- De Novo Design of Chemical Stability Near-Infrared Molecular Probes for High-Fidelity Hepatotoxicity Evaluation in Vivo
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Near-infrared (NIR) fluorescence imaging technique is garnering increasing research attention due to various advantages. However, most NIR fluorescent probes still suffer from a false signals problem owing to their instability in real application. Especially in a pathological environment, many NIR probes can be easily destroyed due to the excessive generation of highly reactive species and causing a distorted false signal. Herein, we proposed an approach for developing a new stable NIR dye platform with an optically tunable group to eliminate false signals using the combination of dyes screening and rational design strategy. The conception is validated by the construction of two high-fidelity NIR fluorescent probes (NIR-LAP and NIR-ONOO-) sensing leucine aminopeptidase (LAP) and peroxynitrite (ONOO-), the markers of hepatotoxicity. These probes (NIR-LAP and NIR-ONOO-) were demonstrated to sensitively and accurately monitor LAP and ONOO- (detection limit: 80 mU/L for LAP and 90 nM for ONOO-), thereby allowing one to precisely evaluate drug-induced hepatotoxicity. In addition, based on the fluctuation of LAP, the therapeutic efficacy of six hepatoprotective medicines for acetaminophen-induced hepatotoxicity was analyzed in vivo. We anticipate the high-fidelity NIR dye platform with an optically tunable group could provide a convenient and efficient tool for the development of future probes applied in the pathological environment.
- Cheng, Dan,Peng, Juanjuan,Lv, Yun,Su, Dongdong,Liu, Dongjie,Chen, Mei,Yuan, Lin,Zhang, Xiaobing
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Read Online
- Pyridazine N-Oxides as Photoactivatable Surrogates for Reactive Oxygen Species
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A method for the photoinduced evolution of atomic oxygen from pyridazine N-oxides was developed. This underexplored oxygen allotrope mediates arene C-H oxidation within complex, polyfunctional molecules. A water-soluble pyridazine N-oxide was also developed and shown to promote photoinduced DNA cleavage in aqueous solution. Taken together, these studies highlight the utility of pyridazine N-oxides as photoactivatable O(3P) precursors for applications in organic synthesis and chemical biology.
- Basistyi, Vitalii S.,Frederich, James H.
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supporting information
p. 1907 - 1912
(2022/03/27)
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- OXAZINE-BASED WATER-SOLUBLE FLUOROPHORE COMPOUNDS FOR IN VIVO NERVE IMAGING
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This invention provides novel oxazine-based, water soluble fluorophore compounds useful in in vivo nerve imaging, as well as compositions comprising them and methods for their use.
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Page/Page column 36-37
(2021/07/10)
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- NERVE-SPECIFIC FLUOROPHORE FORMULATIONS FOR DIRECT AND SYSTEMIC ADMINISTRATION
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Nerve-specific fluorophore formulations of Formula (I) for direct or systemic administration are described. The formulations can be used in fluorescence-guided surgery (FGS) to aid in nerve preservation during surgical interventions.
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Page/Page column 24-25
(2021/08/13)
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- Paracetamol and other acetanilide analogs as inter-molecular hydrogen bonding assisted diamagnetic CEST MRI contrast agents
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Paracetamol and a few other acetanilide derivatives are reported as a special class of diamagnetic Chemical Exchange Saturation Transfer (diaCEST) MRI contrast agents, that exhibit contrast only when the molecules form inter-molecular hydrogen bonding mediated molecular chains or sheets. Without the protection of the hydrogen bonding their contrast producing labile proton exchanges too quickly with the solvent to produce any appreciable contrast. Through a number of variable temperature experiments we demonstrate that under the conditions when the hydrogen bond network breaks and the high exchange returns back, the contrast drops quickly. The well-known analgesic drug paracetamol shows 12% contrast at a concentration of 15 mM at physiological conditions. With the proven safety track-record for human consumption and appreciable physiological contrast, paracetamol shows promise as a diaCEST agent forin vivostudies.
- Chakraborty, Subhayan,Peruncheralathan,Ghosh, Arindam
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p. 6526 - 6534
(2021/02/21)
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- Aminobenzopyran cyanine fluorescent dye and probe as well as synthesis method and application thereof
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The invention discloses an amido benzopyran cyanine fluorochrome and a probe as well as a synthetic method and application thereof. The fluorochrome is any one kind in structural formulas I-II as shown in the description. According to near infrared fluorochromes I and II with an amido benzopyran cyanine structure provided by the invention, the fluorescence quantum yield is high, the light stability is good, the fluorescence-emission spectrum ranges from 650nm to 900nm and belongs to near infrared spectrum areas, the fluorescence imaging analysis in a living body level can be realized, meanwhile, the penetrating power of biological tissue samples is enhanced, the light damage is reduced, the fluorescence of biomolecules per se is relatively weak, and the biological system can be prevented from self-emitting fluorescent interference to obtain a relatively high signal-to-noise ratio, so that the sensitivity is improved.
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Paragraph 0059-0062
(2021/04/14)
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- Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and in Vivo Oral Efficacy Studies
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A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.
