- ISOINDOLINE COMPOUND, AND PREPARATION METHOD, PHARMACEUTICAL COMPOSITION, AND APPLICATION OF ISOINDOLINE COMPOUND
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The present invention relates to an isoindoline compound as represented by general formula (I) and used as a CRBN regulator, and a preparation method, a pharmaceutical composition, and an application of the isoindoline compound. Specifically, a class of polysubstituted isoindoline compound provided in the present invention, as a class of CRL4CRBN E3 ubiquitin ligase regulator having a novel structure, has good anti-tumor activity and immunoregulatory activity, and can be used for preparing drugs for treating diseases associated with a CRL4CRBN E3 ubiquitin ligase.
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- The Stereoselective Oxidation of para-Substituted Benzenes by a Cytochrome P450 Biocatalyst
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The serine 244 to aspartate (S244D) variant of the cytochrome P450 enzyme CYP199A4 was used to expand its substrate range beyond benzoic acids. Substrates, in which the carboxylate group of the benzoic acid moiety is replaced were oxidised with high activity by the S244D mutant (product formation rates >60 nmol.(nmol-CYP)?1.min?1) and with total turnover numbers of up to 20,000. Ethyl α-hydroxylation was more rapid than methyl oxidation, styrene epoxidation and S-oxidation. The S244D mutant catalysed the ethyl hydroxylation, epoxidation and sulfoxidation reactions with an excess of one stereoisomer (in some instances up to >98 %). The crystal structure of 4-methoxybenzoic acid-bound CYP199A4 S244D showed that the active site architecture and the substrate orientation were similar to that of the WT enzyme. Overall, this work demonstrates that CYP199A4 can catalyse the stereoselective hydroxylation, epoxidation or sulfoxidation of substituted benzene substrates under mild conditions resulting in more sustainable transformations using this heme monooxygenase enzyme.
- Chao, Rebecca R.,Lau, Ian C.-K.,Coleman, Tom,Churchman, Luke R.,Child, Stella A.,Lee, Joel H. Z.,Bruning, John B.,De Voss, James J.,Bell, Stephen G.
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supporting information
p. 14765 - 14777
(2021/09/14)
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- Mild oxidation of benzyl alcohols to benzyl aldehydes or ketones catalyzed by visible light
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Induced by visible light, mild oxidation condition to prepare benzyl aldehydes or ketones have been developed by using bromotrichloromethane as photochemical oxidant. This method avoids high temperature, pressure and peroxidation with only visible light as the green driving force.
- Cheng, Dongping,Li, Xiaonian,Ren, Shujian,Xu, Xiaoliang
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supporting information
(2021/07/02)
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- A Hammett Study of Clostridium acetobutylicum Alcohol Dehydrogenase (CaADH): An Enzyme with Remarkable Substrate Promiscuity and Utility for Organic Synthesis
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Described is a physical organic study of the reduction of three sets of carbonyl compounds by the NADPH-dependent enzyme Clostridium acetobutylicum alcohol dehydrogenase (CaADH). Previous studies in our group have shown this enzyme to display broad substrate promiscuity, yet remarkable stereochemical fidelity, in the reduction of carbonyl compounds, including α-, β- and γ-keto esters (d -stereochemistry), as well as α,α-difluorinated-β-keto phosphonate esters (l -stereochemistry). To better mechanistically characterize this promising dehydrogenase enzyme, we report here the results of a Hammett linear free-energy relationship (LFER) study across three distinct classes of carbonyl substrates; namely aryl aldehydes, aryl β-keto esters and aryl trifluoromethyl ketones. Rates are measured by monitoring the decrease in NADPH fluorescence at 460 nm with time across a range of substrate concentrations for each member of each carbonyl compound class. The resulting v 0 versus [S] data are subjected to least-squares hyperbolic fitting to the Michaelis-Menton equation. Hammett plots of log(V max) versus σ X yield the following Hammett parameters: (i) for p -substituted aldehydes, ρ = 0.99 ± 0.10, ρ = 0.40 ± 0.09; two domains observed, (ii) for p -substituted β-keto esters ρ = 1.02 ± 0.31, and (iii) for p -substituted aryl trifluoromethyl ketones ρ = -0.97 ± 0.12. The positive sign of ρ indicated for the first two compound classes suggests that the hydride transfer from the nicotinamide cofactor is at least partially rate-limiting, whereas the negative sign of ρ for the aryl trifluoromethyl ketone class suggests that dehydration of the ketone hydrate may be rate-limiting for this compound class. Consistent with this notion, examination of the 13 C NMR spectra for the set of p -substituted aryl trifluo romethyl ketones in 2percent aqueous DMSO reveals significant formation of the hydrate (gem -diol) for this compound family, with compounds bearing the more electron-withdrawing groups showing greater degrees of hydration. This work also presents the first examples of the CaADH-mediated reduction of aryl trifluoromethyl ketones, and chiral HPLC analysis indicates that the parent compound α,α,α-trifluoroacetophenone is enzymatically reduced in 99percent ee and 95percent yield, providing the (S)-stereoisomer, suggesting yet another compound class for which this enzyme displays high enantioselectivity.
