- Nanocrystalline TiO2-catalyzed photoreversible color switching
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We report a novel photoreversible color switching system based on the photocatalytic activity of TiO2 nanocrystals and the redox-driven color switching property of methylene blue (MB). This system rapidly changes from blue to colorless under UV irradiation and recovers its original blue color under visible light irradiation. We have identified four major competing reactions that contribute to the photoreversible switching, among which two are dominant: the decoloration process is mainly driven by the reduction of MB to leuco MB by photogenerated electrons from TiO2 nanocrystals under UV irradiation, and the recoloration process operates by the TiO 2-induced self-catalyzed oxidation of LMB under visible irradiation. Compared with the conventional color switching systems based on photoisomerization of chromophores, our system has not only low toxicity but also significantly improved switching rate and cycling performance. It is envisioned that this photoreversible system may promise unique opportunities for many light-driven actuating or color switching applications.
- Wang, Wenshou,Ye, Miaomiao,He, Le,Yin, Yadong
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Read Online
- AND molecular logic gates based on host-guest complexation operational in live cells
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We report supramolecular AND logic gates based on host-guest complexation between acid-labile acyclic cucurbit[n]uril (CB[n]) molecular container and NaClO-responsive dye. Supramolecular AND logic gate is turned on due to acid-triggered degradation of mol
- Jiang, Siyang,Mao, Weipeng,Mao, Dake,Li, Zhan-Ting,Ma, Da
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p. 881 - 884
(2021/08/25)
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- Hypochlorous Acid Activating MB-O to Release Methylene Blue for Photodegrading of Aβ Aggregates
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Amyloid-β (Aβ) aggregates are one of biomarkers of Alzheimer's disease (AD). It is well known that Aβ aggregates display neurotoxicty or cytotoxicity to neurons. Thus, degrading Aβ aggregates is crucial for exploring the treatment of AD. Moreover, the excessive production of HOCl in the AD brain is an important feature of the disease. Herein, a novel compound MB-O based on methylene blue (MB) skeleton was designed and synthesized. The probe MB-O can specifically react with HOCl, releasing the fluorophore MB with strong fluorescence intensity increase. More importantly, the released MB is capable of degrading Aβ aggregates under red light irradiation.
- Bao, Xinlu,Yao, Yusi,Xu, Yunze,Shen, Yang,Lv, Guanglei,Zhao, Dian,Li, Chunxia
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p. 1992 - 1996
(2021/09/25)
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- A PROCESS FOR THE PREPARATION OF METHYLENE BLUE
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Provided herein is a process for preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride: Formula (I). The said process comprises preparing 3,7-dibromophenothiazin-5-ium bromide wet Crude(III) from phenothiazine (II) along promoter, catalyst and brominating agent in presence of organic solvent; preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) from 3,7-dibromophenothiazin-5-ium bromide; preparing 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride from 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide and subsequently purifying and removing metal content through metal scavenger from 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I). The present process eliminates the additional step of ion exchange column in the reaction and provides 99 to 99.5 percentage of product purity.
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Page/Page column 10
(2021/09/04)
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- Selective Imaging of HClO in the Liver Tissue In Vivo Using a Near-infrared Hepatocyte-specific Fluorescent Probe
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Liver injury is typified by an inflammatory response. Hypochlorous acid (HClO), an important endogenous reactive oxygen species, is regarded as a biomarker associated with liver injury. Near-infrared (NIR) fluorescent probes with the advantage of deep tissue penetrating and low auto-fluorescence interference are more suitable for bioimaging in vivo. Thus, in this work, we designed and synthesized a novel NIR hepatocyte-specific fluorescent probe named NHF. The probe NHF showed fast response (3 s), large spectral variation, and good selectivity to trace HClO in buffer solution. By employing N-acetylgalactosamine (GalNAc) as the targeting ligand, probe NHF can be actively delivered to the liver tissue of zebrafish and mice. It is important that probe NHF is the first NIR hepatocyte-specific fluorescent probe, which successfully visualized the up-regulation of endogenous HClO in the oxygen-glucose deprivation/reperfusion (OGD/R) model HepG2 cells and dynamically monitored APAP-induced endogenous HClO in the liver tissue of zebrafish and mice.
- Jia, Xu,Wei, Chao,Li, Zimeng,Liu, Liyan,Wang, Mei,Zhang, Pingzhu,Li, Xiaoliu
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p. 1967 - 1972
(2021/06/14)
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- NOVEL IMPROVED METHOD FOR SYNTHESIZING DIAMINOPHENOTHIAZINE COMPOUNDS
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The present invention relates to chemical synthesis and purification. Specifically, the present invention relates to a novel and improved method of synthesizing high purity diaminophenothiazine compounds of Formula I, specifically Methylene Blue and its pharmaceutically acceptable salt or hydrates thereof. The present invention relates to an improved method of synthesizing Methylene Blue compound of higher purities than those achievable by using known methods of synthesis as per the requirements of the international pharmacopoeias like USP and EP.
