cas 27025-41-8, L(-)-Glutathione | Articles data

Articles about 27025-41-8Total 137 be found

Article title
Article abstract
Author
Journal number and time
Download

Interaction between Glutathione and Resveratrol in the Presence of Hydrogen Peroxide: A Kinetic Model
Abstract: The kinetics of interaction between glutathione (GSH) and unsaturated phenol resveratrol (RVT) in deionized water in the presence of hydrogen peroxide (H2O2) is studied. At a physiological concentration (0.1–10 mM), GSH containing two carboxyl groups forms acidic solutions (pH of 3–4); the GSH molecules are associated into dimers. Under these conditions, GSH is quite slowly oxidized by atmospheric oxygen, and the reaction between GSH and H2O2 is accompanied by the formation of radicals. The thiyl radical initiation rate (Wi) is a few fractions of a percent of the GSH consumption rate; however, it is sufficient to initiate a thiol–ene chain reaction between GSH and RVT. Using the experimental data on the kinetics and the product composition and the published data on reactions of GSH with H2O2 and thiyl radicals, a kinetic model of the complex interaction between GSH and RVT in the presence of H2O2 in an aqueous medium at 37°C is proposed. The model includes 19 quasi-elementary reactions with respective rate constants, in particular, the formation of intermediate GSH–H2O2 and GSH–GSH complexes, the formation of radicals, and their subsequent transformations into final products in reactions with RVT and GSH. A computer simulation based on the developed model adequately describes the features of the process kinetics in a wide reactant concentration range.
Zinatullina,Kasaikina,Khrameeva,Indeykina,Kononikhin
p. 255 - 263
(2021/04/26)

Single-Atom Pd Nanozyme for Ferroptosis-Boosted Mild-Temperature Photothermal Therapy
Photothermal therapy (PTT) is an extremely promising tumor therapeutic modality. However, excessive heat inevitably injures normal tissues near tumors, and the damage to cancer cells caused by mild hyperthermia is easily repaired by stress-induced heat shock proteins (HSPs). Thus, maximizing the PTT efficiency and minimizing the damage to healthy tissues simultaneously by adopting appropriate therapeutic temperatures is imperative. Herein, an innovative strategy is reported: ferroptosis-boosted mild PTT based on a single-atom nanozyme (SAzyme). The Pd SAzyme with atom-economical utilization of catalytic centers exhibits peroxidase (POD) and glutathione oxidase (GSHOx) mimicking activities, and photothermal conversion performance, which can result in ferroptosis featuring the up-regulation of lipid peroxides (LPO) and reactive oxygen species (ROS). The accumulation of LPO and ROS provides a powerful approach for cleaving HSPs, which enables Pd SAzyme-mediated mild-temperature PTT.
Chang, Mengyu,Hou, Zhiyao,Li, Chunxia,Li, Fang,Lin, Jun,Liu, Donglian,Peng, Tieli,Wang, Man,Wang, Ruifeng,Yang, Chunzheng
supporting information
p. 12971 - 12979
(2021/05/03)

Growth Factor-Decorated Ti3C2 MXene/MoS2 2D Bio-Heterojunctions with Quad-Channel Photonic Disinfection for Effective Regeneration of Bacteria-Invaded Cutaneous Tissue
Phototherapy has recently emerged as a competent alternative for combating bacterial infection without antibiotic-resistance risk. However, owing to the bacterial endogenous antioxidative glutathione (GSH), the exogenous reactive oxygen species (ROS) generated by phototherapy can hardly behave desired antibacterial effect. To address the daunting issue, a quad-channel synergistic antibacterial nano-platform of Ti3C2 MXene/MoS2 (MM) 2D bio-heterojunctions (2D bio-HJs) are devised and fabricated, which possess photothermal, photodynamic, peroxidase-like (POD-like), and glutathione oxidase-like properties. Under near-infrared (NIR) laser exposure, the 2D bio-HJs both yield localized heating and raise extracellular ROS level, leading to bacterial inactivation. Synchronously, Mo4+ ions can easily invade into ruptured bacterial membrane, arouse intracellular ROS, and deplete intracellular GSH. Squeezed between the “ROS hurricane” from both internal and external sides, the bacteria are hugely slaughtered. After being further loaded with fibroblast growth factor-21 (FGF21), the 2D bio-HJs exhibit benign cytocompatibility and boost cell migration in vitro. Notably, the in vivo evaluations employing a mouse-infected wound model demonstrate the excellent photonic disinfection towards bacterial infection and accelerated wound healing. Overall, this work provides a powerful nano-platform for the effective regeneration of bacteria-invaded cutaneous tissue using 2D bio-HJs.
Yang, Zhaopu,Fu, Xinliang,Ma, Daichuan,Wang, Yulin,Peng, Liming,Shi, Jiacheng,Sun, Jiyu,Gan, Xueqi,Deng, Yi,Yang, Weizhong
(2021/11/01)

Reduction of an asymmetric Pt(IV) prodrug fac-[Pt(dach)Cl3(OC(=O)CH3)] by biological thiol compounds: kinetic and mechanistic characterizations
An asymmetric Pt(IV) prodrug fac-[Pt (dach)Cl3(OC(=O)CH3)] (dach = 1,2-diaminocyclohexane) was synthesized, and the reduction of the Pt(IV) prodrug by three biological thiols glutathione (GSH), cysteine (Cys) and homocysteine (Hcy) was investigated by a stopped-flow spectrometer. All the reductions were followed by an overall second-order reaction with first-order in both [Pt(IV)] and [thiol]. The reduction of the Pt(IV) prodrug occurred through a chloride bridge (Pt-Cl-S) mediated two electron transfer process. Therefore, the coordinated chloride possesses a better bridging effect than the oxygen atom from the coordinated –CH3COO? of the Pt(IV) prodrug. A reactivity trend of k′Cys > k′GSH > k′Hcy is found, illustrating that the reactivity is followed by the trend of Cys > GSH > Hcy in pH 7.4 buffer. Graphical abstract: Transition state is formed between the axially coordinated chloride of the platinum(IV) complex and the sulfur atom from the thiol/thiolate group of Cys/Hcy/GSH.[Figure not available: see fulltext.].
Huo, Shuying,Ma, Dongying,Song, Changying,Sun, Jingjing,Wang, Yafang
p. 623 - 631
(2021/11/22)

Alternative mechanisms of action for the apoptotic activity of terpenoid-like chalcone derivatives
Apoptosis is a defense mechanism against pre-cancerous and infected cells. Although the applicability of β-ionone against diverse cancer cell lines has been exhaustively investigated, the apoptotic activity of terpenoid-like chalcones, as well as their mechanisms of action, is not well understood. Here we present a new terpenoid-like chalcone derivative (I) and its biological potential against HL-60 (leukemia), HCT-116 (colon), and SNB-19 (glioblastoma) cancer cell lines. CompoundIshowed cytotoxicity against over 90% of the tested cell lines. However,Ihas an IC50slightly higher than doxorubicin, a DNA-binding cancer drug, which motivated us to investigate an alternative mechanism of action forIother than DNA-mediated. We performed anin silicostructure-based pharmacophoric screening against various proteins, which indicated mitogen-activated protein kinase 5 (MAP3K5) as a potential protein target. CompoundIwas docked within its active site and was predicted to bind MAP3K5 with a comparable affinity to IM6, a cocrystallized ligand. Finally, we describe the reaction of a reduced glutathione adduct (GSH) with compoundIand previously published derivatives bearing the substitutions 4-chloro (II), 4-bromo (III), and 4-nitro (IV) using HPLC-MS. We show that these are rapid reactions and that the products are stable for up to 24 h. Here, we suggest two alternative mechanisms (MAP3K5 inhibition and thiol reactivity) for the biological potential of a series of terpenoid-like chalcone derivatives. We anticipate that these findings can be explored to design additional derivatives with even more robust apoptotic activity.
Bernardes, Aline,Custodio, Jean M. F.,Molnár, Szilárd,Moura, Andrea F.,Noda-Perez, Caridad,Oliver, Allen G.,Perjési, Pál,Vaz, Wesley F.
supporting information
p. 15267 - 15279
(2021/09/07)

