- Transaminase-Mediated Amine Borrowing via Shuttle Biocatalysis
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Shuttle catalysis has emerged as a useful methodology for the reversible transfer of small functional groups, such as CO and HCN, and goes far beyond transfer hydrogenation chemistry. While a biocatalytic hydrogen-borrowing methodology is well established, the biocatalytic borrowing of alternative functional groups has not yet been realized. Herein, we present a new concept of amine borrowing via biocatalytic shuttle catalysis, which has no counterpart in chemo-shuttle catalysis and allows efficient intermolecular amine shuttling to generate reactive intermediates in situ. By coupling this dynamic exchange with an irreversible downstream step to displace the reaction equilibrium in the forward direction, high conversion to target products can be achieved. We showcase the potential of this amine-borrowing methodology using a biocatalytic equivalent of both the Knorr-pyrrole synthesis and Pictet-Spengler reaction.
- O'Reilly, Elaine,O'Sullivan, Rachel,Ryan, James,Taday, Freya
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supporting information
(2022/01/04)
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- Structure-Enabled Discovery of Novel Macrocyclic Inhibitors Targeting Glutaminase 1 Allosteric Binding Site
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The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural analysis led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate molecule 13b (LL202) was identified with robust GLS1 inhibitory activity (IC50 = 6 nM) and high GLS1 binding affinity (SPR, Kd = 24 nM; ITC, Kd = 37 nM). The X-ray crystal structure of the 13b-GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, 13b clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism. Furthermore, 13b exhibited a similar in vivo antitumor activity as CB839. This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-molecule inhibitors, with the potential to improve the binding affinity to the targets.
- Xu, Xi,Wang, Jubo,Wang, Min,Yuan, Xinyu,Li, Lei,Zhang, Chao,Huang, Huidan,Jing, Tian,Wang, Chenchen,Tong, Chao,Zhou, Liwen,Meng, Ying,Xu, Pengfei,Kou, Junping,Qiu, Zhixia,Li, Zhiyu,Bian, Jinlei
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p. 4588 - 4611
(2021/05/04)
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- Macrocyclic glutaminase GLS1 inhibitor or pharmaceutically acceptable salt thereof and preparation method and application thereof
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The invention relates to the field of biological medicine, in particular to a series of macrocyclic glutaminase inhibitors, a synthesis method and medical application thereof, and particularly relatesto prevention or treatment of glutaminase related diseases. Meanwhile, the inventor performs a series of in-vitro anti-tumor activity evaluation on the synthesized compounds, and particularly, most of the compounds have good inhibitory activity on cancer cells.
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Sheet 0140; 0142-0144
(2020/08/02)
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- Preparation method of phenylacetic acid type compound
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The invention discloses a preparation method of a phenylacetic acid type compound. The preparation method of the phenylacetic acid type compound I comprises the following steps that in a solvent and aCO gas phase system, a benzyl halide type compound II, pyridine-2-cobalt carboxylate, palladium acetate and alkaline neutralizers take carbonylation reaction to obtain the phenylacetic acid type compound I. A mixed catalytic system has a synergistic effect; the whole use quantity of catalysts is greatly reduced. When the mixed catalyst is used, a better catalytic effect can be achieved; the characteristics of easily obtaining the catalyst, avoiding the production safety risk of toxic three wastes and the like, reducing the reaction pressure, realizing mild reaction conditions, reducing the production risk, facilitating the production and the like are realized. The formulas are shown in description.
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Paragraph 0116; 0117; 0118; 0128-0130
(2019/02/21)
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- Ruthenium-catalyzed umpolung carboxylation of hydrazones with CO2
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The first ruthenium-catalyzed umpolung carboxylation of hydrazones with CO2 to generate important aryl acetic acids is reported. Besides aldehyde hydrazones, a variety of ketone hydrazones, which have not been successfully applied in previous umpolung reactions with other reactive electrophiles, also show high reactivity and selectivity under mild conditions. Moreover, this operationally simple protocol features good functional group tolerance, is readily scalable, and offers easy derivation of important structures, including bioactive felbinac and adiphenine. Computational studies reveal that this umpolung reaction proceeds through the generation of a Ru-nitrenoid followed by concerted [4 + 2] cycloaddition with CO2.
- Yan, Si-Shun,Zhu, Lei,Ye, Jian-Heng,Zhang, Zhen,Huang, He,Zeng, Huiying,Li, Chao-Jun,Lan, Yu,Yu, Da-Gang
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p. 4873 - 4878
(2018/06/07)
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- Development of a photoswitchable antagonist of NMDA receptors
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N-methyl–Daspartate receptors (NMDARs) are vital for neurological processes such as learning, memory, and synaptic plasticity. As such, small molecules that modulate their function are of interest in the study of numerous neurological diseases. We have synthesized a small library of photoswitches that modulate NMDAR function. The most efficient photoswitch to date is based on a known ligand of the glycine binding site and shows significant subtype selectivity.