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Paragraph 00214-00223
(2020/12/30)
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- METHOD FOR PREPARING 3,7-BIS(DIMETHYLAMINO)PHENOTHIAZIN-5-YLIUM IODIDE
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Method for preparing 3,7-bis(dimethylamino)phenothiazin-5-ylium iodide, the method resulting in a high purity while being very simple to implement and producing high yields. The method uses phenothiazine as a starting material and includes the following steps: a) treating phenothiazine with diiodine, b) treating the reaction medium directly obtained from step a) with dimethylamine.
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- Peroxynitrite near infrared fluorescent probe ONP and preparation method and application thereof
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The invention discloses a peroxynitrite near infrared fluorescent probe ONP and a preparation method and an application thereof. The near infrared fluorescent probe ONP is obtained by combining boratewith a methylene blue framework. The structure is as sh
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Paragraph 0071-0073
(2019/07/08)
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- A preparation method of methylene blue
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The invention discloses a preparation method of methylene blue, and belongs to the technical field of intermediate synthesis in fine chemical engineering. The preparation method comprises the following steps: in a condensed hydrochloric acid solution, carrying out nitrosation reactions between sodium nitrite and N,N-dimethylaniline so as to obtain an intermediate namely p-nitroso-N,N-dimethylaniline; subjecting p-nitroso-N,N-dimethylaniline to hydrogenation reduction to prepare p-amino-N,N-dimethylaniline; oxidizing p-amino-N,N-dimethylaniline, then adding sodium thiosulfate to carry out addition reactions to prepare 2-amino-5-dimethylaminophenyl thiosulfonic acid, adding N,N-dimethylaniline into 2-amino-5-dimethylaminophenyl thiosulfonic acid to carry out oxidative condensation reactions to generate bis(4-dimethylaminophenyl) thiosulfonic acid; and making bis(4-dimethylaminophenyl) thiosulfonic acid carry out ring-closing reactions to obtain methylene blue. The provided preparation method has the advantages of high product purity, simple technology flow, low manufacture cost, suitability for industrial production, easily-available raw materials, and little pollution to the environment.
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- SYNTHESIS OF A THIOSULFONIC ACID BY A STEP OF PERIODATE MEDIATED OXIDATIVE COUPLING OF A THIOSULFONIC ACID WITH AN ANILINE
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The present invention pertains generally to the field of chemical synthesis, and more particularly to methods for the chemical synthesis of a thiosulfonic acid of Formula (1) by a step of periodate mediated oxidative coupling of a thiosulfonic acid of For
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- Deformylation reaction-based probe for: In vivo imaging of HOCl
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The detection of hypochlorous acid (HOCl) in vivo is vitally important because the local concentration of HOCl is highly correlated with some diseases such as atherosclerosis and rheumatoid arthritis. However, in vivo detection of HOCl remains a challenge due to the lack of a suitable probe. We report here a near-infrared (NIR) emissive "turn-on" probe (FDOCl-1) based on a methylene blue derivative, which can quickly detect HOCl via a newly found deformylation mechanism. FDOCl-1 displays remarkable selectivity and sensitivity towards HOCl. The dramatic changes in colour and NIR emission were used to detect HOCl in vitro and in vivo in a mouse arthritis model.
- Wei, Peng,Yuan, Wei,Xue, Fengfeng,Zhou, Wei,Li, Ruohan,Zhang, Datong,Yi, Tao
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p. 495 - 501
(2018/01/11)
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- METHOD FOR PREPARATION OF 3,7-BIS-(DIMETHYLAMINO)-PHENOTHIAZIN-5-IUM CHLORIDE OR BROMIDE
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The present invention relates to: a process for preparing 3,7-bis-(dimethylamino)-phenothiazin-5- ium bromide or chloride; a method of converting 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide to 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride; and the purification of 7-bis- (dimethylamino)-phenothiazin-5-ium chloride by crystallization from aqueous solution of hydrochloric acid, leading to a pharmaceutically acceptable 3,7-bis-(dimethylamino)-phenothiazin- 5-ium chloride (methylthioninium chloride, methylene blue, MTC) of formula I below reported.
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Page/Page column 20
(2018/10/19)
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- Coenzyme M biosynthesis in bacteria involves phosphate elimination by a functionally distinct member of the aspartase/fumarase superfamily
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For nearly 30 years, coenzyme M (CoM) was assumed to be present solely in methanogenic archaea. In the late 1990s, CoM was reported to play a role in bacterial propene metabolism, but no biosynthetic pathway for CoM has yet been identified in bacteria. Here, using bioinformatics and proteomic approaches in the metabolically versatile bacterium Xanthobacter autotrophicus Py2, we identified four putative CoM biosynthetic enzymes encoded by the xcbB1, C1, D1, and E1 genes. Only XcbB1 was homologous to a known CoM biosynthetic enzyme (ComA), indicating that CoM biosynthesis in bacteria involves enzymes different from those in archaea. We verified that the ComA homolog produces phosphosulfolactate from phosphoenolpyruvate (PEP), demonstrating that bacterial CoM biosynthesis is initiated similarly as the phosphoenolpyruvate-dependent methanogenic archaeal pathway. The bioinformatics analysis revealed that XcbC1 and D1 are members of the aspartase/ fumarase superfamily (AFS) and that XcbE1 is a pyridoxal 5-phosphate– containing enzyme with homology to D-cysteine desulfhydrases. Known AFS members catalyze -elimination reactions of succinyl-containing substrates, yielding fumarate as the common unsaturated elimination product. Unexpectedly, we found that XcbC1 catalyzes -elimination on phosphosulfolactate, yielding inorganic phosphate and a novel metabolite, sulfoacrylic acid. Phosphate-releasing -elimination reactions are unprecedented among the AFS, indicating that XcbC1 is an unusual phosphatase. Direct demonstration of phosphosulfolactate synthase activity for XcbB1 and phosphate -elimination activity for XcbC1 strengthened their hypothetical assignment to a CoM biosynthetic pathway and suggested functions also for XcbD1 and E1. Our results represent a critical first step toward elucidating the CoM pathway in bacteria.