- Dziwornu, Godwin Akpeko,Coertzen, Dina,Leshabane, Meta,Korkor, Constance M.,Cloete, Cleavon K.,Njoroge, Mathew,Gibhard, Liezl,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Wittlin, Sergio,Birkholtz, Lyn-Marie,Chibale, Kelly
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p. 5198 - 5215
(2021/05/06)
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- An Environmentally Benign, Catalyst-Free N?C Bond Cleavage/Formation of Primary, Secondary, and Tertiary Unactivated Amides
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Herein, we report an operationally simple, cheap, and catalyst-free method for the transamidation of a diverse range of unactivated amides furnishing the desired products in excellent yields. This protocol is environmentally friendly and operates under extremely mild conditions without using any promoter or additives. Significantly, this strategy has been implied in the chemoselective synthesis of a pharmaceutical molecule, paracetamol, on a gram-scale with excellent yield. We anticipate that this universally applicable strategy will be of great interest in drug discovery, biochemistry, and organic synthesis.
- Kumar, Vishal,Dhawan, Sanjeev,Girase, Pankaj Sanjay,Singh, Parvesh,Karpoormath, Rajshekhar
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p. 5627 - 5639
(2021/11/11)
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- Efficient nitriding reagent and application thereof
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The invention discloses an efficient nitriding reagent and application thereof, wherein the nitriding reagent comprises nitrogen oxide, an active agent, a reducing agent and an organic solvent. By applying the nitriding reagent, nitrogen-containing compounds such as amide, nitrile and the like can be produced, and the method is simple in condition, low in waste discharge amount and simple in reaction equipment.
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Paragraph 0414-0416
(2021/03/31)
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- NEAR-INFRARED NERVE-SPARING FLUOROPHORES
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Provided are far red to near-infrared nerve-sparing fluorescent compounds, compositions comprising them, and methods of their use in medical procedures.
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Page/Page column 41
(2020/02/17)
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- NERVE-SPECIFIC FLUOROPHORE FORMULATIONS FOR DIRECT AND SYSTEMIC ADMINISTRATION
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Nerve-specific fluorophore formulations for direct or systemic administration are described. The formulations can be used in fluorescence-guided surgery (FGS) to aid in nerve preservation during surgical interventions.
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Paragraph 0150-0151
(2020/03/02)
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- Nitromethane as a nitrogen donor in Schmidt-type formation of amides and nitriles
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The Schmidt reaction has been an efficient and widely used synthetic approach to amides and nitriles since its discovery in 1923. However, its application often entails the use of volatile, potentially explosive, and highly toxic azide reagents. Here, we report a sequence whereby triflic anhydride and formic and acetic acids activate the bulk chemical nitromethane to serve as a nitrogen donor in place of azides in Schmidt-like reactions. This protocol further expands the substrate scope to alkynes and simple alkyl benzenes for the preparation of amides and nitriles.
- Jiao, Ning,Liu, Jianzhong,Qiu, Xu,Song, Song,Wei, Jialiang,Wen, Xiaojin,Zhang, Cheng,Zhang, Ziyao
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supporting information
p. 281 - 285
(2020/01/28)
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- Preparation method of mecitinib raw material (by machine translation)
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The method comprises the following steps: preparing,methyl 3 -(-ethyl-)-amido phenol, dichloro - 5 5-methoxyaniline (by reaction with potassium chloride) sodium 2,4 - to generate (dichloro - 5 5-methan)-methaneth, 2,4 -amidobenzylether (in a chlorine substitution reaction). 2,4 - The method comprises the following steps: reacting m-methyl-methanethinonylphenol and hydrogen peroxide, to generate, dichloro - 5 5-methoxyaniline. The method comprises the following steps of reacting m-aminophenol as a raw material to synthesize methyl chloride 2,4 - potassium, and benzoyl (and reacting; with chloromethane in, a mixture) of, sodium, chloride and methyl chloride, and reacting with chloromethane in a reaction condition. (by machine translation)
- -
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Paragraph 0031; 0033; 0037; 0038; 0047; 0048
(2020/05/30)
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- Beckmann rearrangement: Thiamine hydrochloride as a remarkable catalyst for one-pot synthesis of amides from ketones
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Thiamine hydrochloride catalyzed synthesis of amides from ketones including 3-acetyl coumarin via Beckmann rearrangement has been reported. The reaction is believed to involve oxime formation, cleavage of C[sbnd]C bond followed by C[sbnd]N bond formation in one-pot. Thiamine hydrochloride is stable, cheap, easy to handle and environmentally friendly.
- Mahajan, Sheena,Slathia, Nancy,Kapoor, Kamal K.
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supporting information
(2020/04/08)
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- Bimetallic photoredox catalysis: Visible light-promoted aerobic hydroxylation of arylboronic acids with a dirhodium(ii) catalyst
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We report the use of a rhodium(II) dimer in visible light photoredox catalysis for the aerobic oxidation of arylboronic acids to phenols under mild conditions. Spectroscopic and computational studies indicate that the catalyst Rh2(bpy)2(OAc)4 (1) undergoes metal-metal to ligand charge transfer upon visible light irradiation, which is responsible for catalytic activity. Further reactivity studies demonstrate that 1 is a general photoredox catalyst for diverse oxidation reactions.
