Bathocuproine sulphonate: a tissue culture-compatible indicator of copper-mediated toxicity

Mohindru, Anish; Fisher, Joyce M.; Rabinovitz, M.

doi:10.1038/303064a0

Cited by 119 publications

(68 citation statements)

References 10 publications

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“…4) (1,2,5,6). Therefore, the potential role of fortuitous transition metal ions in the DMPO/DCBQ/t-BuOOH reaction system was examined by the use of several structurally different and relatively specific metal chelators for iron and copper (1,(8)(9)(10). Neither the DMPO/t-BuO • signal nor the DMPO/ • CH 3 signal produced by the DMPO/DCBQ/t-BuOOH system was reduced by the addition of various ferrous iron-specific chelators, namely, bathophenanthroline disulfonate (BPS), ferrozine, and ferene, or the cuprous copper-specific chelator bathocuproine disulfonate (BCS) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of metal-independent decomposition of organic hydroperoxides and formation of alkoxyl radicals by halogenated quinones

Zhu

Zhao²,

Kalyanaraman³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The metal-independent decomposition of organic hydroperoxides and the formation of organic alkoxyl radicals in the absence or presence of halogenated quinones were studied with electron spin resonance (ESR) and the spin-trapping agent 5,5-dimethyl-1-pyrroline N-oxide (DMPO). We found that 2,5-dichloro-1,4-benzoquinone (DCBQ) markedly enhanced the decomposition of tert-butylhydroperoxide (t-BuOOH), leading to the formation of the DMPO adducts with t-butoxyl radicals (t-BuO • ) and methyl radicals ( • CH3). The formation of DMPO/t-BuO • and DMPO/ • CH3 was dosedependent with respect to both DCBQ and t-BuOOH and was not affected by iron-or copper-specific metal chelators. Comparison of the data obtained with DCBQ and t-BuOOH with those obtained in a parallel study with ferrous iron and t-BuOOH strongly suggested that t-BuO • was produced by DCBQ and t-BuOOH through a metal-independent mechanism. Other halogenated quinones were also found to enhance the decomposition of t-BuOOH and other organic hydroperoxides such as cumene hydroperoxide, leading to the formation of the respective organic alkoxyl radicals in a metal-independent manner. Based on these data, we propose a mechanism for DCBQ-mediated t-BuOOH decomposition and formation of t-BuO • : a nucleophilic attack of t-BuOOH on DCBQ, forming a chloro-t-butylperoxyl-1,4-benzoquinone intermediate, which decomposes homolytically to produce t-BuO • . This represents a mechanism of organic alkoxyl radical formation not requiring the involvement of redox-active transition metal ions.electron spin resonance spin-trapping ͉ 2,5-dichloro-1,4-benzoquinone ͉ 2,5-dichlorosemiquinone anion radical ͉ reactive intermediate ͉ metal chelators O rganic hydroperoxides (ROOH) can be formed both nonenzymatically by reaction of free radicals with polyunsaturated fatty acids and enzymatically by lipoxygenase-or cyclooxygenasecatalyzed oxidation of linoleic acid and arachidonic acid (1, 2). It has been shown that organic hydroperoxides can undergo transition metal ion-catalyzed decomposition to alkoxyl radicals (Reaction 1), which may initiate de novo lipid peroxidation or further decompose to ␣,␤-unsaturated aldehydes that can react with and damage DNA and other biological macromolecules (1, 2).where Me represents a transition metal, such as iron or copper. Using the salicylate hydroxylation assay and electron spin resonance (ESR) spin-trapping methods, we reported previously that HO • can be produced from H 2 O 2 by halogenated quinones independent of transition metal ions (3, 4). However, it is not clear whether halogenated quinones react in a similar fashion with organic hydroperoxides to produce alkoxyl radicals independent of transition metal ions.Therefore, in the present study we addressed the following questions. (i) Can halogenated quinones enhance the decomposition of organic hydroperoxides to produce alkoxyl radicals? (ii) if so, is the production of alkoxyl radicals dependent or independent of transition metal ions? (iii) And what is the underlying molecular mechanism? To c...

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Section: Resultsmentioning

confidence: 99%

Mechanism of metal-independent decomposition of organic hydroperoxides and formation of alkoxyl radicals by halogenated quinones

Zhu

Zhao²,

Kalyanaraman³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Lozitsky et. al have reported 4D-QSAR study and anticancer activity of Schiff bases synthesized by the condensation of various aliphatic and aromatic diamines with 2,6-bis(2 and 4 formyl arylosy methyl) pyridine derivatives [15].…”

Section: Introductionmentioning

confidence: 99%

Microwave Irradiated and Conventional Syntheses of Halogenated Symmetric Double Schiff Bases, their Spectral and Microbial Study