- Partovi, Sarah E.,Mus, Florence,Gutknecht, Andrew E.,Martinez, Hunter A.,Tripet, Brian P.,Lange, Bernd Markus,DuBois, Jennifer L.,Peters, John W.
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p. 5236 - 5246
(2018/04/12)
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- PROCESS FOR THE PREPARATION OF DIAMINOPHENOTHIAZINIUM COMPOUNDS HAVING A HIGH DEGREE OF PURITY
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A process for the preparation of diaminophenothiazinium compounds is described, which allows achieving quickly and effectively a high degree of purity of the same.
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Page/Page column 11
(2017/12/15)
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- Triggered and Tunable Hydrogen Sulfide Release from Photogenerated Thiobenzaldehydes
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Hydrogen sulfide (H2S) has been identified as an important cell-signaling mediator and has a number of biological functions, such as vascular smooth muscle relaxation, neurotransmission, and regulation of inflammation. A facile and versatile approach for H2S production initiated by light irradiation and controlled by reaction with an amine or an amino acid was developed. The donor was synthesized in a one-pot reaction, and simple crystallization led to a yield of approximately 90 %. The synthetic strategy is scalable and versatile, and the H2S donors can be expressed ina number of different molecular and macromolecular forms, including crystalline small-molecule compounds, water-soluble polymers, polystyrene films, and hydrogels. The H2S donors based on polystyrene film and hydrogel were used as cell-culture scaffolds. The H2S donor based on water-soluble polymer was applied in photocontrolled inhibition of P-selectin expression on human platelets and subsequent regulation of platelet aggregation. This study provides the simplest controllable H2S source to study its biological functions. The developed materials are also new therapeutic platforms to deliver H2S, as there is no accumulation of toxic byproducts, and the donor materials from polystyrene films and hydrogels can be readily removed after releasing H2S.
- Xiao, Zeyun,Bonnard, Thomas,Shakouri-Motlagh, Aida,Wylie, Ross A. L.,Collins, Joe,White, Jonathan,Heath, Daniel E.,Hagemeyer, Christoph E.,Connal, Luke A.
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supporting information
p. 11294 - 11300
(2017/08/26)
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- METHODS OF CHEMICAL SYNTHESIS OF SUBSTITUTED 10H-PHENOTHIAZINE-3,7-DIAMINE COMPOUNDS
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The present invention pertains generally to the field of chemical synthesis, and more particularly to methods of chemical synthesis which include the step of preparing a substituted 10H-phenothiazine-3,7-diamine compound of Formula (1) by a step of selective alkylation by reductive amination, in which the corresponding unsubstituted diamine of Formula (4) is reacted with aldehyde/ketone, under reductive amination conditions. The present invention also relates to such methods which incorporate additional subsequent and/or preceding steps, for example, to prepare compounds of Formulae (2) and (3) from compounds of Formula (1), and to prepare compounds of Formula (4) from, for example, compounds of Formulae (5), (6), (7), (8), and (9). Compounds of Formula (1), Formula (2), and Formula (3) are useful, for example, in the treatment of diseases of protein aggregation, such as Alzheimer's disease.
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Page/Page column 106-109
(2017/02/09)
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- A process for the preparation of methylene blue (by machine translation)
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The present invention provides a method for preparing methylene blue, belongs to the fine the technical field of chemical synthesis. This invention, in order to the para-nitroaniline and nitrobenzene in the presence of a base to obtain the aromatic nucleo
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Paragraph 0034; 0044; 0051; 0052
(2016/12/07)
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- One step synthesis of silane-capped copper clusters as a sensitive optical probe and efficient catalyst for reversible color switching
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Discrete electron energy levels emerge in ultra small metal clusters due to a strong quantum confinement effect, resulting in some intriguing, unique and superior features such as photoluminescence and catalytic activity. In the present work, silane-capped copper clusters were synthesized by a facile one-pot synthetic protocol for the first time. Electrospray ionization mass spectrometry data shows that the metal core of the cluster is mainly composed of 4-5 copper atoms, and the results of X-ray photoelectron spectroscopy and Fourier-transform infrared spectroscopy indicate that the surface of the as-synthesized copper clusters is capped by a silane stabilizer. These few-atom copper clusters exhibit a dual-peak fluorescence feature, giving emission bands centered at 410 nm and 580 nm, respectively. In addition, the copper clusters also show excellent performance in chemo-sensing of hydrogen peroxide, linearly responding in a concentration range of 5-250 μM. More interestingly, a photo-reversible color switching system based on the redox reaction of methylene blue was built up by employing these Cu clusters as a catalyst. Reduction of methylene blue by Cu clusters' chemo-catalysis at ambient conditions and oxidation of leucomethylene blue by those clusters' photocatalysis under UV light irradiation lead to a recyclable colorless-blue switching effect within ~3 minutes. The present work proves that the versatile silane-capped Cu clusters possess both molecular and semiconductor like properties, holding great promise in optical and catalytic application fields.