Amphiphilic Iodine(III) Reagents for the Lipophilization of Peptides in Water
We report the functionalization of cysteine residues with lipophilic alkynes bearing a silyl group or an alkyl chain using amphiphilic ethynylbenziodoxolone reagents (EBXs). The reactions were carried out in buffer (pH 6 to 9), without organic co-solvent or removal of oxygen, either at 37 °C or room temperature. The transformation led to a significant increase of peptide lipophilicity and worked for aromatic thiols, homocysteine, cysteine, and peptides containing 4 to 18 amino acids. His6-Cys-Ubiquitin was also alkynylated under physiological conditions. Under acidic conditions, the thioalkynes were converted into thioesters, which could be cleaved in the presence of hydroxylamine.
Hari, Durga Prasad,Mishra, Abhaya Kumar,Tessier, Romain,Waser, Jerome
supporting information
p. 17963 - 17968
(2021/07/20)

REAL-TIME MONITORING OF IN VIVO FREE RADICAL SCAVENGERS THROUGH HYPERPOLARIZED N-ACETYL CYSTEINE ISOTOPES
A method of diagnosing or monitoring a patient suffering from cancer, the method comprising: administering a pharmaceutical composition comprising an effective amount of an active agent, wherein the active agent is [1-13C] N-acetyl cysteine, a deuterated derivative thereof, a pharmaceutically acceptable salt of any of the foregoing thereof, or a combination thereof, together with a pharmaceutically acceptable carrier to the patient; and diagnosing or monitoring the patient by hyperpolarized 13C-MRI. Also disclosed is a method of synthesizing [1-13C] N-acetyl cysteine or a deuterated derivative thereof.
-
Paragraph 0148-0150

(2021/07/24)

The thiol-based reduction of Bi(V) and Sb(V) anti-leishmanial complexes
Low molecular weight thiols including trypanothione and glutathione play an important function in the cellular growth, maintenance and reduction of oxidative stress in Leishmania species. In particular, parasite specific trypanothione has been established as a prime target for new anti-leishmania drugs. Previous studies into the interaction of the front-line Sb(V) based anti-leishmanial drug meglumine antimoniate with glutathione, have demonstrated that a reduction pathway may be responsible for its effective and selective nature. The new suite of organometallic complexes, of general formula [MAr3(O2CR)2] (M = Sb or Bi) have been shown to have potential as new selective drug candidates. However, their behaviour towards the critical thiols glutathione and trypanothione is still largely unknown. Using NMR spectroscopy and mass spectrometry we have examined the interaction of the analogous Sb(V) and Bi(V) organometallic complexes, [SbPh3(O2CCH2(C6H4CH3))2] S1 and [BiPh3(O2CCH2(C6H4CH3))2] B1, with the trifluoroacetate (TFA) salt of trypanothione and L-glutathione. In the presence of trypanothione or glutathione at the clinically relevant pH of 4–5 for Leishmania amastigotes, both complexes undergo facile and rapid reduction, with no discernible difference. However, at a higher pH (6–7), the complexes behave quite differently towards glutathione. The Bi(V) complex is again reduced rapidly but the Sb(V) complex undergoes slow reduction over 8 h (t1/2 = 54 min.) These results give the first insights into why the highly oxidising Bi(V) complexes display low selectivity in their cytotoxicity towards leishmanial and mammalian cells, while the Sb(V) complexes show good selectivity.
Duffin, Rebekah N.,Stephens, Liam J.,Blair, Victoria L.,Kedzierski, Lukasz,Andrews, Philip C.
(2021/05/10)

Generation of cyclic glutathione via the thiolactonization of glutathione and identification of a new radical scavenging mechanism
Glutathione (GSH) has two important biological activities, GSH conjugation and radical scavenging. In this work, we determined that GSH can participate in an intramolecular cyclization between the glutamic α-carboxylic acid and the cysteinyl thiol moiety under aqueous conditions. Moreover, we showed that the cyclic glutathione (cGSH) product had more potent radical scavenging activity than GSH. The cGSH radical scavenging activity occurred via a mechanism that differed from that of GSH.
Tsutsui, Ayumi,Morishita, Yuta,Furumachi, Hiyori,Fujimoto, Takashi,Hirai, Rina,Fujita, Tomoyuki,Machinami, Tomoya
(2021/03/01)

Detection of Thiol Functionality and Disulfide Bond Formation by Polyoxometalate
The detection of thiol functionality and intramolecular disulfide bond formation of peptides using the α-Keggin type polyoxometalate molybdenum-oxygen cluster (H3PMo12O40·nH2O) is described. Our method entails the addition of this polyoxometalate to solutions of thiol, whereupon the color of the solution changes from colorless to deep blue. Reduction of the polyoxometalate from Mo(VI) to Mo(V) occurs with concomitant oxidation of the thiol functionality, to form disulfide bonds. To exemplify the utility this phenomenon, we accomplished the oxidation of glutathione, reduced linear oxytocin, bactenecin, and α-conotoxin SI; all of which proceeded smoothly and in good conversion in 24 h to less and were accomplished by a change in the color of the reaction solutions.
Konno, Hiroyuki,Yasumiishi, Haruto,Aoki, Reika,Nitanai, Ikumi,Yano, Shigekazu
supporting information
p. 745 - 749
(2020/11/10)

Biological activity and photocatalytic properties of a naphthyl-imidazo phenanthroline (HNAIP) ligand and its [Ir(ppy)2(HNAIP)]Cl and [Rh(ppy)2(HNAIP)]Cl complexes
The synthesized 2-(hydroxy-1-naphtyl)imidazo-[4,5-f][1,10]phenanthroline (HNAIP) ligand and its new iridium ([Ir(ppy)2(HNAIP)]Cl) and rhodium ([Rh(ppy)2(HNAIP)]Cl) complexes, being ppy = 2-phenylpiridinate, show cytotoxic effects in SW480 (colon adenocarcinoma) and A549 (epithelial lung adenocarcinoma) cells. They all are cytotoxic in the tested cell lines. HNAIP and [Rh(ppy)2(HNAIP)]+ are the most cytotoxic, whereas [Ir(ppy)2(HNAIP)]+ displays negligible cytotoxicity towards A549 cells and moderate activity towards SW480. The interaction of all three compounds with Bovine Serum Albumin (BSA), L-glutathione reduced (GSH), nicotinamide adenine dinucleotide (NADH) and DNA was studied to explain the differences found in terms of cytotoxicity. None of them are able to interact with BSA, thus excluding bioavailability due to plasma protein interaction as the possible differentiating factor in their biological activity. By contrast, small differences have been observed regarding DNA interaction. In addition, taking advantage of the emission properties of these molecules, they have been visualized in the cytoplasmic region of A549 cells. Inductively coupled plasma mass spectrometry (ICP-MS) experiments show, in turn, that the internalization ability follow the sequence [Rh(ppy)2(HNAIP)]+ > [Ir(ppy)2(HNAIP)]+ > cisplatin. Therefore, it seems clear that the cellular uptake by tumour cells is the key factor affecting the different cytotoxicity of the metal complexes and that this cellular uptake is influenced by the hydrophobicity of the studied complexes. On the other hand, preliminary catalytic experiments performed on the photo-oxidation of GSH and some amino acids such as L-methionine (Met), L-cysteine (Cys) and L-tryptophan (Trp) provide evidence for the photocatalytic activity of the Ir(III) complex in this type of reactions.
Rubio, Ana R.,Fidalgo, Jairo,Martin-Vargas, Judit,Pérez-Arnaiz, Cristina,Alonso-Torre, Sara R.,Biver, Tarita,Espino, Gustavo,Busto, Natalia,García, Bego?a
(2019/11/13)

Ligand-centred redox activation of inert organoiridium anticancer catalysts
Organometallic complexes with novel activation mechanisms are attractive anticancer drug candidates. Here, we show that half-sandwich iodido cyclopentadienyl iridium(iii) azopyridine complexes exhibit potent antiproliferative activity towards cancer cells, in most cases more potent than cisplatin. Despite their inertness towards aquation, these iodido complexes can undergo redox activation by attack of the abundant intracellular tripeptide glutathione (GSH) on the chelated azopyridine ligand to generate paramagnetic intermediates, and hydroxyl radicals, together with thiolate-bridged dinuclear iridium complexes, and liberate reduced hydrazopyridine ligand. DFT calculations provided insight into the mechanism of this activation. GS?attack on the azo bond facilitates the substitution of iodide by GS?, and leads to formation of GSSG and superoxide if O2is present as an electron-acceptor, in a largely exergonic pathway. Reactions of these iodido complexes with GSH generateIr-SGcomplexes, which are catalysts for GSH oxidation. The complexes promoted elevated levels of reactive oxygen species (ROS) in human lung cancer cells. This remarkable ligand-centred activation mechanism coupled to redox reactions adds a new dimension to the design of organoiridium anticancer prodrugs.
Banerjee, Samya,Breeze, Ben G.,Bridgewater, Hannah E.,Clarkson, Guy J.,Coverdale, James P. C.,Hughes, George M.,Ponte, Fortuna,Sadler, Peter J.,Sanchez-Cano, Carlos,Sicilia, Emilia,Song, Ji-Inn,Zhang, Wen-Ying
p. 5466 - 5480
(2020/06/10)