- Campbell, Michael G.,Chuang, Gary Jing,Liu, Ming-Lun,Miura-Stempel, Emily,Tu, Jing-Wen,Yang, Hsiang-Ming
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p. 2040 - 2047
(2020/03/13)
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- A method for synthesizing intermediate oxadiazon
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The invention discloses a method for synthesizing intermediate oxadiazon, comprises the following steps: takes amino phenol as an initial raw material; to m-aminophenol acylation reaction is carried out, thereby obtaining a reaction solution A; the reaction solution A to proceed chlorination reaction, to obtain 2, 4 - dichloro - 5 hydroxy acetanilide; to the 2, 4 - dichloro - 5 hydroxy acetanilide etherification reaction, to obtain 2, 4 - dichloro - 5 isopropoxy acetanilide; to the 2, 4 - dichloro - 5 isopropoxy acetyl aniline to deprotected, get 2, 4 - dichloro - 5 isopropoxyaniline. The invention of 2, 4 - dichloro - 5 - isopropoxy aniline synthesis method to avoid the pollution of the environment, but there are few process steps, high yield.
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Paragraph 0056; 0087-0093; 0110-0114; 0132-0136
(2019/07/04)
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- Silver-Mediated Trifluoromethoxylation of (Hetero)aryldiazonium Tetrafluoroborates
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Here we report a silver-mediated trifluoromethoxylation of (hetero)aryldiazonium tetrafluoroborates by converting an aromatic amino group into an OCF3 group. This method, which can be considered to be a trifluoromethoxylation variation of the classic Sandmeyer-type reaction, uses readily available aryl and heteroaromatic amines as starting materials and AgOCF3 as trifluoromethoxylating reagents. The broad substrate scope and simple, mild reaction condition made this transformation a valuable method in constructing aryl-OCF3 bonds.
- Yang, Yu-Ming,Yao, Jian-Fei,Yan, Wei,Luo, Zhuangzhu,Tang, Zhen-Yu
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supporting information
p. 8003 - 8007
(2019/10/11)
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- Antimalarial Pyrido[1,2- a]benzimidazole Derivatives with Mannich Base Side Chains: Synthesis, Pharmacological Evaluation, and Reactive Metabolite Trapping Studies
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A novel series of pyrido[1,2-a]benzimidazoles bearing Mannich base side chains and their metabolites were synthesized and evaluated for in vitro antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation, and in vivo antimalarial efficacy in a mouse model. Oral administration of one of the derivatives at 4 × 50 mg/kg reduced parasitemia by 95% in Plasmodium berghei-infected mice, with a mean survival period of 16 days post-treatment. The in vivo efficacy of these derivatives is likely a consequence of their active metabolites, two of which showed potent in vitro antiplasmodium activity against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum (P. falciparum) strains. Rapid metabolism was observed for all the analogues with 40% of parent compound remaining after 30 min of incubation in liver microsomes. RM trapping studies detected glutathione adducts only in derivatives bearing 4-aminophenol moiety, with fragmentation signatures showing that this conjugation occurred on the phenyl ring of the Mannich base side chain. As with amodiaquine (AQ), interchanging the positions of the 4-hydroxyl and Mannich base side group or substituting the 4-hydroxyl with fluorine appeared to block bioactivation of the AQ-like derivatives though at the expense of antiplasmodium activity, which was significantly lowered.
- Okombo, John,Brunschwig, Christel,Singh, Kawaljit,Dziwornu, Godwin Akpeko,Barnard, Linley,Njoroge, Mathew,Wittlin, Sergio,Chibale, Kelly
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p. 372 - 384
(2019/01/26)
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- Thioesters as Acyl Donors in Biocatalytic Friedel-Crafts-type Acylation Catalyzed by Acyltransferase from Pseudomonas Protegens
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Functionalization of aromatic compounds by acylation has considerable significance in synthetic organic chemistry. As an alternative to chemical Friedel-Crafts acylation, the C-acyltransferase from Pseudomonas protegens has been found to catalyze C?C bond formation with non-natural resorcinol substrates. Extending the scope of acyl donors, it is now shown that the enzyme is also able to catalyze C?S bond cleavage prior to C?C bond formation, thus aliphatic and aromatic thioesters can be used as acyl donors. It is worth to mention that this reaction can be performed in aqueous buffer. Identifying ethyl thioacetate as the most suitable acetyl donor, the products were obtained with up to >99 % conversion and up to 88 % isolated yield without using additional base additives; this represents a significant advancement to prior protocols.