- Zhou, Shaochen,Li, Yingxuan,Wang, Fu,Wang, Chuanyi
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p. 38897 - 38905
(2016/06/06)
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- METHODS OF CHEMICAL SYNTHESIS OF DIAMINOPHENOTHIAZINIUM COMPOUNDS INCLUDING METHYLTHIONINIUM CHLORIDE (MTC)
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Methods of synthesizing and purifying certain 3,7-diamino-phenothiazin-5-ium compounds (referred to herein as "diaminophenothiazinium compounds") including Methythioninium Chloride (MTC) (also known as Methylene Blue) are provided.
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- Phase purification of Cu-S system towards Cu1.8S and its catalytic properties for a clock reaction
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Controlling the composition and crystal phase is an important issue to tune material physical/chemical properties. Herein, it was found that triphenyl phosphine (TPP) can be used as a phase transfer agent to transform CuS, Cu39S28 phases into pure low-sulfur Cu1.8S phase. When mixed phase copper sulfides were reacted with triphenyl phosphine under suitable temperature, sulfur was extracted to produce the low-sulfur Cu1.8S phase. It was also demonstrated that the Cu-S product can effectively catalyze a clock reaction between methylene blue and hydrazine in aqueous medium. In addition, the photothermal conversion properties of the Cu-S based products were studied. The results show that the purified Cu1.8S materials show enhanced or similar properties than the original mixed-phase Cu-S products.
- Liu, Yuanjun,Zhu, Guoxing,Yang, Jing,Bao, Chunlin,Wang, Jing,Yuan, Aihua
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p. 103458 - 103464
(2015/12/23)
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- A novel set of symmetric methylene blue derivatives exhibits effective bacteria photokilling - A structure-response study
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This study focuses on the structure-response relationship of symmetrically substituted phenothiazinium dyes. Four hydrophilic derivatives with the ability of additional hydrogen bonding (5, 6) or additional electrostatic interaction (3, 4) were synthesized, photophysically characterized and compared to the parent compound methylene blue (MB, 1) and a lipophilic derivative (2) without additional coordination sites. Derivative 5 was most effective against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli reaching a maximum photodynamic efficacy of >5log10 steps (≥99.999%) of bacteria killing in 10 minutes (5 μM, 30 J cm-2) without inherent dark toxicity after one single treatment with the incoherent light source PDT1200 (λmax = 660 nm, 50 mW cm-2). Interestingly, one derivative with two additional primary positive charges (3) showed selective killing of Escherichia coli (5 μM, 30 J cm-2, 4log10 steps inactivation (≥99.99%)) and no antimicrobial effect on Staphylococcus aureus. This might allow the development of a new generation of photosensitizers with higher antimicrobial efficacy and selectivity for future applications. This journal is
- Gollmer, Anita,Felgentr?ger, Ariane,B?umler, Wolfgang,Maisch, Tim,Sp?th, Andreas
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p. 335 - 351
(2015/03/05)
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- PROCESS FOR THE PURIFICATION OF DIAMINOPHENOTHIAZINIUM COMPOUNDS
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A process for the purification of diaminophenothiazinium compounds, and particularly of methylene blue, is described. The process provides for simple and affective purification by reduction of the post-synthesis or commercially available diaminophenothiazinium compound to form a reduced complex thereof. This can then be purified in a more straightforward mannandr than the original compound by, for example, recrystaliisation before being allowed to oxidise back to the diaminophenothiazinium compound.
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Paragraph 00125; 00130; 00131
(2015/02/25)
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- Chemical synthetic strategy for single-layer transition-metal chalcogenides
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A solution-phase synthetic protocol to form two-dimensional (2D) single-layer transition-metal chalcogenides (TMCs) has long been sought; however, such efforts have been plagued with the spontaneous formation of multilayer sheets. In this study, we discovered a solution-phase synthetic protocol, called "diluted chalcogen continuous influx (DCCI)", where controlling the chalcogen source influx (e.g., H2S) during its reaction with the transition-metal halide precursor is the critical parameter for the formation of single-layer sheets as examined for the cases of group IV TMCs. The continuous influx of dilute H2S throughout the entire growth period is necessary for large sheet formation through the exclusive a- and b-axial growth processes. By contrast, the burst influx of highly concentrated H2S in the early stages of the growth process forms multilayer TMC nanodiscs. Our DCCI protocol is a new synthetic concept for single-layer TMCs and, in principle, can be operative for wide range of TMC nanosheets.