Gangani¹,

Parsania

2015

ILCPA

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ABSTRACT. The aim of the present work was to discover various synthetic route of biological active halogenated symmetric double Schiff bases of 1,1'-bis(4-aminophenyl)cyclohexane, their spectral and microbial study. Symmetric double Schiff base ligands of halogenated benzaldehyde and 1,1'-bis(4-aminophenyl)cyclohexane were synthesized by conventional and green chemistry approach. The purity of Schiff bases was checked by Thin Layer Chromatography (TLC). The structures of these ligands were elucidated by UV, FTIR, 1 HNMR and MS; and assayed for their antibacterial activity against Escherichia coli (E. coli), Bacillus megaterium (B.mega), Proteus vulgaris (P. vulgaris, Staphylococcus aureus (S. aureus) and Aspergillus niger (A. niger)The minimum inhibition concentrations (MIC) of the compounds were studied by cup plate method. Schiff bases revealed moderate antimicrobial activity and good antifungal activity against chosen standard drugs and microorganisms.

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“…[1][2][3][4][5] 2,9-Dimethyl-1,10-phenanthroline (2,9-Me 2 OP; also called neocuproine) and its water-soluble analogue bathocuproine disulfonate (BCS) are two such chelating agents. The cuprous complexes with these ligands possess greater stability than other biologically relevant complexes with other transition metals due to the steric hindrance provided by the two CH 3 groups at the 2,9 positions of the 1,10-phenanthroline ring structure.…”

Section: Introductionmentioning

confidence: 99%

“…The cuprous complexes with these ligands possess greater stability than other biologically relevant complexes with other transition metals due to the steric hindrance provided by the two CH 3 groups at the 2,9 positions of the 1,10-phenanthroline ring structure. [3,4] Reductions in toxicity and decreased molecular damage, which are caused by addition of these chelators, have been used to support the involvement of copper in deleterious reactions in vivo and in vitro. [5][6][7][8][9][10][11][12][13] In one of these studies, 2,9-Me 2 OP protected isolated rat hearts against ischemia/reperfusion-induced injury.…”

Section: Introductionmentioning

confidence: 99%

“…[13] In another study, BCS reversed copper-mediated growth inhibition of L1210 cells. [4] We found recently that the combination of tetrachlorocatechol (TCC) and sodium azide (NaN 3 ) caused a pronounced synergistic cytotoxicity in a bacterial model. [14,15] During our study on the role of transition-metal ions, especially Cu and Fe, we found, unexpectedly, that only 2,9-Me 2 OP, but not any other well-known metal chelating agents, markedly inhibited the synergistic toxicity induced by TCC/NaN 3 .…”

Section: Introductionmentioning

confidence: 99%

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Detoxifying Polyhalogenated Catechols through a Copper‐Chelating Agent by Forming Stable and Redox‐Inactive Hydrogen‐Bonded Complexes with an Unusual Perpendicular Structure

Li¹,

Huang²,

Liu³

et al. 2014

Chemistry A European J

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The use of selective metal chelating agents with preference for binding of a specific metal ion to investigate its biological role is becoming increasingly common. We found recently that a well-known copper-specific chelator 2,9-dimethyl-1,10-phenanthroline (2,9-Me 2 OP) could completely inhibit the synergistic toxicity induced by tetrachlorocatechol (TCC) and sodium azide (NaN 3 ). However, its underlying molecular mechanism is still not clear. Here, we show that the protection by 2,9-Me 2 OP is not due to its classic copper-chelating property, but rather due to formation of a multiple hydrogen-bonded complex between 2,9-Me 2 OP and TCC, featuring an unusual perpendicular arrangement of the two binding partners. The two methyl groups at the 2,9 positions in 2,9-Me 2 OP were found to be critical to stabilize the 2,9-Me 2 OP/TCC complex due to steric hindrance, and therefore completely prevents the generation of the reactive and toxic semiquinone radicals by TCC/NaN 3 . This represents the first report showing that an unexpected new protective mode of action for the copper "specific" chelating agent 2,9-Me 2 OP by using its steric hindrance effect of the two CH 3 groups not only to chelate copper, but also to "chelate" a catechol through multiple H-bonding. These findings may have broad biological implications for future research of this widely used copper-chelating agent and the ubiquitous catecholic compounds.

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Bathocuproine sulphonate: a tissue culture-compatible indicator of copper-mediated toxicity

Cited by 119 publications

References 10 publications

Mechanism of metal-independent decomposition of organic hydroperoxides and formation of alkoxyl radicals by halogenated quinones

Mechanism of metal-independent decomposition of organic hydroperoxides and formation of alkoxyl radicals by halogenated quinones

Microwave Irradiated and Conventional Syntheses of Halogenated Symmetric Double Schiff Bases, their Spectral and Microbial Study

Detoxifying Polyhalogenated Catechols through a Copper‐Chelating Agent by Forming Stable and Redox‐Inactive Hydrogen‐Bonded Complexes with an Unusual Perpendicular Structure

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