Construction of pH sensitive smart glutathione peroxidase (GPx) mimics based on pH responsive pseudorotaxanes
Two organoselenium compounds, both of which were modified with two primary amine groups, were designed and synthesized to mimic the catalytic properties of glutathione peroxidase (GPx). It was demonstrated that the catalytic mechanism of the diselenide organoselenium compound (compound 1) was a ping-pong mechanism while that of the selenide organoselenium compound (compound 2) was a sequential mechanism. The pH-controlled switching of the catalytic activities was achieved by controlling the formation and dissociation of the pseudorotaxanes based on the organoselenium compounds and cucurbit[6]uril (CB[6]). Moreover, the switching was reversible at pH between 7 and 9 for compound 1 or between 7 and 10 for compound 2.
An, Shaojie,Jia, Wenlong,Li, Jiaxi,Ma, Ganghui,Shi, Shan,Wang, Tao,Zhang, Xiaoyin
supporting information
p. 3125 - 3134
(2020/05/08)

Derivatization of chlorin e6 with maleimide enhances its photodynamic efficacy in HepG2 cells
Three derivatives of chlorin e6 (1-3) were synthesized by introduction of maleimide, cysteine and glutathione at C-13 carboxyl of the chlorin scaffold. The evaluation of their PDT effects showed that compound 1, the derivative with a maleimide group, exhibited more potent photocytotoxicity against HepG2 cells (IC50 3.2 μM) than 2 (IC50 6.7 μM) and 3 (IC50 10.2 μM), although the cellular uptake of 1 was slightly lower than that of 2 and 3. The high PDT effect of 1 was found to be in agreement with the high level of intracellular singlet oxygen. Further investigation of the mechanism revealed that 1 can significantly lower the GSH level in HepG2 cells due to the addiction reaction of maleimide and GSH, thus resulting in the reduction of ROS scavenging and the enhancement of cellular oxidative stress. This approach to improve PDT effects of photosensitizers by means of interfering with the cellular redox system and enhancing cellular oxidative stress offers a new strategy for development of photosensitizers in cancer therapy.
Guo, Xiuhan,Wang, Shisheng,Zhang, Fan,Li, Guangzhe,Li, Yueqing,Zhao, Weijie
p. 1093 - 1098
(2020/07/10)

Redox Activity of Ce(IV)-Substituted Polyoxometalates toward Amino Acids and Peptides
Redox reactions between polyoxometalates (POMs) and biologically relevant molecules have been virtually unexplored but are important, considering the growing interest in the biological applications of POMs. In this work we give a detailed account on the redox behavior of CeIV-substituted polyoxometalates (CeIV-POMs) toward a range of amino acids and peptides. CeIV-POMs have been shown to act as artificial proteases that promote the selective hydrolysis of peptide bonds. In presence of a protein, a concomitant reduction of CeIV to CeIII ion is frequently observed, leading us to examine the origins of this redox reaction by first using amino acid building blocks as simple models. Among all of the examined amino acids, cysteine (Cys) showed the highest activity in reducing CeIV-POMs to CeIII-POMs, followed by the aromatic amino acids tryptophan (Trp), tyrosine (Tyr), histidine (His), and phenylalanine (Phe). While the redox reaction with Cys afforded the well-defined product cystine, no oxidation products were detected for the Trp, His, Tyr, and Phe amino acids after their reaction with CeIV-POMs, suggesting a radical pathway in which the solvent likely regenerates the amino acid. In general, the rate of redox reactions increased upon increasing the pD, temperature, and ionic strength of the reaction. Moreover, the redox reaction is highly sensitive to the type of polyoxometalate scaffold, as complexation of CeIV to a Keggin (K) or Wells-Dawson (WD) polyoxotungstate anion resulted in a large difference in the rate of redox reaction for both Cys and aromatic amino acids. The reduction of CeIVK was at least 1 order of magnitude faster in comparison to CeIVWD, in accordance with the higher redox potential of CeIVK in comparison to CeIVWD. The reaction of CeIVPOMs with a range of peptides containing redox-active amino acids revealed that the redox reaction is influenced by their coordination mode with CeIV ion, but in all examined peptides the redox reaction is favored in comparison to the hydrolytic cleavage of the peptide bond.
Abdelhameed, Shorok A. M.,De Azambuja, Francisco,Parac-Vogt, Tatjana N.,Vandebroek, Laurens
supporting information

(2020/07/06)

A simultaneously GSH-depleted bimetallic Cu(ii) complex for enhanced chemodynamic cancer therapy
A bimetallic Cu(ii) complex as a novel antitumor chemodynamic therapy agent with glutathione (GSH) depletion properties is successfully synthesized and well characterized. In tumor cells, the Cu2+ions of the complex are reduced to Cu+ions by GSH and then catalyzed by the overexpressed H2O2to generate highly cytotoxic hydroxyl radicals (˙OH) that kill cancer cells. The complex is quickly taken up by cancer cells and distributed in multiple organelles including mitochondria and the nucleus. The complex demonstrates good cytotoxicity toward various cancer cell lines. However, its toxicity toward normal cells is significantly lower than that toward cancer cells due to the limited expression of H2O2. In addition, the complex could arrest the cell cycle of the G0/G1 phase, thereby inducing apoptosis rather than necrosis.
Cao, Shuhua,Cao, Xuanxuan,Dai, Yiwen,Gao, Yong,Li, Fahui,Li, Kaoxue,Li, Xuezhao,Mao, Lirong,Tai, Xishi,Wang, Shanshan
p. 11851 - 11858
(2020/09/21)

Benzisothiazolinone Derivatives as Potent Allosteric Monoacylglycerol Lipase Inhibitors That Functionally Mimic Sulfenylation of Regulatory Cysteines
We describe a set of benzisothiazolinone (BTZ) derivatives that are potent inhibitors of monoacylglycerol lipase (MGL), the primary degrading enzyme for the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Structure-activity relationship studies evaluated various substitutions on the nitrogen atom and the benzene ring of the BTZ nucleus. Optimized derivatives with nanomolar potency allowed us to investigate the mechanism of MGL inhibition. Site-directed mutagenesis and mass spectrometry experiments showed that BTZs interact in a covalent reversible manner with regulatory cysteines, Cys201 and Cys208, causing a reversible sulfenylation known to modulate MGL activity. Metadynamics simulations revealed that BTZ adducts favor a closed conformation of MGL that occludes substrate recruitment. The BTZ derivative 13 protected neuronal cells from oxidative stimuli and increased 2-AG levels in the mouse brain. The results identify Cys201 and Cys208 as key regulators of MGL function and point to the BTZ scaffold as a useful starting point for the discovery of allosteric MGL inhibitors.
Castelli, Riccardo,Scalvini, Laura,Vacondio, Federica,Lodola, Alessio,Anselmi, Mattia,Vezzosi, Stefano,Carmi, Caterina,Bassi, Michele,Ferlenghi, Francesca,Rivara, Silvia,M?ller, Ingvar R.,Rand, Kasper D.,Daglian, Jennifer,Wei, Don,Dotsey, Emmanuel Y.,Ahmed, Faizy,Jung, Kwang-Mook,Stella, Nephi,Singh, Simar,Mor, Marco,Piomelli, Daniele
p. 1261 - 1280
(2019/12/25)

Cyclic telluride reagents with remarkable glutathione peroxidase-like activity for purification-free synthesis of highly pure organodisulfides
Monoamino cyclic tellurides with a five- or six-membered ring structure and their derivatives were developed as a new class of catalyst for the oxidation of organothiols to organodisulfides in a glutathione peroxidase-like catalytic reaction. Quantitative conversion and high reaction rate were achieved by performing the reaction in an organic-aqueous segmented microflow system. Importantly, the process circumvented product purification, which is a major limitation of current organodisulfide synthetic methods.
Arai, Kenta,Osaka, Yuui,Haneda, Masahiro,Sato, Yuumi
p. 3647 - 3655
(2019/07/22)