- Yoo, Dongwon,Kim, Minkyoung,Jeong, Sohee,Han, Jeonghee,Cheon, Jinwoo
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p. 14670 - 14673
(2015/01/08)
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- Reactions of Antimalarial Peroxides with Each of Leucomethylene Blue and Dihydroflavins: Flavin Reductase and the Cofactor Model Exemplified
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Flavin adenine dinucleotide (FAD) is reduced by NADPH-E.coli flavin reductase (Fre) to FADH2 in aqueous buffer at pH7.4 under argon. Under the same conditions, FADH2 in turn cleanly reduces the antimalarial drug methylene blue (MB) to leucomethylene blue. The latter is rapidly re-oxidized by artemisinins, thus supporting the proposal that MB exerts its antimalarial activity, and synergizes the antimalarial action of artemisinins, by interfering with redox cycling involving NADPH reduction of flavin cofactors in parasite flavin disulfide reductases. Direct treatment of the FADH2 generated from NADPH-Fre-FAD by artemisinins and antimalaria-active tetraoxane and trioxolane structural analogues under physiological conditions at pH7.4 results in rapid reduction of the artemisinins, and efficient conversion of the peroxide structural analogues into ketone products. Comparison of the relative rates of FADH2 oxidation indicate optimal activity for the trioxolane. Therefore, the rate of intraparastic redox perturbation will be greatest for the trioxolane, and this may be significant in relation to its enhanced invitro antimalarial activities. 1HNMR spectroscopic studies using the BNAH-riboflavin (RF) model system indicate that the tetraoxane is capable of using both peroxide units in oxidizing the RFH2 generated insitu. Use of the NADPH-Fre-FAD catalytic system in the presence of artemisinin or tetraoxane confirms that the latter, in contrast to artemisinin, consumes two reducing equivalents of NADPH. None of the processes described herein requires the presence of ferrous iron. Ferric iron, given its propensity to oxidize reduced flavin cofactors, may play a role in enhancing oxidative stress within the malaria parasite, without requiring interaction with artemisinins or peroxide analogues. The NADPH-Fre-FAD system serves as a convenient mimic of flavin disulfide reductases that maintain redox homeostasis in the malaria parasite. Antimalarial peroxides and flavin reductase: NADPH-E.coli flavin reductase (Fre) reduces FAD to FADH2, which in turn rapidly reduces artemisinins and antimalarial peroxides to deoxy or ketone products under physiological conditions. Thus, antimalarial activity is due to perturbation of intraparasitic redox homeostasis by oxidation of FADH2 in critical flavoenzymes with consequent sequestration of NADPH. The tetraoxane uses both peroxide units in consuming two equivalents of NADPH in the NADPH-Fre-FAD system.
- Haynes, Richard K.,Cheu, Kwan-Wing,Tang, Maggie Mei-Ki,Chen, Min-Jiao,Guo, Zu-Feng,Guo, Zhi-Hong,Coghi, Paolo,Monti, Diego
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experimental part
p. 279 - 291
(2012/01/12)
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- METHODS OF CHEMICAL SYNTHESIS OF DIAMINOPHENOTHIAZINIUM COMPOUNDS INVOLVING THE USE OF PERSULFATE OXIDANTS
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This invention pertains generally to the field of chemical synthesis and purification, and more specifically to methods of synthesizing and purifying certain 3,7-diamino- phenothiazin-5-ium compounds (referred to herein as "diaminophenothiazinium compound
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Page/Page column 60
(2010/12/17)
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- Facile oxidation of leucomethylene blue and dihydroflavins by artemisinins: Relationship with flavoenzyme function and antimalarial mechanism of action
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The antimalarial drug methylene blue (MB) affects the redox behaviour of parasite flavin-dependent disulfide reductases such as glutathione reductase (GR) that control oxidative stress in the malaria parasite. The reduced flavin adenine dinucleotide cofactor FADH2 initiates reduction to leucomethylene blue (LMB), which is oxidised by oxygen to generate reactive oxygen species (ROS) and MB. MB then acts as a subversive substrate for NADPH normally required to regenerate FADH2 for enzyme function. The synergism between MB and the peroxidic antimalarial artemisinin derivative artesunate suggests that artemisinins have a complementary mode of action. We find that artemisinins are transformed by LMB generated from MB and ascorbic acid (AA) or N-benzyldihydronicotinamide (BNAH) in situ in aqueous buffer at physiological pH into single electron transfer (SET) rearrangement products or two-electron reduction products, the latter of which dominates with BNAH. Neither AA nor BNAH alone affects the artemisinins. The AA-MB SET reactions are enhanced under aerobic conditions, and the major products obtained here are structurally closely related to one such product already reported to form in an intracellular medium. A ketyl arising via SET with the artemisinin is invoked to explain their formation. Dihydroflavins generated from riboflavin (RF) and FAD by pretreatment with sodium dithionite are rapidly oxidised by artemisinin to the parent flavins. When catalytic amounts of RF, FAD, and other flavins are reduced in situ by excess BNAH or NAD(P)H in the presence of the artemisinins in the aqueous buffer, they are rapidly oxidised to the parent flavins with concomitant formation of twoelectron reduction products from the artemisinins; regeneration of the reduced flavin by excess reductant maintains a catalytic cycle until the artemisinin is consumed. In preliminary experiments, we