- ??d?o-Dobrowolska, Anna,Schmidt, Nina G.,Kroutil, Wolfgang
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p. 1064 - 1068
(2019/01/14)
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- An alternative way to analogues of avenanthramides and their antiradical activity
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Abstract: The paper is devoted to the synthesis of arylidene malonic acid monoanilides and cinnamoyl anilines by condensation of malonic acid monoanilides with aromatic aldehydes. The presented synthetic route applies simple, cheap, and commercially available aromatic aldehydes and amines, thus overcoming traditional schemes, which involve derivatives of hydroxycinnamic acids. Besides, a mild and effective pyridine-mediated decarboxylation of carboxylic group at Csp2 in arylidene malonic acid monoanilides leading to cinnamoyl anilines is presented. The structures of obtained selected arylidene derivatives were approved additionally by X-ray analysis. The antiradical properties (2,2-diphenyl-1-picrylhydrazyl and galvinoxyl tests) and structure–activity relationships of the synthesized compounds were studied. Graphical abstract: [Figure not available: see fulltext.].
- Mierina, Inese,Stikute, Agnese,Mishnev, Anatoly,Jure, Mara
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- A practical method for preparation of phenols from arylboronic acids catalyzed by iodopovidone in aqueous medium
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A novel and efficient strategy for the ipso-hydroxylation of arylboronic acids to phenols has been developed using inexpensive, readily available, air-stable water-soluble povidone iodine as catalyst and aqueous hydrogen peroxide as oxidizing agent. The reactions were performed at room temperature under metal-, ligand- and base-free condition in a short reaction time. The corresponding substituted phenols were obtained in moderate to good yields by oxidative hydroxylation of arylboronic acids in aqueous medium.
- Dong, Bin,Ke, Yanxiong,Lu, Guangying,Ren, Jiangmeng,Ren, Yaoyao,Zeng, Bu-Bing,Zhou, Bin
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- Synthesis of acetamides from aryl amines and acetonitrile by diazotization under metal-free conditions
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An efficient and metal-free coupling reaction has been developed that affords acetamides from the corresponding aryl amines and acetonitrile. This method tolerates a wide range of functional groups and is selective toward aryl amines. Preliminary mechanistic studies were conducted.
- Duan, Pan,Guo, Yu,Kang, Huan,Li, Yi-Na,Wen, Xianghao,Xiao, Fang,Zeng, Yao-Fu,Zhang, Na-Na
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supporting information
p. 2169 - 2172
(2019/11/25)
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- Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the γ-Aminobutyric Acid Type A Receptor (GABAAR) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability
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Recent reports indicate that α6β2/3γ2 GABAAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAAR α6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6β2/3γ2 GABAARs and were functionally silent at diazepam sensitive α1β2/3γ2 GABAARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABAAR α6β2/3γ2 subtypes.
- Knutson, Daniel E.,Kodali, Revathi,Divovi?, Branka,Treven, Marco,Stephen, Michael R.,Zahn, Nicolas M.,Dobri?i?, Vladimir,Huber, Alec T.,Meirelles, Matheus A.,Verma, Ranjit S.,Wimmer, Laurin,Witzigmann, Christopher,Arnold, Leggy A.,Chiou, Lih-Chu,Ernst, Margot,Mihovilovic, Marko D.,Savi?, Miroslav M.,Sieghart, Werner,Cook, James M.
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p. 2422 - 2446
(2018/03/26)
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- Dibasic derivatives of phenylcarbamic acid against mycobacterial strains: Old drugs and new tricks?
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In order to provide a more detailed view on the structure–antimycobacterial activity relationship (SAR) of phenylcarbamic acid derivatives containing two centers of protonation,1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (1a–d)/dichlorides (1e–h) as wellas1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (1i–l)/dichlorides (1m–p; alkoxy = butoxy to heptyloxy) were physicochemically characterized by estimation of their surface tension (γ; Traube’s stalagmometric method), electronic features (log ε; UV/Vis spectrophotometry) and lipophilic properties (log kw; isocratic RP-HPLC) as well. The experimental log kw dataset was studied together with computational logarithms of partition coefficients (log P) generated by various methods based mainly on atomic or combined atomic and fragmental principles. Similarities and differences between the experimental and in silico lipophilicity descriptors were analyzed by unscaled principal component analysis (PCA). The in vitro activity of compounds 1a–p was inspected against Mycobacterium tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794, respectively), M. tuberculosis H37Ra ATCC 25177, M. kansasii CNCTC My 235/80 (identical with ATCC 12478), the M. kansasii 6509/96 clinical isolate, M. kansasii DSM 44162, M. avium CNCTC My 330/80 (identical with ATCC 25291), M. smegmatis ATCC 700084 and M. marinum CAMP 5644, respectively. In vitro susceptibility of the mycobacteria to reference drugs isoniazid, ethambutol, ofloxacin or ciprofloxacin was tested as well. A very unique aspect of the research was that many compounds from the set 1a–p were highly efficient almost against all tested mycobacteria. The most promising derivatives showed MIC values varied from 1.9 μM to 8 μM, which were lower compared to those of used standards, especially if concerning ability to fight M. tuberculosis H37Ra ATCC 25177, M. kansasii DSM 44162 or M. avium CNCTC My 330/80. Current in vitro biological assays and systematic SAR studies based on PCA approach as well as fitting procedures, which were supported by relevant statistical descriptors, proved that the compounds 1a–p represented a very promising molecular framework for development of ‘non-traditional’ but effective antimycobacterial agents.