- Berkowitz, David B.,Kudalkar, Gaurav P.,Lee, Joshua D.,Tiwari, Virendra K.
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supporting information
p. 237 - 247
(2020/02/18)
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- A method of synthesis of primary alcohol (by machine translation)
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The invention discloses a method for synthesizing a primary alcohol, using transition metal catalysis, the use of isopropanol as a hydrogen source to synthesize primary alcohol, the reaction not only using a cheap, environmental protection of isopropanol as a hydrogen source and solvent, and has high yield, environmental protection and the like, so that the reaction has broad prospects for development. (by machine translation)
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Paragraph 0099; 0100; 0101; 0102; 0103
(2019/03/17)
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- Transfer Hydrogenation of Aldehydes and Ketones with Isopropanol under Neutral Conditions Catalyzed by a Metal-Ligand Bifunctional Catalyst [Cp?Ir(2,2′-bpyO)(H2O)]
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A Cp?Ir complex bearing a functional bipyridonate ligand [Cp?Ir(2,2′-bpyO)(H2O)] was found to be a highly efficient and general catalyst for transfer hydrogenation of aldehydes and chemoselective transfer hydrogenation of unsaturated aldehydes with isopropanol under neutral conditions. It was noteworthy that many readily reducible or labile functional groups such as nitro, cyano, ester, and halide did not undergo any change under the reaction conditions. Furthermore, this catalytic system exhibited high activity for transfer hydrogenation of ketones with isopropanol. Notably, this research exhibited new potential of metal-ligand bifunctional catalysts for transfer hydrogenation.
- Wang, Rongzhou,Tang, Yawen,Xu, Meng,Meng, Chong,Li, Feng
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p. 2274 - 2281
(2018/02/23)
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- Synthesis and biological evaluation of curcumin inspired indole analogues as tubulin polymerization inhibitors
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In our endeavour towards the development of potent cytotoxic agents, a series of some new curcumin inspired indole analogues, in which indole and phenyl moieties are linked on either sides of 1,5-diaryl-1,4-pentadien-3-one system have been synthesized and characterized by spectral data. All the newly synthesized analogues were tested for their cytotoxic potential against a panel of eight cancer cell lines namely, lung (A549), breast (MDA-MB-231, BT549 and 4T1), prostate (PC-3, DU145), gastric (HGC-27) and cervical (HeLa). Notably, among all the compounds tested, compounds 11c, 11d and 11f showed potent growth inhibition on PC-3 and BT549 with IC50values in the range of 3.12–6.34?μM and 4.69–8.72?μM respectively. The most active compound (11c) was also tested on RWPE-1 (normal prostate) cells and was found to be safe compared to the PC-3?cells. In tubulin polymerization assay, compounds 11c and 11f effectively inhibited microtubule assembly with IC50values of 10.21?±?0.10 and 8.83?±?0.06?μM respectively. The results from molecular modelling studies revealed that these compounds bind at the colchicine binding site of the tubulin. Moreover, DAPI and acridine orange/ethidium bromide staining studies indicated that compounds 11c and 11f can induce apoptosis in PC-3?cells. Further flow-cytometry analysis revealed that compound 11c arrests PC-3?cells in G2/M phase of the cell cycle while compound 11f treatment resulted in moderate increase in the G2/M population. Additionally, the treatment by these compounds led to the impairment of mitochondrial membrane potential (DΨm) in PC-3?cells.
- Sri Ramya,Angapelly, Srinivas,Guntuku, Lalita,Singh Digwal, Chander,Nagendra Babu, Bathini,Naidu,Kamal, Ahmed
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p. 100 - 114
(2016/12/30)
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- Stable and easily handled FeIII catalysts for hydrosilylation of ketones and aldehydes
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The amine-bis(phenolate) iron(III)-catalysed reduction of ketones and aldehydes to the corresponding secondary and primary alcohols by a consecutive hydrosilylation/hydrolysis process is reported. The amine-bis(phenolate) iron(III) catalyst is easily accessible, stable towards moisture and air and has a broad substrate scope.
- Zhu, Kailong,Shaver, Michael P.,Thomas, Stephen P.