show that NADPH consumption in yeast GR with redox behaviour similar to that of parasite GR is enhanced by artemisinins, especially under aerobic conditions. Recombinant human GR is not affected. Artemisinins thus may act as antimalarial drugs by perturbing the redox balance within the malaria parasite, both by oxidising FADH2 in parasite GR or other parasite flavoenzymes, and by initiating autoxidation of the dihydroflavin by oxygen with generation of ROS. Reduction of the artemisinin is proposed to occur via hydride transfer from LMB or the dihydroflavin to O1 of the peroxide. This hitherto unrecorded reactivity profile conforms with known structure-activity relationships of artemisinins, is consistent with their known ability to generate ROS in vivo, and explains the synergism between artemisinins and redox-active antimalarial drugs such as MB and doxorubicin. As the artemisinins appear to be relatively inert towards human GR, a putative model that accounts for the selective potency of artemisinins towards the malaria parasite also becomes apparent. Decisively, ferrous iron or carbon-centered free radicals cannot be involved, and the reactivity described herein reconciles disparate observations that are incompatible with the ferrous iron-carbon radical hypothesis for antimalarial mechanism of action. Finally, the urgent enquiry into the emerging resistance of the malaria parasite to artemisinins may now in one part address the possibilities either of structural changes taking place in parasite flavoenzymes that render the flavin cofactor less accessible to artemisinins or of an enhancement in the ability to use intra-erythrocytic human disulfide reductases required for maintenance of parasite redox balance.
- Haynes, Richard K.,Chan, Wing-Chi,Wong, Ho-Ning,Li, Ka-Yan,Wu, Wai-Keung,Fan, Kit-Man,Sung, Herman H. Y.,Williams, Ian D.,Prosperi, Davide,Melato, Sergio,Coghi, Paolo,Monti, Diego
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experimental part
p. 1282 - 1299
(2011/01/04)
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- PROCESS FOR PREPARING DIAMINOPHENOTHIAZINIUM COMPOUNDS
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Process for preparing compounds of the diaminophenothiazinium type comprising a step for purification of derivatives (II). The products resulting from this process have a high degree of purity. Use of these compounds for the preparation of medicaments.
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Page/Page column 5
(2009/12/05)
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- METHODS OF SYNTHESIS AND/OR PURIFICATION OF DIAMINOPHENOTHIAZINIUM COMPOUNDS
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This invention pertains generally to the field of chemical synthesis and purification, and more specifically to methods of synthesis and/or purification of certain 3,7 diamino-phenothiazin-5-ium compounds (referred to herein as "diaminophenothiazinium compounds") including Methylthioninium Chloride (MTC) (also known as Methylene Blue). The present invention also pertains to the resulting (high purity) compounds, compositions comprising them (e.g., tablets, capsules), and their use in methods of inactivating pathogens, and methods of medical treatment, prophylaxis, and diagnosis, etc., for example, a tauopathy; a disease of tau protein aggregation; Alzheimer's disease (AD); Pick's disease; Progressive Supranuclear Palsy (PSP); fronto temporal dementia (FTD); parkinsonism linked to chromosome 17 (FTDP-17); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC); pallido-ponto-nigral degeneration (PPND); Guam-ALS syndrome; pallido-nigro-luysian degeneration (PNLD); cortico-basal degeneration (CBD); mild cognitive impairment (MCI); skin cancer; melanoma; methemoglobinemia; a viral infection; a bacterial infection; a protozoal infection; a parasitic infection; malaria; visceral leishmaniasis; African sleeping sickness; toxoplasmosis; giardiasis; Chagas' disease; Hepatitis C virus (HCV) infection; human immunodeficiency virus (HIV) infection; West Nile virus (WNV) infection; a synucleinopathy; Parkinson's disease (PD); dementia with Lewy bodies (DLB); multiple system atrophy (MSA); drug-induced parkinsonism; and pure autonomic failure (PAF).
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Page/Page column 89
(2008/06/13)
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- METHODS OF CHEMICAL SYNTHESIS AND PURIFICATION OF DIAMINOPHENOTHIAZINIUM COMPOUNDS INCLUDING METHYLTHIONINIUM CHLORIDE (MTC)
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This invention pertains generally to the field of chemical synthesis and purification, and more specifically to methods of synthesizing and purifying certain 3,7 diamino-phenothiazin-5-ium compounds (referred to herein as "diaminophenothiazinium compounds") including Methythioninium Chloride (MTC) (also known as Methylene Blue). In one embodiment, the method comprises the steps of, in order: nitrosylation (NOS); nitrosyl reduction (NR); thiosulfonic acid formation (TSAF); oxidative coupling (OC); Cr(VI) reduction (CR); isolation and purification of zwitterionic intermediate (IAPOZI); ring closure (RC); chloride salt formation (CSF); one of: sulphide treatment (ST); dimethyldithiocarbamate treatment (DT); carbonate treatment (CT); ethylenediaminetetraacetic acid treatment (EDTAT); organic extraction (OE); and recrystallisation (RX). The present invention also pertains to the resulting (high purity) compounds, compositions comprising them (e.g., tablets, capsules), and their use in methods of inactivating pathogens, and methods of medical treatment and diagnosis, etc., for example, for tauopathies, Alzheimer's disease (AD), skin cancer, melanoma, viral diseases, bacterial diseases, or protozoal diseases.
