Controlled masking and targeted release of redox-cycling ortho-quinones via a C-C bond-cleaving 1,6-elimination.
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ABSTRACT:
SUBMITTER: Dunsmore L
PROVIDER: S-EPMC9252919 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The effects of quinone-generated active oxygen species on rat hepatocyte protein kinase C were investigated. The specific activity of cytosolic protein kinase C was increased 2-3-fold in hepatocytes incubated with the redox-cycling quinones, menadione, duroquinone or 2,3-dimethoxy-1,4-naphthoquinone, without alterations in particulate protein kinase C specific activity or Ca2+- and lipid-independent kinase activities. Redox-cycling quinones did not stimulate translocation of protein kinase C; however, activated protein kinase C was redistributed from cytosol to the particulate fraction when quinone-treated hepatocytes were exposed to 12-O-tetradecanoylphorbol 13-acetate (TPA). Quinone treatment did not alter cytosolic phorbol 12,13-dibutyrate (PDBu) binding capacity, and the cytosol of both control and quinone-treated hepatocytes exhibited a Kd for PDBu binding of 2 nM. Quinone-mediated activation of cytosolic protein kinase C was reversed by incubation with 10 mM-beta-mercaptoethanol, dithiothreitol or GSH, at 4 degrees C for 24 h. Furthermore, protein kinase C specific activity in control cytosol incubated in air increased by over 100% within 3 h; this increase was reversed by thiol-reducing agents. Similarly, incubation of partially-purified rat brain protein kinase C in air, or with low concentrations of GSSG in the presence of GSH, resulted in a 2-2.5-fold increase in Ca2+- and lipid-dependent kinase activity. In contrast with the effects of the redox-cycling quinones, when hepatocytes were treated with the thiol agents N-ethylmaleimide (NEM), p-benzoquinone (pBQ) or p-chloromercuribenzoic acid (pCMB), the cytosolic Ca2+- and lipid-dependent kinase activity was significantly inhibited, but the particulate-associated protein kinase C activity was unaffected. The Ca2+- and lipid-independent kinase activity of both the cytosolic and particulate fractions was significantly stimulated by NEM, but was unaffected by pBQ and pCMB. These results show that hepatocyte cytosolic protein kinase C is activated to a high-Vmax form by quinone-generated active oxygen species, and this effect is due to a reduction-sensitive modification of the thiol/disulphide status of protein kinase C.
| S-EPMC1138696 | biostudies-other
Project description:BACKGROUND:Cancer cell sensitivity to drugs may be associated with disturbed antioxidant enzymes expression. We investigated mechanisms of resistance by using oxidative stress-resistant MCF-7 breast cancer cells (Resox cells). Since nicotinamide adenine dinucleotide phosphate (NAD(P)H): quinone oxidoreductase-1 (NQO1) is modified in tumors and oxidative stress-resistant cells, we studied its role in cells exposed to ?-lapachone, menadione, and doxorubicin. METHODS:Normal mammary epithelial 250MK, MCF-7, and Resox cells were employed. NQO1 expression and enzyme activity were determined by quantitative polymerase chain reaction (RT-PCR), immunoblotting, and biochemical assays. Dicoumarol and gene silencing (siRNA) were used to modulate NQO1 expression and to assess its potential drug-detoxifying role. MTT (3-(4,5-dimethylthia-zolyl-2)-2,5-diphenyltetrazolium bromide) or clonogenic assays were used to investigate cytotoxicity. NQO1 variants, NQO1*1 (wt), and NQO1*2 (C609T), were obtained by transfecting NQO1-null MDA-MB-231 cell line. RESULTS:Resox cells have higher NQO1 expression than MCF-7 cells. In 250MK cells its expression was low but enzyme activity was higher suggesting a variant NQO1 form in MCF-7 cells. MCF-7 and Resox cells are heterozygous NQO1*1 (wt)/ NQO1*2 (C609T). Both NQO1 polymorphism and NQO1 overexpression are main determinants for cell resistance during oxidative stress. NQO1 overexpression increases cell sensitivity to ?-lapachone whereas NQO1*2 polymorphism triggers quinone-based chemotherapies-sensitivity. CONCLUSIONS:NQO1 influences cancer cells redox metabolism and their sensitivity to drugs. We suggest that determining NQO1 polymorphism may be important when considering the use of quinone-based chemotherapeutic drugs.