Understanding the role of oxo and peroxido species in the glutathione peroxidase (GPx)-like activity of metal based nanozymes
Nanomaterials having enzyme-like activities (nanozymes) attract significant attention. Particularly, metal-based nanozymes that exhibit superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities find applications in controlling the redox state of the cells. It has been shown that V2O5 functionally mimic the GPx enzyme by catalytically reducing H2O2 in the presence of glutathione (GSH). In this paper, we discuss the role of oxo and peroxido species in the GPx activity of V2O5 and MoO3. A detailed mechanistic study reveals that the GPx activity of these materials depends on the reactivity of oxo moiety on the surface of the material with H2O2 to form the peroxido linkages.
Ghosh, Sourav,Prasad, Sanjay,Mugesh, Govindasamy
supporting information
p. 283 - 290
(2018/10/02)

A New Quantification Method Using Electrochemical Mass Spectrometry
Mass spectrometry-based quantification method has advanced rapidly. In general, the methods for accurate quantification rely on the use of authentic target compounds or isotope-labeled compounds as standards, which might be not available or difficult to synthesize. To tackle this grand challenge, this paper presents a novel approach, based on electrochemistry (EC) combined with mass spectrometry (MS). In this approach, a target compound is allowed to undergo electrochemical oxidation and then subject to MS analysis. The oxidation current recorded from electrochemistry (EC) measurement provides information about the amount of the oxidized analyte, based on the Faraday’s Law. On the other hand, the oxidation reaction yield can be determined from the analyte MS signal changes upon electrolysis. Therefore, the total amount of analyte can be determined. In combination with liquid chromatography (LC), the method can be applicable to mixture analysis. The striking strength of such a method for quantitation is that neither standard compound nor calibration curve is required. Various analyte molecules such as dopamine, norepinephrine, and rutin as well as peptide glutathione in low quantity were successfully quantified using our method with the quantification error ranging from ? 2.6 to +?4.6%. Analyte in a complicated matrix (e.g., uric acid in urine) was also accurately measured. [Figure not available: see fulltext.].
Xu, Chang,Zheng, Qiuling,Zhao, Pengyi,Paterson, Joseph,Chen, Hao
p. 685 - 693
(2019/05/08)

Similarities and differences in d6 low-spin ruthenium, rhodium and iridium half-sandwich complexes: synthesis, structure, cytotoxicity and interaction with biological targets
In this paper, we discussed the similarities and differences in d6 low-spin half-sandwich ruthenium, rhodium and iridium complexes containing 2,2′-biimidazole (H2biim). Three new complexes, {[RuCl(H2biim)(η6-p-cymene)]PF6}2·H2O (1), [(η5-Cp)RhCl(H2biim)]PF6 (2), and [(η5-Cp)IrCl(H2biim)]PF6 (3), were fully characterized by CHN, X-ray diffraction analysis, UV–Vis, FTIR, and 1H, 13C and 15N NMR spectroscopies. The complexes exhibit a typical pseudooctahedral piano-stool geometry, in which the aromatic arene ring (p-cymene or Cp) forms the seat, while the bidentate 2,2′-biimidazole and chloride ion form the three legs of the piano stool. Moreover, the cytotoxic activities of the compounds were examined in the LoVo, HL-60, MV-4-11, MCF-7 human cancer cell lines and BALB/3T3 normal mouse fibroblasts. Notably, the investigated complexes showed no cytotoxic effects towards the normal BALB/3T3 cell line compared to cisplatin, which has an IC50 value of 2.20?μg. Importantly, 1 displayed the highest activity against HL-60 (IC50 4.35?μg). To predict a binding mode, we explored the potential interactions of the metal complexes with CT-DNA and protein using UV absorption and circular dichroism. The obtained data suggest that the complexes could interact with CT-DNA via an outside binding mode. Moreover, binding of the complexes with the GSH via UV–Vis and ESI mass spectra was determined. Comparative studies have shown that the rhodium complex (2) is the most GSH reactive, which is probably responsible for its deactivation towards LoVo and MCF-7 tumour cells. The influence of the metal ion on the biological activity of isostructural Rh(III) and Ir(III) complexes was an important goal of the presented investigation.
Gilewska, Agnieszka,Barszcz, Barbara,Masternak, Joanna,Kazimierczuk, Katarzyna,Sitkowski, Jerzy,Wietrzyk, Joanna,Turlej, Eliza
p. 591 - 606
(2019/06/04)

Interaction of Glutathione with Hydrogen Peroxide: A Kinetic Model
Abstract: The kinetics of the interaction of glutathione (GSH) with hydrogen peroxide (H2O2) was studied. It was shown that the rate of GSH consumption nonlinearly depended on reactant concentrations and the process was accompanied by the appearance of radicals with a relatively low rate, which was a fraction of a percent of the rate of GSH consumption. Based on the experimental results and literature data on the reactions of GSH with H2O2 and thiyl radicals, a kinetic model of the complex interaction of GSH and H2O2 in an aqueous solution at 37°C was proposed. The model includes 15 quasi-elementary reactions with corresponding rate constants, including the formation of the intermediate complex GSH–H2O2 and its subsequent reactions with the formation of final products. Computer simulation based on the model developed satisfactorily described the reaction kinetics in a wide range of reactant concentrations.
Zinatullina,Kasaikina,Kuz’min,Khrameeva
p. 266 - 272
(2019/06/24)

The interaction of silver(II) complexes with biological macromolecules and antioxidants
Silver is widely used for its antimicrobial properties, but microbial resistance to heavy metals is increasing. Silver(II) compounds are more oxidizing and therefore have the potential to overcome resistance via extensive attack on cellular components, but have traditionally been hard to stabilize for biological applications. Here, the high oxidation state cation was stabilised using pyridinecarboxylate ligands, of which the 2,6-dicarboxypyridine Ag(II) complex (Ag2,6P) was found to have the best tractability. This complex was found to be more stable in phosphate buffer than DMSO, allowing studies of its interaction with water soluble antioxidants and biological macromolecules, with the aim of demonstrating its potential to oxidize them, as well as determining the reaction products. Spectrophotometric analysis showed that Ag2,6P was rapidly reduced by the antioxidants glutathione, ascorbic acid and vitamin E; the unsaturated lipids arachidonic and linoleic acids, model carbohydrate β-cyclodextrin, and protein cytochrome c also reacted readily. Analysis of the reaction with glutathione by NMR and electrospray mass spectrometry confirmed that the glutathione was oxidized to the disulfide form. Mass spectrometry also clearly showed the addition of multiple oxygen atoms to the unsaturated fatty acids, suggesting a radical mechanism, and cross-linking of linoleic acid was observed. The seven hydroxyl groups of β-cyclodextrin were found to be completely oxidized to the corresponding carboxylates. Treatment of cytochrome c with Ag2,6P led to protein aggregation and fragmentation, and dose-dependent oxidative damage was demonstrated by oxyblotting. Thus Ag2,6P was found to be highly oxidizing to a wide variety of polar and nonpolar biological molecules.
Trotter, Katherine D.,Owojaiye, Olawale,Meredith, Stuart P.,Keating, Pat E.,Spicer, Mark D.,Reglinski, John,Spickett, Corinne M.
p. 627 - 640
(2019/05/28)

Effect of phosphate buffer solutions on the reactions of glutathione with hydrogen peroxide and peroxyl radicals
Differences in the kinetics and mechanism of the reaction of glutathione (GSH) with hydrogen peroxide (H2O2) in deionized water and in phosphate buffer systems with pH ≥ 7 frequently used in biochemical studies were revealed. The formation of GSH dimers and complexes with H2O2 in water plays a substantial role in the kinetics of the process, which is manifested as nonlinear dependences of the rate of GSH consumption (WGSH) and the rate of radical formation (Wi) on the reagent concentrations. In phosphate buffer solutions (PBS), the oxidation of GSH by air oxygen is enhanced and the radical formation rate decreases sharply. An effect of NaCl and KCl in PBS on WGSH and Wi was observed, unlike a sodium—potassium phosphate buffer mixture (PB). Under other equivalent conditions, WGSH PBS is several times lower and Wi is higher than those in PB containing no chlorides. It was found that the rate of the thiol-ene reaction of unsaturated phenol resveratrol (RVT) with GSH initiated by the radicals formed in the presence of H2O2 in PBS is nearly three times lower than that in water, whereas in PB resveratrol is not consumed under the same conditions. However, in the reactions with peroxyl radicals formed upon the decomposition of 2,2′-azobis(2-methylpropionamidine) dihydrochloride the GSH consumption rate is the same in both phosphate buffer systems.
Zinatullina,Kasaikina,Kuzmin,Khrameeva,Pisarenko
p. 1441 - 1444
(2019/08/12)