- Malík, Ivan,Csollei, Jozef,Solovi?, Ivan,Pospísilová, Sárka,Michnová, Hana,Jampílek, Josef,?ízek, Alois,Kapustíková, Iva,?urillová, Jana,Pechá?ová, Mária,Stola?íková, Ji?ina,Pecher, Daniel,Oravec, Michal
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supporting information
(2018/10/05)
-
- Development of a novel protocol for chemoselective deprotection of N/O-benzyloxycarbonyl (Cbz) at ambient temperature
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Abstract: A novel protocol for the deprotection of N-benzyloxycarbonyl and O-benzyloxycarbonyl groups by nickel boride generated in situ from NaBH4 and NiCl2·6H2O in methanol at room temperature has been developed to give the corresponding amines and phenols. This protocol is chemoselective as groups like chloro, bromo, amide, ester, pyridine, and tert-butyloxycarbonyl moiety are unaffected under these conditions. The deprotection has also been validated in gram scale reactions, to establish the wider appropriateness of this protocol. Graphical abstract: [Figure not available: see fulltext.].
- Saroha, Mohit,Aggarwal, Komal,Bartwal, Gaurav,Khurana, Jitender M.
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p. 2231 - 2235
(2018/10/02)
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- Continuous synthesis method of m-acetamido phenol
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The invention discloses a continuous synthesis method of m-acetamido phenol. The method comprises the following steps: respectively preparing two solutions from m-aminoacetanilide, sulfuric acid, sodium nitrite and the like, respectively continuously pumping the solutions into a tubular reactor by a metering pump at a preset flow velocity, performing diazotization and hydrolysis reactions, and cooling, extracting, drying and desolventizing the obtained reaction product to obtain the product, wherein the diazotization reaction and the hydrolysis reaction are completed in the same tubular reactor. The method has the characteristics of sufficient sources and low price of raw materials, high safety in the synthesis process, high product yield, less pollution of three wastes, and high industrialization values.
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Paragraph 0022-0025
(2018/10/26)
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- C70 Fullerene-Catalyzed Metal-Free Photocatalytic ipso-Hydroxylation of Aryl Boronic Acids: Synthesis of Phenols
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A metal-free C70 fullerene-catalyzed method has been developed for the ipso-hydroxylation of aryl and heteroaryl boronic acids to corresponding phenols under photocatalytic conditions. The reaction proceeds under oxygen atmosphere and the mechanistic study revealed that C70 plays a critical role in the generation of reactive oxygen species in the presence of blue light. Reactions in the presence of 18O-labelled water and oxygen confirmed the generation of reactive oxygen species from oxygen molecule. Amine used as a reductant could be recovered in the form of imine. The current method is also applicable to the synthesis of aryl ethers in one-pot two-step process. (Figure presented.).
- Kumar, Inder,Sharma, Ritika,Kumar, Rakesh,Kumar, Rakesh,Sharma, Upendra
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supporting information
p. 2013 - 2019
(2018/04/02)
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- Picosecond Electron Transfer from Quantum Dots Enables a General and Efficient Aerobic Oxidation of Boronic Acids
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General visible light-mediated aerobic oxidation of boronic acids is unveiled using CdSe nanocrystal quantum dots (QDs) as the photoredox catalyst. This protocol requires mild reaction conditions and low catalyst loading (down to 10 ppm), and tolerates various functional groups. The resulting phenols and aliphatic alcohols are produced in good to high yield with turnover numbers as high as >62000. The reaction mechanism is probed using ultrafast transient absorption and luminescence spectroscopy. The existence of a rapid 350 ps initial electron transfer followed by a hole transfer is demonstrated.
- Simlandy, Amit Kumar,Bhattacharyya, Biswajit,Pandey, Anshu,Mukherjee, Santanu
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p. 5206 - 5211
(2018/05/15)
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- Promiscuous activity of C-acyltransferase from: Pseudomonas protegens: Synthesis of acetanilides in aqueous buffer
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Amide bond formation has considerable significance in synthetic chemistry. Although the C-acyltransferase from Pseudomonas protegens has been found to catalyze C-C bond formation in nature as well as in in vitro experiments with non-natural substrates, it is now shown that the enzyme is also able to catalyze amide formation using aniline derivatives as substrates with promiscuous activity. Importantly, the amide formation was enabled in aqueous buffer. Identifying phenyl acetate as the most suitable acetyl donor, the products were obtained with up to >99% conversion and up to 99% isolated yield.
- Zad?o-Dobrowolska, Anna,Schmidt, Nina G.,Kroutil, Wolfgang
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supporting information
p. 3387 - 3390
(2018/04/05)
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- An Efficient Synthesis of Ivacaftor
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New and practical synthetic route of ivacaftor is described on a grams scale. An electrophilic addition of two t-butyl groups to the aromatic ring is adopted to prepare 5-amino-2,4-di-t-butylphenol in 61% yield over three steps with 98.1% purity (high-performance liquid chromatography). An intramolecular cyclization of ethyl 3-(2-aminophenyl)-3-oxo-propanoate with dimethylformamide-dynamic mechanical analysis is used to prepare 4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 54% yield over four steps. Ivacaftor is obtained by condensation of the two parts in 71% yield with 99.1% purity (high-performance liquid chromatography).