| S-EPMC6770057 | biostudies-literature
Project description:High-valent iron-oxo intermediates have been identified as the key oxidants in the catalytic cycles of many nonheme enzymes. Among the large number of synthetic Fe(IV)=O complexes characterized to date, [Fe(IV)(O)(N4Py)](2+) (1) exhibits the unique combination of thermodynamic stability, allowing its structural characterization by X-ray crystallography, and oxidative reactivity sufficient to cleave C-H bonds as strong as those in cyclohexane (D(C-H) = 99.3 kcal mol(-1)). However, its redox properties are not yet well understood. In this work, the effect of protons on the redox properties of 1 has been investigated electrochemically in nonaqueous and aqueous solutions. While the cyclic voltammetry of 1 in CH(3)CN is complicated by coupling of several chemical and redox processes, the Fe(IV/III) couple is reversible in aqueous solution with E(1/2) = +0.41 V versus SCE at pH 4 and involves the transfer of one electron and one proton to give the Fe(III)-OH species. This is in fact the first example of reversible electrochemistry to be observed for this family of nonheme oxoiron (IV) complexes. C-H bond oxidations by 1 have been studied in H(2)O and found to have reaction rates that depend on the C-H bond strength but not on the solvent. Furthermore, our electrochemical results have allowed a D(O-H) value of 78(2) kcal mol(-1) to be calculated for the Fe(III)-OH unit derived from 1. Interestingly, although this D(O-H) value is 6-11 kcal mol(-1) lower than those corresponding to oxidants such as [Fe(IV)(O)(TMP)] (TMP = tetramesitylporphinate), [Ru(IV)(O)(bpy)(2)(py)](2+) (bpy = bipyridine, py = pyridine), and the tert-butylperoxyl radical, the oxidation of dihydroanthracene by 1 occurs at a rate comparable to rates for these other oxidants. This comparison suggests that the nonheme N4Py ligand environment confers a kinetic advantage over the others that enhances the C-H bond cleavage ability of 1.
| S-EPMC2887765 | biostudies-literature
Project description:Aging and oxidative stress are two prominent pathological mechanisms for Parkinson's disease (PD) that are strongly associated with the degeneration of dopamine (DA) neurons in the midbrain. DA and other catechols readily oxidize into highly reactive o-quinone species that are precursors of neuromelanin (NM) pigment and under pathological conditions can modify and damage macromolecules. The role of DA oxidation in PD pathogenesis remains unclear in part due to the lack of appropriate disease models and the absence of a simple method for the quantification of DA-derived oxidants. Here, we describe a rapid, simple, and reproducible method for the quantification of o-quinones in cells and tissues that relies on the near-infrared fluorescent properties of these species. Importantly, we demonstrate that catechol-derived oxidants can be quantified in human neuroblastoma cells and midbrain dopamine neurons derived from induced pluripotent stem cells, providing a novel model to study the downstream actions of o-quinones. This method should facilitate further study of oxidative stress and DA oxidation in PD and related diseases that affect the dopaminergic system.
| S-EPMC5555314 | biostudies-literature
Project description:ortho-Quinones are produced in vivo through the oxidation of catecholic substrates by enzymes such as tyrosinase or by transition metal ions. Neuromelanin, a dark pigment present in the substantia nigra and locus coeruleus of the brain, is produced from dopamine (DA) and norepinephrine (NE) via an interaction with cysteine, but it also incorporates their alcoholic and acidic metabolites. In this study we examined the metabolic fate of ortho-quinones derived from the catecholamine metabolites, 3,4-dihydroxyphenylethanol (DOPE), 3,4-dihydroxyphenylethylene glycol (DOPEG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylmandelic acid (DOMA). The oxidation of catecholic substrates by mushroom tyrosinase was followed by UV-visible spectrophotometry. HPLC analysis after reduction with NaBH? or ascorbic acid enabled measurement of the half-lives of ortho-quinones and the identification of their reaction products. Spectrophotometric examination showed that the ortho-quinones initially formed underwent extensive degradation at pH 6.8. HPLC analysis showed that DOPE-quinone and DOPEG-quinone degraded with half-lives of 15 and 30 min at pH 6.8, respectively, and >100 min at pH 5.3. The major product from DOPE-quinone was DOPEG which was produced through the addition of a water molecule to the quinone methide intermediate. DOPEG-quinone yielded a ketone, 2-oxo-DOPE, through the quinone methide intermediate. DOPAC-quinone and DOMA-quinone degraded immediately with decarboxylation of the ortho-quinone intermediates to form 3,4-dihydroxybenzylalcohol (DHBAlc) and 3,4-dihydroxybenzaldehyde (DHBAld), respectively. DHBAlc-quinone was converted to DHBAld with a half-life of 9 min, while DHBAld-quinone degraded rapidly with a half-life of 3 min. This study confirmed the fact that ortho-quinones from DOPE, DOPEG, DOPAC and DOMA are converted to quinone methide tautomers as common intermediates, through proton rearrangement or decarboxylation. The unstable quinone methides afford stable alcoholic or carbonyl products.