Copper ion vs copper metal–organic framework catalyzed NO release from bioavailable S-Nitrosoglutathione en route to biomedical applications: Direct 1H NMR monitoring in water allowing identification of the distinct, true reaction stoichiometries and thiol dependencies
Copper containing compounds catalyze decomposition of S-Nitrosoglutathione (GSNO) in the presence of glutathione (GSH) yielding glutathione disulfide (GSSG) and nitric oxide (NO). Extended NO generation from an endogenous source is medically desirable to achieve vasodilation, reduction in biofilms on medical devices, and antibacterial activity. Homogeneous and heterogeneous copper species catalyze release of NO from endogenous GSNO. One heterogeneous catalyst used for GSNO decomposition in blood plasma is the metal-organic framework (MOF), H3[(Cu4Cl)3-(BTTri)8, H3BTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl) benzene] (CuBTTri). Fundamental questions about these systems remain unanswered, despite their use in biomedical applications, in part because no method previously existed for simultaneous tracking of [GSNO], [GSH], and [GSSG] in water. Tracking these reactions in water is a necessary step towards study in biological media (blood is approximately 80% water) where NO release systems must operate. Even the balanced stoichiometry remains unknown for copper-ion and CuBTTri catalyzed GSNO decomposition. Herein, we report a direct 1H NMR method which: simultaneously monitors [GSNO], [GSH], and [GSSG] in water; provides the experimentally determined stoichiometry for copper-ion vs CuBTTri catalyzed GSNO decomposition; reveals that the CuBTTri-catalyzed reaction reaches 10% GSNO decomposition (16 h) without added GSH, yet the copper-ion catalyzed reaction reaches 100% GSNO decomposition (16 h) without added GSH; and shows 100% GSNO decomposition upon addition of stoichiometric GSH to the CuBTTri catalyzed reaction. These observations provide evidence that copper-ion and CuBTTri catalyzed GSNO decomposition in water operate through different reaction mechanisms, the details of which can now be probed by 1H NMR kinetics and other needed studies.
Tuttle, Robert R.,Rubin, Heather N.,Rithner, Christopher D.,Finke, Richard G.,Reynolds, Melissa M.
(2019/07/31)

Synthesis and characterization of cobalt(III) complex of 1,5-bis(2-hydroxybenzamido)-3-aza pentane and its interaction with glutathione: A kinetic and spectrophotometric study
A new octahedral cobalt(III) complex of 1,5-bis(2-hydroxybenzamido)-3-aza pentane was synthesized and characterized by elemental analysis, UV-visible, IR, mass spectrometry and thermal analysis methods. Oxidative behaviour of the complex towards the physiologically abundant tripeptide, glutathione(GSH) was studied by UV-visible and FT-NMR techniques. Kinetics of electron transfer between the complex and GSH was studied at 25.0 ≤ t/°C ≤ 45.0, 0.025 ≤ [H+]/mol dm-3 ≤ 0.20 and I = 1.0 mol dm-3 (NaClO4). NMR spectra of the reaction mixture were taken as a function of time. Changes observed in the NMR-spectrum during the period of scanning are the initial disappearance of the fine structure and subsequent broadening of the signals of GSH protons. Peaks at (δ, ppm): 2.93 and 2.98, characteristics of Cys-CH2 δ protons in GSH get disappear slowly and new peaks develop at (δ, ppm): 3.33 and 3.38, corresponding to resonating frequencies of Cys-CH2 δ protons in GSSG. Likewise, the peak at (δ, ppm):2.93, characteristic of Cys-CH2 δ proton in GSH is replaced by the resurgence of two peaks at (δ, ppm): 4.3 and 4.1 ppm, commensurate with the resonating frequencies of same set of protons as that of GSH but in a dimeric environment. The time dependent NMR simulation of the reaction reveals that GSH reduces the CoIII moiety successfully, while it gets converted into the dimer, GSSG. The relatively fast transformation of GSH to GSSG as evident from both electronic spectra and NMR studies together with the activation parameters obtained from the temperature dependence of reaction rate suggest that there is no involvement of any bridging group for electron transfer and the redox process may be taking place via outer sphere mechanism.
Rudrarapu, Aravind,Brahma, Gouri Sankhar,Nayak, Suprava
p. 2022 - 2028
(2019/08/08)

Crystal-facet-dependent denitrosylation: Modulation of NO release from S-nitrosothiols by Cu2O polymorphs
Nitric oxide (NO), a gaseous small molecule generated by the nitric oxide synthase (NOS) enzymes, plays key roles in signal transduction. The thiol groups present in many proteins and small molecules undergo nitrosylation to form the corresponding S-nitrosothiols. The release of NO from S-nitrosothiols is a key strategy to maintain the NO levels in biological systems. However, the controlled release of NO from the nitrosylated compounds at physiological pH remains a challenge. In this paper, we describe the synthesis and NO releasing ability of Cu2O nanomaterials and provide the first experimental evidence that the nanocrystals having different crystal facets within the same crystal system exhibit different activities toward S-nitrosothiols. We used various imaging techniques and time-dependent spectroscopic measurements to understand the nature of catalytically active species involved in the surface reactions. The denitrosylation reactions by Cu2O can be carried out multiple times without affecting the catalytic activity.
Ghosh, Sourav,Roy, Punarbasu,Prasad, Sanjay,Mugesh, Govindasamy
p. 5308 - 5318
(2019/05/29)

Iterative synthetic strategies and gene deletant experiments enable the first identification of polysulfides in: Saccharomyces cerevisiae
New evidence on the role of H2S as a gasotransmitter suggests that the true signalling effectors are polysulfides. Both oxidized polysulfides and hydropolysulfides were synthesized and their presence in S. cerevisiae was observed for the first time. A single gene-deletant approach allowed observation of the modulation of polysulfide species and levels.
Pilkington, Lisa I.,Deed, Rebecca C.,Parish-Virtue, Katie,Huang, Chien-Wei,Walker, Michelle E.,Jiranek, Vladimir,Barker, David,Fedrizzi, Bruno
supporting information
p. 8868 - 8871
(2019/08/01)

Covalent inhibition of histone deacetylase 8 by 3,4-dihydro-2H-pyrimido[1,2-c][1,3]benzothiazin-6-imine
Background: HDAC8 is an established target for T-cell lymphoma and childhood neuroblastoma. Benzothiazine-imines are promising HDAC8 inhibitors with unknown binding mechanism lacking a usual zinc binding group. Methods: In this study high-resolution and quantitative HPLC-coupled ESI-MS/MS techniques are combined with crystal structure determination and a variety of biochemical and computational methods to elucidate the reaction mechanism between benzothiazine-imine 1 and HDAC8. Results: 1) 1 is a covalent inhibitor of HDAC8; 2) inhibition is reversible in the presence of reducing agents; 3) C153 in the active site and C102 are involved in the inhibition mechanism; 4) 1 modifies various cysteines in HDAC8 forming either thiocyanates or mixed disulfides with 3; 5) 1 and 5 dock in close proximity to C153 within the active site. This is supposed to accelerate covalent inactivation particularly in HDAC8 and suggested as major determinant for the observed nanomolar potency and selectivity of 1. Conclusions: 1 and its analogs are interesting model compounds but unsuitable for therapeutic treatment due to their high unselective reactivity towards thiol groups. However, the postulated preceding non-covalent binding mode of 1 opens a door to optimized next generation compounds that combine potent and selective non-covalent recognition with low reactivity towards C153 at the active site of HDAC8. General significance: 1 represents a completely new class of inhibitors for HDAC8. Initial non-covalent interaction at the bottom of the active site is suggested to be the key for its selectivity. Further optimization of non-covalent interaction and thiol-reactivity provides opportunities to develop therapeutic useful covalent HDAC8 inhibitors.
Muth, Marius,J?nsch, Niklas,Kopranovic, Aleksandra,Kr?mer, Andreas,W?ssner, Nathalie,Jung, Manfred,Kirschh?fer, Frank,Brenner-Wei?, Gerald,Meyer-Almes, Franz-Josef
p. 577 - 585
(2019/01/10)