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Page/Page column 68-75
(2010/10/20)
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- DEVELOPMENTS IN BIOLOGICALLY ACTIVE METHYLENE BLUE DERIVATIVES (2)
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A phenothiazinium compound of Formula (I) for use as an antimicrobial agent for the prevention of microbial infections wherein: Rl, R2, R3 and R4 each independently is an optionally substituted linear, branched or cyclic hydrocarbon group;or Rl and R2 or R3 and R4 together with the N atom to which they are attached form an optionally substituted 5-, 6- or 7- membered ring; XP- is a counteranion; and P is 1, 2 or 3. The invention also relates to compositions comprising phenothiazinium. compounds, to selected compounds and their use as medicaments, as PDT agents, as photodiagnostic agents, to a conjugate or composite formed between a phenothiazinium. and a polymer; and to a method for sterilising fluids in which the fluid is passed over the conjugate or composite whilst it is illuminated. The compounds are biologically active photosensitisers which are strongly photocytotoxic and have application in the areas of photodynamic therapy (PDT), as well as for the diagnosis and detection of medical conditions and related uses in photochemical internalisation, in the production of cancer vaccines, in the treatment and prevention of microbial infections and in photodisinfection or photosterilisation.
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Page/Page column 25-26
(2010/02/12)
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- A highly sensitive spectrophotometric method for the determination of Cr(VI) concentration
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A highly sensitive spectrophotometric method, which is based on the oxidation of leuco methylene blue (colorless) to methylene blue (colored) by Cr(VI), was developed for the determination of the dissolved hexavalent chromium concentrations in water. Copyright
- Lee, Soo-Keun,Choi, Wonyong
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p. 816 - 817
(2007/10/03)
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- Ultratrace kinetic measurements of the reduction of methylene blue
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The kinetics of methylene blue reduction by ascorbic acid in acetonitrile was investigated by cavity ring-down spectroscopy. Because of our high sensitivity we were able to use very low concentrations (1-10 nM) of the dye. Under these conditions, we observed a second-order loss of dye as well as a competing back reaction with dissolved oxygen. The use of an inexpensive diode laser and a relatively simple setup should make ultratrace kinetic studies more accessible. Copyright
- Hallock, Alexander J.,Berman, Elena S. F.,Zare, Richard N.
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p. 1158 - 1159
(2007/10/03)
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- Kinetic study on the reversible hydride transfer between methylene blue and thionine
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The kinetics of the hydride transfer reaction between leuco methylene blue and thionine was investigated spectrophotometrically by means of the stopped-flow technique. Leuco methylene blue and leuco thionine were produced by photoreduction of methylene bl
- Liu,Yamamoto,Fujiyama,Sueishi
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p. 2367 - 2371
(2007/10/03)
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- Chiral assembly of a pair of free base porphyrins and peroxidase-like activity of iron(III) porphyrins in four-α-helix bundle structures with dimerized two-α-helix polypeptides
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A 5-(4α-bromoacetamidophenyl)-10,15,20-tritolylporphyrin was incorporated into a single-chain two-α-helix polypeptide containing 29 amino acid residues via the thiol side chain of a Cys residue. Two molecules of two-α-helix polypeptide connecting free base porphyrin (H2-porphyrin) were strongly associated to form a four-α-helix bundle structure by hydrophobic interaction among α-helix segments and porphyrin rings in aqueous solution. The dimer formation was demonstrated by gel filtration chromatography and various spectroscopic measurements. The Soret band in the UV/vis spectrum was broadened and red-shifted in aqueous solution. In the fluorescence spectrum with excitation at the Soret band the emission at 650 nm was quenched to 40% of the intensity measured in methanol. Especially, at the Soret band was observed a strongly split circular dichroism (CD) signal, which demonstrated the chiral assembly of a pair of porphyrins in a left-handed sense. With increasing methanol content, the intensity of this split signal was decreased and finally diminished probably due to dissociation of the porphyrin moieties in the peptides. The dimerized Fe(III)-porphyrin-linked two-α-helix polypeptide was examined for biomimetic peroxidase-like activity with H2O2 or 3-chloroperbenzoic acid (MCPBA) as the oxidant. The kcat/KM value for the oxidation of 3,7-dimethylamino-10-methylcarbamoylphenothiazine by the polypeptide with MCPBA was increased by 5000 times compared to that with H2O2. This fact suggests that Fe(III) porphyrin was located in the hydrophobic core and more easily accommodated an organic oxidant than does H2O2. The interior of the four-α-helix bundle structure may be further designed to mimic various haemproteins.