- Zhang, Rui,Han, Guanyu,Jiang, Luobin,Shen, Yao,Yang, Rui,Mao, Yongjun,Wang, Hang
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p. 3169 - 3173
(2017/10/05)
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- Discovery of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as new potent and selective human sirtuin 2 inhibitors
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Human sirtuin 2 (SIRT2) plays pivotal roles in multiple biological processes such as cell cycle regulation, autophagy, immune and inflammatory responses. Dysregulation of SIRT2 was considered as a main aspect contributing to several human diseases, including cancer. Development of new potent and selective SIRT2 inhibitors is currently desirable, which may provide a new strategy for treatment of related diseases. Herein, a structure-based optimization approach led to new 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as SIRT2 inhibitors. SAR analyses with new synthesized derivatives revealed a number of new potent SIRT2 inhibitors, among which 28e is the most potent inhibitor with an IC50 value of 42?nM. The selectivity analyses found that 28e has a very good selectivity to SIRT2 over SIRT1 and SIRT3. In cellular assays, 28e showed a potent ability to inhibit human breast cancer cell line MCF-7 and increase the acetylation of α-tubulin in a dose-dependent manner. This study will aid further efforts to develop highly potent and selective SIRT2 inhibitors for the treatment of cancer and other related diseases.
- Yang, Lingling,Ma, Xiaobo,Yuan, Chen,He, Yanying,Li, Ling,Fang, Sha,Xia, Wei,He, Tao,Qian, Shan,Xu, Zhihong,Li, Guobo,Wang, Zhouyu
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p. 230 - 241
(2017/04/19)
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- Novel SIRT2 protein inhibitor and usage thereof in pharmacy
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The invention discloses a compound or salt, crystallographic form and solvate compounds of the compound acceptable in pharmacy, and the compound and the salt, crystallographic form, solvate compounds of the compound are shown as formula I, wherein X is selected from the formulas (please see the specifications for the formula); R1 is selected from aryl or ceteroary or substituted aryl or substituted ceteroary or from the formula (please see the specifications for the formula); R2 is selected from the formulas (please see the specifications for the formula); and R3 is selected from halogen or C1-C4 alkyl or C1-C4 alkoxy. The novel compound shown in formula I has the advantages that not only is good inhibitory activity achieved to SIRT2, but also the inhibiting effect is achieved to the tumor, and the novel compound has good pharmaceutical potentiality and provides a novel potential choice for the clinical medicament.
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Paragraph 0149; 0150
(2017/08/28)
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- Indane derivative and synthetic method and medicinal application thereof
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The invention discloses an indane derivative and a synthetic method and medicinal application thereof. The structural general formula is as shown in the specification. The indane derivative disclosed by the invention has excellent inhibitory activity and high selectivity on MAO-B.
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Paragraph 0209; 0211; 0212; 0213
(2017/09/02)
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- LIGANDS SELECTIVE TO ALPHA 6 SUBUNIT-CONTAINING GABAA RECEPTORS ANS THEIR METHODS OF USE
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Provided herein are novel pyrazoloquinolinone compounds and method of using such compounds to treat disorders such as neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia, tic disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, panic disorder, Huntington's disease and nocturnal enuresis;depression; temporomandibular myofascial pain; disorders of trigeminal nerve, such as trigeminal neuralgia and trigeminal neuropathy; migraine; and tinnitus.
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Paragraph 00134
(2016/12/22)
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- 2,4-di-tert-butyl-5-aminophenol method for the preparation of (by machine translation)
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The present invention relates to organic synthesis, and technical field of preparing intermediates of raw materials, in particular to a new medicine for the treatment of cystic fibrosis is a key intermediate (ivacaftor) according to cuts down Catto 2, the 4 [...] di-tert-butyl -5 the method for the preparation of phenol [...], comprising the following steps : (1) acetylation: to (A) aminophenol between, (B) acetic anhydride or acetyl chloride as a raw material, prepared by reaction of N-(the 3 [...] hydroxy-phenyl) acetamide ; (2) tert-butyl substituted: N-(the 3 [...] hydroxy-phenyl) acetamide sulfuric acid catalyzed after thickwith uncle butanol, by preparing N-(2,4 the [...] di-tert-butyl -5 the [...] hydroxy-phenyl-acetamide ; (3) deacetyl: N-(2,4 the [...] di-tert-butyl -5 the [...] hydroxy-phenyl) acetamide using acid or alkali hydrolysis to obtain 2,4 the [...] di-tert-butyl -5 the aminophenol [...]. This synthetic route easy availability of raw materials, mild reaction conditions, post-processing is simple and convenient, suitable for enlarging preparation, and have high yield. (by machine translation)
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Paragraph 0038; 0039; 0040; 0041; 0051-53
(2016/11/24)
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- Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study
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Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl but also other acyl groups from the ε-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure-activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure.