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supporting information
p. 2119 - 2123
(2015/03/31)
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- General and highly efficient iron-catalyzed hydrogenation of aldehydes, ketones, and α,β-unsaturated aldehydes
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EnvIRONmentally friendly: The title hydrogenation of aldehydes, ketones, and α,β-unsaturated aldehydes is reported. In the presence of the catalyst 1, primary, secondary, and allylic alcohols were obtained in good to excellent yields under mild reaction conditions. The catalyst is easily and inexpensively prepared, and is also stable to air, water, and column chromatography. Copyright
- Fleischer, Steffen,Zhou, Shaolin,Junge, Kathrin,Beller, Matthias
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p. 5120 - 5124
(2013/06/27)
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- Discrete iron complexes for the selective catalytic reduction of aromatic, aliphatic, and α,β-unsaturated aldehydes under water-gas shift conditions
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Iron-catalyzed reductions: Selective iron-catalyzed reduction of aldehydes with hydrogen generated in situ by the water-gas shift reaction is presented (see scheme). The generality and selectivity of this mild procedure are demonstrated by the efficient reduction of various aromatic, aliphatic and α,β-unsaturated aldehydes.
- Tlili, Anis,Schranck, Johannes,Neumann, Helfried,Beller, Matthias
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p. 15935 - 15939
(2013/02/21)
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- SULFONYL-SUBSTITUTED BICYCLIC COMPOUNDS AS MODULATORS OF PPAR
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The present invention relates to compounds and methods useful as inhibitors of PPAR, particularly PPARδ, and for the treatment or prevention of PPAR-mediated diseases, including metabolic diseases.
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Page/Page column 17
(2008/06/13)
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- Further naphthylcombretastatins. An investigation on the role of the naphthalene moiety
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By synthesis and biological studies of new naphthalene analogues of combretastatins, we have found that the naphthalene is a good surrogate for the isovanillin moiety (3-hydroxy-4-methoxyphenyl) of combretastatin A-4, always generating highly cytotoxic analogues when combined with the 3,4,5-trimethoxyphenyl or related systems. On the other hand, when the naphthalene replaces the 3,4,5-trimethoxyphenyl moiety, the cytotoxic activity is largely decreased. The most cytotoxic naphthalene analogues of combretastatins, which also produce inhibition of tubulin polymerization, exerted their antimitotic effects through microtubule network disruption and subsequent G2/M arrest of the cell cycle in human cancer cells.
- Maya, Ana B. S.,Pérez-Melero, Concepción,Mateo, Carmen,Alonso, Dulce,Fernández, José Luis,Gajate, Consuelo,Mollinedo, Faustino,Peláez, Rafael,Caballero, Esther,Medarde, Manuel
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p. 556 - 568
(2007/10/03)
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- Process for preparing benzyl alcohols and their use
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Benzyl alcohols, particularly those which bear fluorine substituents or fluoroalkyl substituents on the benzyl ring, can be obtained by formylation of corresponding aryl bromides to form benzaldehydes and reduction of the latter using further formate, wherein the benzaldehydes formed do not have to be isolated.
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- METHOD FOR TREATING ANXIETY
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The present invention provides a method for treating anxiety in humans using azacyclic or azabicyclic compounds.
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- HETEROCYCLIC COMPOUNDS AND THEIR PREPARATION AND USE
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The present invention relates to therapeutically active azacyclic or azabicyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating diseases in the central nervous system caused by malfunctioning of the muscarinic cholinergic system.
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- DIPHENYLETHANE DERIVATIVES
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Diphenylethane derivatives of the formula are described; wherein R1 is a heterocyclyl radical selected from the group consisting of 1,2,4-triazolyl, optionally-substituted imidazolyl, pyridyl and pyrimidinyl radicals; R2 and R3, which may be the same or d
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- Antimalarials. Synthesis and antimalarial activity of 1 (4 methoxycinnamoyl) 4 (5 phenyl 4 oxo 2 oxazolin 2 yl)piperazine and derivatives
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The preparation and activity against Plasmodium berghei of derivatives of 1 (4 methoxycinnamoyl) 4 (5 phenyl 4 oxo 2 oxazolin 2 yl)piperazine are described. Replacement of the cinnamoyl group was accomplished by acylation or alkylation of 1 (5 phenyl 4 oxo 2 oxazolin 2 yl)piperazine. Modifications of the 5 phenyl group were prepared either by a sequence of reactions involving mandelic ester pemoline piperazine pemoline or by the reaction of 5 aryl 2 thio 2,4 oxazolidinedione with piperazine or N substituted piperazines. In a similar manner, pemoline was allowed to react with N arylpiperazine, hexahydro 1H 1,4 diazepine, and 2,6 dimethylpiperazine to provide N arylpiperazine pemoline derivatives and variations in the piperazine moiety. Several compounds in which the 2 oxazolin 4 one ring was replaced with other heterocyclic rings were prepared as were several open chain analogs. Five compounds (three of them substituted in the para position of the 5 phenyl group and two N arylpiperazine pemoline derivatives) were found to be active against Plasmodium berghei. The remaining active compound possessed changes in the cinnamoyl group and substitution on the 5 phenyl group.
- Herrin,Pauvlik,Schuber,Geiszler
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p. 1216 - 1223
(2007/10/04)
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