An Organodiselenide with Dual Mimic Function of Sulfhydryl Oxidases and Glutathione Peroxidases: Aerial Oxidation of Organothiols to Organodisulfides
A novel organodiselenide, which mimics sulfhydryl oxidases and glutathione peroxidase (GPx) enzymes for oxidation of thiols by oxygen and hydrogen peroxide, respectively, into disulfides has been presented. The developed catalyst oxidizes an array of organothiols into respective disulfides in practical yields by using aerial O2 to avoid any reagents/additives, base, and light source. The synthesized diselenide also catalyzes the reduction of hydrogen peroxide into water by following the GPx enzymatic catalytic cycle with a reduction rate of 49.65 ± 3.7 μM·min-1.
Rathore, Vandana,Upadhyay, Aditya,Kumar, Sangit
supporting information
p. 6274 - 6278
(2018/10/05)

Novel functionalized organotellurides with enhanced thiol peroxidase catalytic activity
The thiol peroxidase-like activity of a series of novel functionalized tellurium containing catalysts has been investigated with different models. Dialkyl- and aryl-alkyl-tellurides, conveniently achieved through the ring opening of strained heterocycles, exhibited remarkable catalytic antioxidant activity, being able to reduce hydrogen peroxide in the presence of different thiols (benzenethiol, dithiothreitol and glutathione) under different conditions. The nature of the β-substituent strongly influenced the performances of the studied catalysts, thus giving useful criteria for the design of good synthetic mimics of glutathione peroxidase. The catalytic activity of functionalized organotellurides has been compared with that of their selenated analogues, showing as the latter behave as less efficient catalysts.
Tanini, Damiano,Grechi, Anna,Ricci, Lorenzo,Dei, Silvia,Teodori, Elisabetta,Capperucci, Antonella
p. 6077 - 6083
(2018/04/23)

Discovery and Optimization of Novel Hydrogen Peroxide Activated Aromatic Nitrogen Mustard Derivatives as Highly Potent Anticancer Agents
We describe several new aromatic nitrogen mustards with various aromatic substituents and boronic esters that can be activated with H2O2 to efficiently cross-link DNA. In vitro studies demonstrated the anticancer potential of these compounds at lower concentrations than those of other clinically used chemotherapeutics, such as melphalan and chlorambucil. In particular, compound 10, bearing an amino acid ester chain, is selectively cytotoxic toward breast cancer and leukemia cells that have inherently high levels of reactive oxygen species. Importantly, 10 was 10-14-fold more efficacious than melphalan and chlorambucil for triple-negative breast-cancer (TNBC) cells. Similarly, 10 is more toxic toward primary chronic-lymphocytic-leukemia cells than either chlorambucil or the lead compound, 9. The introduction of an amino acid side chain improved the solubility and permeability of 10. Furthermore, 10 inhibited the growth of TNBC tumors in xenografted mice without obvious signs of general toxicity, making this compound an ideal drug candidate for clinical development.
Chen, Wenbing,Fan, Heli,Balakrishnan, Kumudha,Wang, Yibin,Sun, Huabing,Fan, Yukai,Gandhi, Varsha,Arnold, Leggy A.,Peng, Xiaohua
p. 9132 - 9145
(2018/10/20)

Hydrophilic azaspiroalkenes as robust bioorthogonal reporters
Two hydrophilic spiroalkenes, azaspiro[2.3]hex-1-ene and azaspiro[2.4]hept-1-ene, were designed and synthesized. Compared to the previously reported spiro[2.3]hex-1-ene, the azaspiroalkenes exhibited greater water solubility and reactivity as dipolarophiles in the photoinduced tetrazole-alkene cycloaddition reaction. In addition, an azaspiro[2.3]hex-1-ene-containing amino acid, AsphK, was found to be charged by an engineered pyrrolysyl-tRNA synthetase into proteins via amber codon suppression in E. coli as well as in mammalian cells.
An, Peng,Wu, Hsuan-Yi,Lewandowski, Tracey M.,Lin, Qing
supporting information
p. 14005 - 14008
(2019/01/03)

Redox-regulated methionine oxidation of Arabidopsis thaliana glutathione transferase Phi9 induces H-site flexibility
Glutathione transferase enzymes help plants to cope with biotic and abiotic stress. They mainly catalyze the conjugation of glutathione (GSH) onto xenobiotics, and some act as glutathione peroxidase. With X-ray crystallography, kinetics, and thermodynamics, we studied the impact of oxidation on Arabidopsis thaliana glutathione transferase Phi 9 (GSTF9). GSTF9 has no cysteine in its sequence, and it adopts a universal GST structural fold characterized by a typical conserved GSH-binding site (G-site) and a hydrophobic co-substrate-binding site (H-site). At elevated H2O2 concentrations, methionine sulfur oxidation decreases its transferase activity. This oxidation increases the flexibility of the H-site loop, which is reflected in lower activities for hydrophobic substrates. Determination of the transition state thermodynamic parameters shows that upon oxidation an increased enthalpic penalty is counterbalanced by a more favorable entropic contribution. All in all, to guarantee functionality under oxidative stress conditions, GSTF9 employs a thermodynamic and structural compensatory mechanism and becomes substrate of methionine sulfoxide reductases, making it a redox-regulated enzyme.
Tossounian, Maria-Armineh,Wahni, Khadija,Van Molle, Inge,Vertommen, Didier,Astolfi Rosado, Leonardo,Messens, Joris
(2018/07/31)

Gold-Catalyzed C–S Aryl-Group Transfer in Zinc Finger Proteins
Reaction of the Au–C N chelate [Au(bnpy)Cl2] with the full-length zinc finger (ZnF; ZnCys3His) of HIV nucleocapsid protein NCp7 results in C–S aryl transfer from the AuIII organometallic species to a cysteine of the ZnF. T
de Paiva, Raphael E. F.,Du, Zhifeng,Nakahata, Douglas H.,Lima, Frederico A.,Corbi, Pedro P.,Farrell, Nicholas P.
supporting information
p. 9305 - 9309
(2018/07/25)

Dialkyl Dicyanofumarates as Oxidizing Reagents for the Conversion of Thiols into Disulfides and Selenols into Diselenides
Aliphatic and aromatic thiols react smoothly with dialkyl dicyanofumarates in CH2Cl2 at room temperature to give the corresponding disulfides in excellent yields. Aliphatic 1,2-, 1,3-, and 1,4-dithiols afford cyclic disulfides. Analogous reaction courses were observed for selenols, and the required diselenides also formed in nearly quantitative yields. In all of the reactions, dialkyl dicyanosuccinates formed as 1:1 mixtures of diastereoisomers as the only other product. Cysteamine (2-mercaptoethylamine) behaved differently; the Michael addition of the primary amine group led to the complete consumption of the dicyanofumarate, and the formation of the disulfide containing an enamine moiety occurred without the formation of dicyanosuccinate.
Mlostoń, Grzegorz,Capperucci, Antonella,Tanini, Damiano,Hamera-Fa?dyga, Ró?a,Heimgartner, Heinz
p. 6831 - 6839
(2017/09/11)

Kinetic characteristics of the reaction of resveratrol with peroxyl radicals and natural thiols in aqueous medium
The method of competing reactions was used to determine the rate constants of the reaction of resveratrol (RVT) with peroxyl radicals formed on decomposition of the azoinitiator in aqueous solutions at 37 °С. The polymethine dye A (3,3′-di-γ-sulfopropyl-9-metylthiacarbocyanine-betaine pyridinium salt) was used as a competing acceptor of radicals. It was found that resveratrol can be involved in the reaction with natural thiols, glutathione (GSH) and cysteine (CSH), in aqueous solutions at 37 °С. The reaction of RVT with thiols (thiol—еne reaction) follows a chain mechanism and accelerates in the presence of Н2О2. The results obtained can be useful for understanding the physiological role of thiols in oxidation processes.
Zinatullina,Khrameeva,Kasaikina,Shapiro,Kuzmin
p. 2145 - 2151
(2018/03/22)