- Schiedel, Matthias,Rumpf, Tobias,Karaman, Berin,Lehotzky, Attila,Oláh, Judit,Gerhardt, Stefan,Ovádi, Judit,Sippl, Wolfgang,Einsle, Oliver,Jung, Manfred
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supporting information
p. 1599 - 1612
(2016/03/05)
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- Selective N-acetylation of aromatic amines using acetonitrile as acylating agent
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A method for N-acetylation of amines has been developed using acetonitrile as an acylating agent and in situ generated trimethylsilyl iodide as the catalyst under microwave heating condition. The reaction is selective toward aromatic amines while aliphatic amines remain intact. The process eliminates the requirement of toxic acylating reagents like acetic anhydride and acetyl chloride.
- Saikia, Ujwal Pratim,Hussain, Farhaz L.,Suri, Mrinaly,Pahari, Pallab
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supporting information
p. 1158 - 1160
(2016/03/09)
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- New Synthetic Process for Bosutinib
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A new and improved synthetic route to bosutinib is described on a hectogram scale. The key step is the intramolecular cyclization of a 3-(2-aminophenyl)-3-oxopropanenitrile with N,N-dimethylformamide dimethyl acetal to form the 3-cyano-4-hydroxyquinoline ring of 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile. A practical synthetic method to 2,4-dichloro-5-methoxyaniline is also established. Bosutinib is obtained in 18.0% yield over nine steps from acetovanillone with 98.9% purity (HPLC).
- Mao, Yongjun,Zhu, Chunping,Kong, Ziyang,Wang, Jiao,Zhu, Guoqing,Ren, Xinfeng
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p. 3133 - 3138
(2015/10/19)
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- Beckmann rearrangement of oximes using doped silica gel complex
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A new complex of perchloric acid absorbed on silica gel (doped silica gel) and dichloromethane was found to be very effective for converting ketoximes into their corresponding amides or lactams with excellent conversion via the Beckmann rearrangement. This method offers significant advantages such as efficiency and mild reaction conditions with shorter reaction time.
- Umanadh,Reddy, N. Srinivasa,Mukkanti, Khagga,Omprakash
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p. 1209 - 1211
(2015/02/19)
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- Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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Paragraph 0491
(2015/09/22)
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- A binuclear Mn(ii) complex as an efficient catalyst for transamidation of carboxamides with amines
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A binuclear Mn(ii) complex has been synthesized and characterized by different structural methods. The complex contains two unique oxo-bridged metal centres and has been explored as an excellent catalyst for transamidation of carboxamides with amines under solvent-free conditions.
- Singh, Divya Pratap,Allam, Bharat Kumar,Singh, Krishna Nand,Singh, Vinod Prasad
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p. 1155 - 1158
(2014/01/06)
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- ZnAl2O4@SiO2 nanocomposite catalyst for the acetylation of alcohols, phenols and amines with acetic anhydride under solvent-free conditions
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A ZnAl2O4@SiO2 nanocomposite was prepared from metal nitrates and tetraethyl orthosilicate by the sol-gel process, and characterized by X-ray diffraction, Fourier transform infrared, transmission electron microscopy, and N2 adsorption-desorption measurements. The nanocomposite was tested as a heterogeneous catalyst for the acetylation of alcohols, phenols, and amines under solvent-free conditions. Under optimized conditions, efficient acetylation of these substrates with acetic anhydride over the ZnAl2O4@SiO2 nanocomposite was obtained. Acetylation of anilines and primary aliphatic amines proceeded rapidly at room temperature, while the reaction time was longer for the acetylation of alcohols and phenols, showing that an amine NH2 group can be selectively acetylated in the presence of alcoholic or phenolic OH groups. The catalyst can be reused without obvious loss of catalytic activity. The catalytic activity of the ZnAl2O4@SiO2 nanocomposite was higher than that of pure ZnAl2O4. The method gives high yields, and is clean, cost effective, compatible with substrates having other functional groups and it is suitable for practical organic synthesis.
- Farhadi, Saeed,Jahanara, Kosar
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p. 368 - 375
(2014/04/03)
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- Synthesis and biological evaluation of substituted 2-anilino-7H- pyrrolopyrimidines as PDK1 inhibitors
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An efficient and scalable route for a series of novel substituted 2-anilino-7H-pyrrolopyrimidine compounds as potential inhibitors of PDK1, an important regulator of the PI3K/Akt pathway that is dysregulated in many cancers, was developed and is described. The synthetic strategy was designed around Suzuki and Buchwald-Hartwig cross-couplings of a boronate fragment and various customised anilines sequentially with 2,4-dichloro-7-tosyl-7H- pyrrolopyrimidine. All fragments were constructed separately and cross-coupled to provide access to a range of novel compounds. Biological evaluation of these was undertaken, with modest inhibition observed.
- O'Brien, Nathan J.,Brzozowski, Martin,Wilson, David J.D.,Deady, Leslie W.,Abbott, Belinda M.
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p. 4947 - 4956
(2014/07/07)
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- Reductive removal of methoxyacetyl protective group using sodium borohydride
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Herein, we have developed a mild and selective reductive deprotection method for the MAc protected alcohols using sodium borohydride. The new deprotection conditions provide a complete orthogonality between O-MAc and other protecting groups such as tert-butyl ester, N-Boc, Fmoc, Cbz, O-TBDMS, N-benzyl, O-benzyl, O-acetyl, N-acetyl, N-MAc, etc. In addition to O-MAc deprotection, this method is also applicable for S-MAc deprotection.