| S-EPMC4783898 | biostudies-other
Project description:The rational design of quinones with specific redox properties is an issue of great interest because of their applications in pharmaceutical and material sciences. In this work, the electrochemical behavior of a series of four p-quinones was studied experimentally and theoretically. The first and second one-electron reduction potentials of the quinones were determined using cyclic voltammetry and correlated with those calculated by density functional theory (DFT) using three different functionals, BHandHLYP, M06-2x and PBE0. The differences among the experimental reduction potentials were explained in terms of structural effects on the stabilities of the formed species. DFT calculations accurately reproduced the first one-electron experimental reduction potentials with R² higher than 0.94. The BHandHLYP functional presented the best fit to the experimental values (R² = 0.957), followed by M06-2x (R² = 0.947) and PBE0 (R² = 0.942).
| S-EPMC6154728 | biostudies-literature
Project description:Ambient noise is a major constraint on acoustic communication in both animals and humans. One mechanism to overcome this problem is Spatial Release from Masking (SRM), the ability to distinguish a target sound signal from masking noise when both sources are spatially separated. SRM is well described in humans but has been poorly explored in animals. Although laboratory tests with trained individuals have suggested that SRM may be a widespread ability in vertebrates, it may play a limited role in natural environments. Here we combine field experiments with investigations in captivity to test whether crocodilians experience SRM. We show that 2 species of crocodilians are able to use SRM in their natural habitat and that it quickly becomes effective for small angles between the target signal source and the noise source, becoming maximal when the angle exceeds 15∘. Crocodiles can therefore take advantage of SRM to improve sound scene analysis and the detection of biologically relevant signals.
| S-EPMC9411511 | biostudies-literature
Project description:Despite their broad utility, the synthesis of ortho-quinones remains a significant challenge, in particular, access to electron-deficient derivatives remains an unsolved problem. Reported here is the first general method for the synthesis of electron-deficient ortho-quinones by direct oxidation of phenols. The reaction is enabled by a novel bidentate nitrogen-ligated iodine(V) reagent, a previously unexplored class of compounds which we have termed Bi(N)-HVIs. The reaction is extremely general and proceeds with excellent regioselectivity for the ortho over para isomer. Functionalization of the ortho-quinone products was examined, resulting in a facile one-pot synthesis of catechols, as well as the incorporation of a variety of heteroatom nucleophiles. This method represents the first synthetic application of Bi(N)-HVIs and demonstrates their potential as a platform for the further development of highly reactive, but also highly tunable, I(V) reagents.
| S-EPMC6814494 | biostudies-literature
Project description:The chemistry of strained unsaturated cyclic compounds has experienced remarkable growth in recent years via the development of metal-free click reactions. Among these reactions, the cycloaddition of cyclopropenes and their analogues to ortho-quinones has been established as a highly promising click reaction. The present work investigates the mechanism involved in the cycloaddition of strained dienes to ortho-quinones and structural factors that would influence this reaction. For this purpose, we use B97D density functional theory calculations throughout, and for relevant cases, we use spin component-scaled MP2 calculations and single-point domain-based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) calculations. The outcomes are analyzed in detail using the distortion/interaction model, and suggestions for future experimental work are made.
| S-EPMC7656516 | biostudies-literature
Project description:The toxicity of acetylacetone has been demonstrated in various studies. Little is known, however, about metabolic pathways for its detoxification or mineralization. Data presented here describe for the first time the microbial degradation of acetylacetone and the characterization of a novel enzyme that initiates the metabolic pathway. From an Acinetobacter johnsonii strain that grew with acetylacetone as the sole carbon source, an inducible acetylacetone-cleaving enzyme was purified to homogeneity. The corresponding gene, coding for a 153 amino acid sequence that does not show any significant relationship to other known protein sequences, was cloned and overexpressed in Escherichia coli and gave high yields of active enzyme. The enzyme cleaves acetylacetone to equimolar amounts of methylglyoxal and acetate, consuming one equivalent of molecular oxygen. No exogenous cofactor is required, but Fe(2+) is bound to the active protein and essential for its catalytic activity. The enzyme has a high affinity for acetylacetone with a K (m) of 9.1 microM and a k(cat) of 8.5 s(-1). A metabolic pathway for acetylacetone degradation and the putative relationship of this novel enzyme to previously described dioxygenases are discussed.
| S-EPMC1223103 | biostudies-other