Chlorambucil conjugates of dinuclear p-cymene ruthenium trithiolato complexes: synthesis, characterization and cytotoxicity study in vitro and in vivo
Abstract: Four diruthenium trithiolato chlorambucil conjugates have been prepared via Steglich esterification from chlorambucil and the corresponding trithiolato precursors. All conjugates are highly cytotoxic towards human ovarian A2780 and A2780cisR cancer cell lines with IC50 values in the nanomolar range. The conjugates exhibit selectivity towards A2780 cells as compared to non-cancerous HEK293 cells, while being only slightly selective for RF24 and A2780cisR cells. In vivo, the conjugate [10]BF4 suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival. The reactivity of the chlorambucil conjugates with glutathione, a potential target of the dinuclear ruthenium motive, and with the 2-deoxyguanosine 5′-monophosphate (dGMP—a model target of chlorambucil) was studied by mass spectrometry and NMR spectroscopy. The conjugates did not show catalytic activity for the oxidation of glutathione nor binding to nucleotides, indicating that glutathione oxidation and DNA alkylation are not key mechanisms of action. Graphical abstract: Four highly cytotoxic diruthenium trithiolato chlorambucil conjugates have been prepared. All conjugates exhibit selectivity towards A2780 cells as compared to HEK293 cells, while being only slightly active in RF24 and A2780cisR cells. In vivo, the best candidate suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival.[Figure not available: see fulltext.]
Stíbal, David,Therrien, Bruno,Süss-Fink, Georg,Nowak-Sliwinska, Patrycja,Dyson, Paul J.,?ermáková, Eva,?ezá?ová, Martina,Tom?ík, Pavel
p. 443 - 452
(2016/07/06)

Enhanced Glutathione Peroxidase Activity of Water-Soluble and Polyethylene Glycol-Supported Selenides, Related Spirodioxyselenuranes, and Pincer Selenuranes
Diaryl selenides containing o-hydroxymethylene substituents function as peroxide-destroying mimetics of the antioxidant selenoenzyme glutathione peroxidase (GPx), via oxidation to the corresponding spirodioxyselenuranes with hydrogen peroxide and subsequent reduction back to the original selenides with glutathione. Parent selenides with 3-hydroxypropyl or 2,3-dihydroxypropyl groups produced the novel compounds 10 and 11, respectively, with greatly improved aqueous solubility and catalytic activity. The phenolic derivative 28 displayed similarly ameliorated properties and also modest radical-inhibiting antioxidant activity, as evidenced by an assay based on phenolic hydrogen atom transfer to the stable free radical DPPH. In contrast, several selenides that afford pincer selenuranes (e.g., 20 and 21) instead of spiroselenuranes upon oxidation showed inferior catalytic activity. Several selenide analogues were attached to polyethylene glycol (PEG) oligomers, as PEG substituents can improve water solubility and bioavailability, while retarding clearance. Again, the PEG derivatives afforded remarkable activity when oxidation generated spirodioxyselenuranes and diminished activity when pincer compounds were produced. Several such compounds proved to be ca. 10- to 100-fold catalytically superior to the diaryl selenides and their spirodioxyselenurane counterparts investigated previously. Finally, an NMR-based assay employing glutathione in D2O was designed to accommodate the faster reacting water-soluble mimetics and to more closely duplicate in vivo conditions.
McNeil, Nicole M. R.,Press, David J.,Mayder, Don M.,Garnica, Pablo,Doyle, Lisa M.,Back, Thomas G.
p. 7884 - 7897
(2016/10/03)

Kiteplatin: Differential binding between GSH and GMP
Glutathione (GSH) plays an important role in the development of resistance to platinum-based chemotherapy, since it can prevent drug binding to DNA and resulting apoptosis of tumor cells. The recently re-discovered drug candidate kiteplatin was found active toward cisplatin- and oxaliplatin-resistant tumor cells, and this could be related to a different interplay of drug-inactivation/DNA-interaction processes. In this study GSH and GMP have been chosen as simple models of platinophiles and DNA, respectively, and the reactivity of kiteplatin has been tested toward GMP, after previous interaction with GSH; toward GSH, after previous interaction with GMP; and toward GMP and GSH simultaneously.
Petruzzella, Emanuele,Curci, Alessandra,Margiotta, Nicola,Natile, Giovanni,Hoeschele, James D.
supporting information
p. 130 - 136
(2016/10/04)

Oxidation of thiols to disulfides by dioxygen catalyzed by a bioinspired organocatalyst
2,3-Dihydro-2,2,2-triphenylphenanthro[9,10-d]-1,3,2-λ5-oxazaphosphole serves as good catalyst for the oxidation of thiophenol, cysteine and glutathione to their disulfides by molecular oxygen. The kinetics of the reactions unveiled an overall second order rate equation for all reactions and pure dioxygen chemistry for all three substrates. The formation of an unstable hydroperoxide from the catalyst is assumed to be a key step during the reaction.
Bagi, Nárcisz,Kaizer, József,Speier, Gábor
p. 45983 - 45986
(2015/06/08)

A SERS study of oxidation of glutathione under plasma irradiation
This paper reports a new application of surface enhanced Raman scattering (SERS) in analysis of oxidation of glutathione (GSH) to oxidized glutathione (GSSG), an important biochemical redox reaction in biological systems, under oxidative stress imposed by dielectric barrier discharge (DBD). Using the silver nanoparticles (NPs) prepared through the reduction of AgNO3 by beta-cyclodextrin (β-CD), the transformation of GSH to GSSG under DBD irradiation can be probed with only a small quantity of sample at low concentration. Based on the intensity ratio of two characteristic Raman bands, i.e., the band at 1051 cm-1 (C-N stretching) and the band at 509 cm-1 (S-S stretching), which stem respectively from GSH and GSSG, the conversion between the reduced and oxidized glutathione can be determined quantitatively. This work demonstrates another useful extension of the SERS technique applied to bioscience research, i.e., rapid probing and quantitative assessing of chemical reactions of biomolecules under oxidative stress conditions.
Ma, Shanshan,Huang, Qing
p. 57847 - 57852
(2015/07/20)

A novel gold nanoparticle decorated nanocrystalline zeolite based electrochemical sensor for the nanomolar simultaneous detection of cysteine and glutathione
In this work, highly dispersed gold nanoparticle decorated nanocrystalline zeolite was synthesized by the electrostatic interaction between the functionalized gold nanoparticles and functionalized nanocrystalline zeolite. An electrochemical sensor based on the gold nanoparticle decorated nanocrystalline zeolite was developed for the nanomolar simultaneous detection of cysteine and glutathione with high sensitivity, selectivity, and remarkably low detection limit. A wide linear range was obtained from 2 nM to 800 μM and 3 nM to 800 μM with a limit of detection of 0.3 nM and 0.6 nM for cysteine and glutathione, respectively. The analytical performance of the developed sensor was demonstrated in the determination of cysteine and glutathione in commercial pharmaceutical preparations with satisfactory results even in the presence of several amino acids. The proposed methodology provides promising application in clinical diagnostic and drug analysis.
Kaur, Balwinder,Srivastava, Rajendra,Satpati, Biswarup
p. 95028 - 95037
(2015/11/24)

Diallyl Trisulfide Is a Fast H2S Donor, but Diallyl Disulfide Is a Slow One: The Reaction Pathways and Intermediates of Glutathione with Polysulfides
Diallyl trisulfide (DATS) reacts rapidly with glutathione (GSH) to release H2S through thiol-disulfide exchange followed by allyl perthiol reduction by GSH. Yet diallyl disulfide (DADS) only releases a minute amount of H2S via a sluggish reaction with GSH through an α-carbon nucleophilic substitution pathway. The results clarify the misunderstanding of DADS as a rapid H2S donor, which is attributed to its DATS impurity.
Liang, Dong,Wu, Haixia,Wong, Ming Wah,Huang, Dejian
supporting information
p. 4196 - 4199
(2015/09/15)

