymus DNA. 24 , 31 , 32 …”

Section: Introductionmentioning

confidence: 99%

Radio-Sensitizing Effects of Cu^II and Zn^II Complexes of Ornidazole: Role of Nitro Radical Anion

et al. 2020

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“…Constancy of charge transferred to compounds was checked by chrono-amperometry. This enabled a proper comparison of results obtained the following interaction of species (radical anions or radicals) generated in solution with a target maintained in the vicinity of such generation [ 38 , 39 , 40 ]. A semiquinone radical anion or protonated semiquinone under de-aerated condition or superoxide radical-anion alongwith the semiquinone radical anion (under aerated condition) interact with nucleobases or DNA, that was maintained in the electrochemical cell ( Figure 4 ).…”

Section: Methodsmentioning

confidence: 99%

“…-0.65 V for alizarin and -0.75 V for the complex) were applied using the same glassy carbon electrode with either a chosen nucleobase or calf thymus DNA in solution. Needless to say, all potentials were maintained and applied accurately since this formed the basis of our experiments [ 38 , 39 , 40 ]. Concentration of nucleobases present in solution was approximately ten times that of the compounds used.…”

Section: Methodsmentioning

confidence: 99%

“…Although this is widely accepted as a logical explanation on the performance of metal complexes of anthracyclines or their analogues, there are only a few studies that show a comparative investigation of anthracyclines, its analogues and their respective complexes that involve the free radical pathway. We made attempts to explore aspects related to free radical pathways of some drugs or their analogues when they are either on their own or complexed with metal ions [ 38 , 39 , 40 ]. For anthracyclines, accumulating evidence suggest there is in vivo formation of semiquinone either due to one-electron reduction or by comproportionation when they undergo two-electron reduction to form quinone-dianion [ 28 , 33 , 41 , 42 , 43 ].…”

Section: Introductionmentioning

confidence: 99%

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Free radical induced activity of an anthracycline analogue and its MnII complex on biological targets through in situ electrochemical generation of semiquinone

Saha

Das

2021

Heliyon

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Cytotoxicity by anthracycline antibiotics is attributed to several pathways. Important among them are formation of free-radical intermediates. However, their generation makes anthracyclines cardiotoxic which is a concern on their use as anticancer agents. Hence, any change in redox behavior that address cardiotoxicity is welcome. Modulation of redox behavior raises the fear that cytotoxicity could be compromised. Regarding the generation of free radical intermediates on anthracyclines, a lot depends on the surrounding environment (oxic or anoxic), polarity and pH of the medium. In case of anthracyclines, one-electron reduction to semiquinone or two-electron reduction to quinone-dianion are crucial both for cytotoxicity and for cardiotoxic side effects. The disproportion-comproportionation equilibria at play between quinone-dianion, free quinone and semiquinone control biological activity. Whatever is the form of reduction, semiquinones are generated as a consequence of the presence of anthracyclines and these interact with a biological target. Alizarin, a simpler anthracycline analogue and its Mn II complex were subjected to electrochemical reduction to realize what happens when anthracyclines are reduced by compounds present in cells as members of the electron transport chain. Glassy carbon electrode maintained at the pre-determined reduction potential of a compound was used for reduction of the compounds. Nucleobases and calf thymus DNA that were maintained in immediate vicinity of such radical generation were used as biological targets. Changes due to the generated species under aerated/de-aerated conditions on nucleobases and on DNA helps one to realize the process by which alizarin and its Mn II complex might affect DNA. The study reveals alizarin was more effective on nucleobases than the complex in the free radical pathway. Difference in damage caused by alizarin and the Mn II complex on DNA is comparatively less than that observed on nucleobases; the complex makes up for any inefficacy in the free radical pathway by its other attributes.

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Anti-toxoplasma activity and DNA-binding of copper(II) and zinc(II) coordination compounds with 5-nitroimidazole-based ligands

Navarro-Peñaloza,

Anacleto-Santos,

Rivera-Fernández

et al. 2023

J Biol Inorg Chem

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Tetrahedral copper(II) and zinc(II) coordination compounds from 5-nitroimidazole derivatives, viz. 1-(2-chloroethyl)-2-methyl-5-nitroimidazole (cenz) and ornidazole 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (onz), were synthesized and spectroscopically characterized. Their molecular structures were determined by X-ray diffraction studies. The complexes [Cu(onz)2X2], [Zn(onz)2X2], [Cu(cenz)2X2] and [Zn(cenz)2X2] (X− = Cl, Br), are stable in solution and exhibit positive LogD7.4 values that are in the range for molecules capable of crossing the cell membrane via passive difussion. Their biological activity against Toxoplasma gondi was investigated, and IC50 and lethal dose (LD50) values were determined. The ornidazole copper(II) compounds showed very good antiparasitic activity in its tachyzoite morphology. The interaction of the coordination compounds with DNA was examined by circular dichroism, fluorescence (using intercalating ethidium bromide and minor groove binding Hoechst 33258) and UV–Vis spectroscopy. The copper(II) compounds interact with the minor groove of the biomolecule, whereas weaker electrostatic interactions take place with the zinc(II) compounds. The spectroscopic data achieved for the two series of complexes (namely with copper(II) and zinc(II) as metal center) agree with the respective DNA-damage features observed by gel electrophoresis. Graphical abstract

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In situ reactivity of electrochemically generated nitro radical anion on Ornidazole and its monomeric Cu(II) complex with nucleic acid bases and calf thymus DNA

Cited by 8 publications

References 25 publications

Radio-Sensitizing Effects of Cu^II and Zn^II Complexes of Ornidazole: Role of Nitro Radical Anion

Radio-Sensitizing Effects of Cu^II and Zn^II Complexes of Ornidazole: Role of Nitro Radical Anion

Free radical induced activity of an anthracycline analogue and its MnII complex on biological targets through in situ electrochemical generation of semiquinone

Anti-toxoplasma activity and DNA-binding of copper(II) and zinc(II) coordination compounds with 5-nitroimidazole-based ligands

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In situ reactivity of electrochemically generated nitro radical anion on Ornidazole and its monomeric Cu(II) complex with nucleic acid bases and calf thymus DNA

Cited by 8 publications

References 25 publications

Radio-Sensitizing Effects of CuII and ZnII Complexes of Ornidazole: Role of Nitro Radical Anion

Radio-Sensitizing Effects of CuII and ZnII Complexes of Ornidazole: Role of Nitro Radical Anion

Free radical induced activity of an anthracycline analogue and its MnII complex on biological targets through in situ electrochemical generation of semiquinone

Anti-toxoplasma activity and DNA-binding of copper(II) and zinc(II) coordination compounds with 5-nitroimidazole-based ligands

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Radio-Sensitizing Effects of Cu^II and Zn^II Complexes of Ornidazole: Role of Nitro Radical Anion

Radio-Sensitizing Effects of Cu^II and Zn^II Complexes of Ornidazole: Role of Nitro Radical Anion