- Tomizaki, Kin-Ya,Murata, Tomonori,Kaneko, Kazuaki,Miike, Akira,Nishino, Norikazu
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p. 1067 - 1074
(2007/10/03)
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- Kinetic studies on oxidations of leucomethylene blue and leucothionine by iron (III) in aqueous solution
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The reaction kinetics and mechanism of the oxidations of leucomethylene blue (MBH) and leucothionine (TH) by iron (III) sulfate in aqueous solution were studied spectrophotometrically by the stopped-flow technique. MBH and TH, which were freshly prepared by photoreduction of methylene blue and thionine, respectively, with ascorbic acid were used in the kinetic measurements. The pseudo-first-order rate constants (kobsd) show kinetic saturation at high initial concentrations of iron (III) sulfate for MBH and TH. It was found that the reciprocal of kobsd increases linearly with increase in the reciprocal of [Fe3+]0. A broad absorption band was observed on mixing MBH and Fe3+ solutions at low temperatures, and this was attributed to a charge-transfer complex between MBH and Fe3+. The effects of Fe2+ ion and L-(+)-ascorbic acid on the rates of oxidation were also investigated. A small kinetic isotope effect on the oxidation rate for MBH was observed. The results can be explained by a general mechanism with stepwise electron-proton-electron transfers with the formation of a complex between reactants. Copyright
- Liu, Yingjin,Yamamoto, Shunzo,Sueishi, Yoshimi
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p. 194 - 200
(2007/10/03)
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- Relationships between the Molecular Structures and Stabilities of Functional Dyes with a Phenothiazine Skeleton
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10-N-Methylcarbamoyl-3,7-bis(dimethylamino)-10H-phenothiazine (MCDP) is one of the functional dyes which are applied clinically as diagnostics. MCDP spontaneously decomposes to methylene blue while increasing the undesirable background of diagnosis. Understanding the mechanisms of spontaneous decomposition is essential for the molecular design of better functional dyes. X-Ray analyses of two derivatives of MCDP, 10-N-methylthiocarbamoyl-3,7-bis(dimethylamino)-10H-phenothiazine and 10-N-benzylthiocarbamoyl-3,7-bis(dimethylamino)-10H-phenothiazine, have been undertaken. Based on the three-dimensional structures the structure-property relationships between them were analysed.
- Fujii, Isao,Hirayama, Noriaki,Aoyama, Norihito,Miike, Akira
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p. 1423 - 1427
(2007/10/03)
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- Kinetics of the Oxidation of NADH by Methylene Blue in a Closed System
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The kinetics of anaerobic oxidation of nicotinamide adenine dinucleotide (NADH) by methylene blue was investigated in phosphate and glycine buffers with an excess of NADH in a closed system.The reaction is first order with respect to the concentration of methylene blue.The observed rate constant is pH independent over the pH range of 7.0-10.6 and increases with NADH concentration in a saturated mode.The oxidation process was also investigated under aerobic conditions in a closed system.Applying the steady-state approximation to methylene blue, the rate constant for reoxidation of the reduced form of methylene blue by oxygen was esti mated to be 1.62 x 102 M-1s-1 at pH 9.0 at 25 deg C.The implications of the present results for NAD(1+) regeneration and oscillatory reactions are noted.
- Sevcik, Peter,Dunford, H. Brian
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p. 2411 - 2415
(2007/10/02)
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- Topsentin compounds effective against viruses and certain tumors
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A new class of novel, biologically active bisindole alkaloid compounds, which have been named topsentins, pharmaceutical compositions containing them, methods of producing the compounds and methods of using them are disclosed. This new class of compounds
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- Uncatalyzed and V(V)-Catalyzed Reaction of Methylene Blue with Potassium Bromate in Aqueous Sulfuric Acid
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The uncatalyzed and V(V)-catalyzed kinetics of reaction between methylene blue (phenotiazinium, 3,7-bis(dimethylamino)-,chloride) and acidic bromate has been studied monitoring the absorbance of methylene blue (MB) at 665 nm.Both the reactions involved competitive and sequential steps, having slow reaction in the initial stages.A rapid reaction followed after an induction time.For the two reactions, the orders with respect to the reactants are the same: second order with H+, first order each with respect to bromate ion and MB.In addition, the catalyzed reaction had first order dependence on catalyst concentration.In both the reactions HOBr is found to be the reaction intermediate.HOBr competed with bromate ion in the depletion of MB to give an intermediate, possibly phenothiazin-5-ium, 3-methylamino-7-dimethylamino-, chloride.The intermediate is further oxidized possibly by HOBr in fast step to final product, phenothiazin-5-ium, 3-amino-7-dimethylamino, -chloride.The stoichiometric ratios of MB to bromate are 2:3.The dual role of bromide ion as an inhibitor at low concentration and as an autocatalyst at higher concentrations above a certain critical concentration in the reaction mechanism is discussed.
- Muthakia, G. K.,Jonnalagadda, S. B.
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p. 4751 - 4756
(2007/10/02)
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- Stabilizer for biological staining solutions
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Stabilized staining solutions containing dyestuffs and stabilizers, which contain dimethylammonium sulfate as a stabilizer.
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- Process for preparing methylene blue
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Methylene Blue and the zinc chloride double salt thereof are prepared by using manganese dioxide as the oxidizing agent in the substantial absence of toxic dichromates.
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