Uncatalyzed and copper(II) catalyzed oxidation of glutathione by Co(III)2 bound superoxide complex
In acid media, glutathione (GSH) is oxidised by metal bound superoxo complex, [(NH3)5Co(III)(μ-O2)Co(III)(NH 3)5]5+ (1) to GSSG. Complex 1 is reduced to its corresponding peroxo complex, [(NH3)5Co(III)(μ-O 2)Co(III)(NH3)5]4+ (2) which readily decomposes in acid media to Co(III), NH4+ and O 2. The oxidation of GSH is profoundly catalyzed by the presence of Cu2+ ion. The observed rate constant ko was found to be proportional to [GSH]2 for both uncatalyzed and catalyzed reaction and for the latter ko was also proportional to [Cu]T 2 ([Cu]T is the analytical concentration of Cu 2+). The rate for uncatalyzed reaction decreases for with increasing ionic strength (I) of the reaction media whereas, ko for catalyzed reaction is invariant of ionic strength (I). Both for the uncatalyzed and catalyzed reaction, ko is proportional to [H+] -3. Under the reaction condition employed, it has been seen that GSH reduces Cu(II) to Cu(I) and forms either mononuclear Cu(I)-GSH or dinuclear (Cu(I)-GSH)2 complex with Cu(I) with a 1:1 composition. Suitable mechanistic pathways for the uncatalyzed and catalyzed reactions through the intermediate formation of mononuclear or dinuclear Cu-GSH complex have been suggested. The activation energy for the uncatalyzed and catalyzed reaction has been calculated as 97.1 ± 5.7 and 29.9 ± 1.2 kJ M-1 respectively.
Singh, Bula,Das, Ranendu Sekhar,Banerjee, Rupendranath,Mukhopadhyay, Subrata
p. 51 - 58
(2014/06/09)

Amino acid and water-driven tunable green protocol to access S-S/C-S bonds via aerobic oxidative coupling and hydrothiolation
A green methodology utilizing a natural supplement such as l-arginine in conjunction with water and oxygen led to oxidative coupling of thiols into disulfides (S-S bond) whereas thiol-yne coupling to access vinyl sulfides (C-S bond) was facilitated in a nitrogen atmosphere. The tunable protocol offers several advantages such as low catalyst loading, high yields, clean reaction, no over-oxidation of the S-S bond besides being metal/base/waste-free. The synthesis of ubiquitous cystine and glutathione disulfide in the same catalytic system is an added advantage and the catalytic system has been recycled up to seven times. the Partner Organisations 2014.
Shard, Amit,Kumar, Rajesh,Saima,Sharma, Nidhi,Sinha, Arun K.
p. 33399 - 33407
(2014/08/18)

Adsorption, photodegradation and antibacterial study of graphene-Fe 3O4 nanocomposite for multipurpose water purification application
Graphene-Fe3O4 (G-Fe3O4) composite was prepared from graphene oxide (GO) and FeCl3· 6H2O by a one-step solvothermal route. The as-prepared composite was characterized by field-emission scanning electron microscopy, transmission electron microscopy, dynamic light scattering and X-ray powder diffraction. SEM analysis shows the presence of Fe3O4 spheres with size ranging between 200 and 250 nm, which are distributed and firmly anchored onto the wrinkled graphene layers with a high density. The resulting G-Fe 3O4 composite shows extraordinary adsorption capacity and fast adsorption rates for the removal of Pb metal ions and organic dyes from aqueous solution. The adsorption isotherm and thermodynamics were investigated in detail, and the results show that the adsorption data was best fitted with the Langmuir adsorption isotherm model. From the thermodynamics investigation, it was found that the adsorption process is spontaneous and endothermic in nature. Thus, the as-prepared composite can be effectively utilized for the removal of various heavy metal ions and organic dyes. Simultaneously, the photodegradation of methylene blue was studied, and the recycling degradation capacity of dye by G-Fe3O4 was analyzed up to 5 cycles, which remained consistent up to ～97% degradation of the methylene blue dye. Although iron oxide has an affinity towards bacterial cells, its composite with graphene still show antibacterial property. Almost 99.56% cells were viable when treated with Fe3O4 nanoparticle, whereas with the composite barely 3% cells survived. Later, the release of ROS was also investigated by membrane and oxidative stress assay. Total protein degradation was analyzed to confirm the effect of the G-Fe3O4 composite on E. coli cells.
Santhosh, Chella,Kollu, Pratap,Doshi, Sejal,Sharma, Madhulika,Bahadur, Dhirendra,Vanchinathan, Mudaliar T.,Saravanan,Kim, Byeong-Su,Grace, Andrews Nirmala
p. 28300 - 28308
(2014/07/22)

Monothiolato-bridged dinuclear arene ruthenium complexes: The missing link in the reaction of arene ruthenium dichloride dimers with thiols
The monothiolato complexes [(η6-p-MeC6H4iPr)2Ru2Cl2(μ-Cl)(μ-SR)] with R = CH2C6H5 (1), p-CH2C6H4NO2 (2), C10H15 (3), m-9-B10C2H11 (4) were synthesized by treating [(η6-p-MeC6H4iPr)2Ru2Cl2(μ-Cl)2] with the corresponding thiols RSH. The reaction of p-cymene ruthenium dichloride dimer with thiols is well known to give the cationic trithiolato complexes [(η6-p-MeC6H4iPr)2Ru2(μ-SR)3]+, but recently the intermediary dithiolato complexes [(η6-p-MeC6H4iPr)2Ru2Cl2(μ-SR)2] could also be isolated and characterized in some cases. The monothiolato complexes 1-4 now observed represent the missing link in the stepwise formation of the trithiolato complexes. The single-crystal X-ray structure analyses of complexes 1 and 2 show the two ruthenium atoms to be bridged by a chlorido ligand and by the thiolato ligand without a metal-metal bond, which is in accordance with the eighteen-electron rule.
Stíbal, David,Therrien, Bruno,Giannini, Federico,Paul, Lydia E. H.,Furrer, Julien,Süss-Fink, Georg
p. 5925 - 5931
(2015/02/02)

Study on the intermediate ions formed by glutathione peroxidase mimic 2,2'-ditellurobis(2-deoxy-β-cyclodextrin) by electrospray ionization mass spectrometry
RATIONALE 2,2'-Ditellurobis(2-deoxy-β-cyclodextrin) (2-TeCD) is one of the most well-known glutathione peroxidase (GPx) mimics. However, because the critical reaction intermediates had not previously been isolated or directly detected due to its short lifetime, the catalytic mechanism of 2-TeCD is not very clear and further experiments are needed to characterize each of the intermediates in the catalytic cycle. METHODS Using electrospray ionization mass (and tandem) spectrometry (ESI-MS and ESI-MS/MS) experiments, the decomposition of hydrogen peroxide at the expense of glutathione (GSH) catalyzed by 2-TeCD was monitored on-line. RESULTS The key intermediates were successfully intercepted and structurally characterized for the first time by coupling a microreactor on-line to the ESI ion source, which permitted the fast screening of intermediates directly from solution. CONCLUSIONS The catalytic mechanism of 2-TeCD catalysis has been elaborated based on mass spectrometric data and exerted its peroxidase activity via tellurol, tellurenic acid, and tellurosulfide, in analogy with natural GPX. Copyright
Jiao, Aiquan,Yang, Na,Xu, Xueming,Jin, Zhengyu
p. 319 - 324
(2013/02/22)

Turning pyridoxine into a catalytic chain-breaking and hydroperoxide- decomposing antioxidant
Vitamin B6 is involved in a variety of enzymatic transformations. Some recent findings also indicate an antioxidant role of the vitamin in biological systems. We set out to turn pyridoxine (1a) into a catalytic chain-breaking and hydroperoxide-decomposing antioxidant by replacing the 2-methyl substituent with an alkyltelluro group. Target molecules 12 and derivatives 14, 17, 18, and 20 thereof were accessed by subjecting suitably substituted 2-halopyridin-3-ols to aromatic substitution using sodium alkanetellurolates as nucleophiles and then LAH-reduction of ester groups. The novel pyridoxine compounds were found to inhibit azo-initiated peroxidation of linoleic acid an order of magnitude more efficiently than α-tocopherol in a water/chlorobenzene two-phase system containing N-acetylcysteine as a reducing agent in the aqueous phase. The most lipid-soluble pyridoxine derivative 20c was regenerable and could inhibit peroxidation for substantially longer time (>410 min) than α-tocopherol (87 min). The chalcogen-containing pyridoxines could also mimic the action of the glutathione peroxidase enzymes. Thus, compound 20a catalyzed reduction of hydrogen peroxide three times more efficiently than Ebselen in the presence of glutathione as a stoichiometric reducing agent.
Singh, Vijay P.,Poon, Jia-Fei,Engman, Lars
p. 1478 - 1487
(2013/04/10)