- Gadekar, Pradip K.,Hoermann, Maryann,Corbo, Faith,Sharma, Rajiv,Sarveswari,Roychowdhury, Abhijit
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p. 503 - 506
(2014/01/06)
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- Natural organic acids promoted Beckmann rearrangement: Green and expeditious synthesis of amides under solvent-free conditions
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Naturally occurring organic acids are reported to be highly efficient promoters of the Beckmann rearrangement. Citric, oxalic, tartaric, malic, succinic, malonic, and fumaric acids efficiently promote the Beckmann rearrangement under solvent-free conditions and thermal and microwave irradiation. Tartaric acid was found to be the best promoter of the Beckmann rearrangement under conventional conditions as well as under microwave irradiation. Compared with conventional heating, microwave irradiation provides higher reaction rate and slightly higher yields.
- Rohokale, Sandeep Vasantrao,Kote, Santosh Rajaram,Deshmukh, Santosh Rangnath,Thopate, Shankar Ramchandra
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p. 575 - 578
(2014/01/17)
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- Amidation of phenol derivatives: A direct synthesis of paracetamol (acetaminophen) from hydroquinone
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A direct synthesis of paracetamol (acetaminophen) from hydroquinone has been developed using ammonium acetate as an amidating agent. The reaction proceeds in acetic acid at elevated temperatures without any metallic catalyst. Under these conditions, paracetamol was obtained with high yield and selectivity (>95%). The reaction has also been carried out on the multi-gram scale (44 g of hydroquinone) and a potential process has been proposed based on the recycling of the solvent and by-products. This amidation protocol has also been extended to other phenol derivatives. This journal is the Partner Organisations 2014.
- Joncour, Roxan,Duguet, Nicolas,Metay, Estelle,Ferreira, Amadeo,Lemaire, Marc
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supporting information
p. 2997 - 3002
(2014/06/10)
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- Hypervalent iodine catalyzed transamidation of carboxamides with amines
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This protocol describes the catalytic use of diacetoxyiodobenzene (DIB) for the efficient transamidation of carboxamides with amines under mild conditions.
- Vanjari, Rajeshwer,Kumar Allam, Bharat,Nand Singh, Krishna
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p. 1691 - 1694
(2013/03/28)
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- Syntheses, characterization and antioxidant activity of some oxadiazoles
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Oxadiazole derivatives are an important class of heterocyclic compounds, specifically 2-amino substituted oxadiazoles with biological activities such as antioxidant, anticancer, antibacterial, antifungal, analgesic and antiinflammatory activities. The above observations prompted us to synthesize new oxadiazoles with various substitutions. The starting material 2-amino-5-(3′-acetamidophenyl)-1,3,4-oxadiazole (SBM-4) was synthesized by refluxing a mixture of 3-aminophenol and acetic anhydride in glacial acetic acid. This was followed by refluxing with ethyl chloroacetate and anhydrous K2CO3 in dry acetone, followed by refluxing with hydrazine hydrate in ethanol and the hydrazide was finally treated with CNBr in methanol. The parent compound was then converted to the oxadiazoles by reacting with various substituted aromatic aldehydes. The new compounds were evaluated for in vitro antioxidant activity using ascorbic acid as standard. Among the compounds tested, SBM-4a with 4″-chloro, SBM-4g with 2″-chloro and SBM-4h with 4″-methyl substitution at R showed good antioxidant activity. Copyright
- Nimavat,Mohan,Saravanan,Patel,Deka,Talukdar,Basak,Sarma
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p. 1691 - 1694
(2013/05/09)
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- Synthesis and evaluation of a photochromic surfactant for organic reactions in aqueous media
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A novel photochromic azobenzene-based surfactant was described for organic chemistry in water. The molecule 4-butylazobenzyl-4′-triazologlucuronic acid sodium salt thus synthesized can be isomerized from its trans to its cis form reversibly in solution by simple light irradiation. That property allowed the recyclability of a model acetylation reaction performed in the surfactant media, compared to the well-known, commercially available sodium dodecyl sulfate surfactant media.
- Drillaud, Nicolas,Banaszak-Léonard, Estelle,Pezron, Isabelle,Len, Christophe
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p. 9553 - 9561
(2013/01/15)
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- Highly efficient and versatile acetylation of alcohols, phenols and amines catalyzed by methylenediphosphonic acid (MDP) under solvent-free conditions
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Methylenediphosphonic Acid (MDP) was found to be a simple, cheap and reusable heterogeneous catalyst for the acetylation of structurally diverse alcohols, phenols and amines with acetic anhydride under solvent-free conditions at room temperature. This method showed preferential selectivity for the acetylation of the amino group in the presence of hydroxyl group. The method is very mild and the yields were in excellent.
- Xie, Minhao,Wang, Hongyong,Wu, Jun,He, Yongjun,Liu, Yaling,Zou, Pei
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experimental part
p. 884 - 886
(2012/04/23)
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