- Hartrampf, Felix W.W.,Barber, David M.,Gottschling, Kevin,Leippe, Philipp,Hollmann, Michael,Trauner, Dirk
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p. 4905 - 4912
(2017/07/27)
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- QUINOLONE DERIVATIVES AS FIBROBLAST GROWTH FACTOR RECEPTOR INHIBITORS
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Compounds of formula (I) that are Fibroblast Growth Factor Inhibitors (FGFR) and are therefore useful for the treatment of diseases treatable by inhibition of FGFR are disclosed. Also disclosed are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 78
(2016/12/16)
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- Metal-free, catalytic regioselective oxidative conversion of vinylarenes: A mild approach to phenylacetic acid derivatives
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A new synthetic approach towards the synthesis of phenylacetic acids from aromatic alkenes has been developed for the first time under mild conditions by employing non-toxic reagents such as molecular iodine and oxone. This metal-free catalytic regioselective oxygenation of vinylarenes proceeds via tandem iodofunctionalization/de-iodination induced rearrangement.
- Kodumuri, Srujana,Peraka, Swamy,Mameda, Naresh,Chevella, Durgaiah,Banothu, Rammurthy,Nama, Narender
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p. 6719 - 6723
(2016/02/03)
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- QUINOLONE DERIVATIVES AS FIBROBLAST GROWTH FACTOR INHIBITORS
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Compounds of formula (Ι') that are Fibroblast Growth Factor Inhibitors (FGFR) and are therefore useful for the treatment of diseases treatable by inhibition of FGFR are disclosed. Also disclosed are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 55
(2014/12/09)
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- Palladium-catalyzed silver-mediated α-arylation of acetic acid: A new approach for the α-arylation of carbonyl compounds
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A new approach for the α-arylation of acetic acid through Pd-catalyzed silver-mediated direct C-H arylation of acetic acid with aryl iodides was developed. This protocol provided a straightforward method for the synthesis of a diverse set of α-phenylacetic acids. Palladium served on a silver platter: A new approach for the α-arylation of acetic acid through Pd-catalyzed silver-mediated direct C-H arylation of acetic acid with aryl iodides is presented. This protocol provides a straightforward method for the synthesis of a diverse set of α-phenylacetic acids. Deuteration experiments are performed to help elucidate the reaction mechanism.
- Wu, Guo-Jie,Guan, Jing,Han, Fu-She,Zhao, Yu-Long
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p. 1589 - 1593
(2014/06/24)
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- Development of a one-pot method for the homologation of aldehydes to carboxylic acids
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A highly efficient method is described for the one-carbon homologation of aldehydes to carboxylic acid derivatives employing the reaction of a 1,1-bis-dimethylphosphonate derivative with the aldehyde and controlled acid hydrolysis of the derived α-phosphonoenamine intermediate.
- McNulty, James,Das, Priyabrata
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experimental part
p. 7794 - 7800
(2009/12/26)
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- An improved synthesis of α-phosphonoenamines based on a modified Peterson olefination
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An efficient, stereoselective method for the synthesis of α-phosphonoenamines based on a modified Peterson olefination is described. The carbanion derived from isolatable intermediate 2 reacts with aromatic or aliphatic aldehydes selectively eliminating in Peterson fashion to deliver functionally rich α-phosphonoenamines 3. The synthetic utility of these enamines is demonstrated by their hydrolysis yielding the homologous carboxylic acids in good yield.
- McNulty, James,Das, Priyabrata,Gosciniak, Don
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p. 281 - 285
(2008/03/30)
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- COMPOUNDS
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A compound of formula (I): compositions and medicaments containing the same as well as processes for the preparation and use of such compounds, compositions and medicaments, particularly in diseases associated with inappropriate Aurora activity.
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Page/Page column 44
(2010/11/26)
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- ENZYME MODULATORS AND TREATMENTS
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Novel compounds and methods of using those compounds for the treatment of inflammatory conditions, hyperproliferative diseases, cancer, and diseases characterized by hypervascularization are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein ab1 kinase protein, bcr-ab1 kinase protein, braf kinase protein, VEGFR kinase protein, or PDGFR kinase protein comprises the step of contacting said kinase protein with the novel compounds.
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Page/Page column 350
(2008/06/13)
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- A novel method for synthesis of arylacetic acids from aldehydes, N-(2,3,4,6-tetra-O-pivaloylated-D-glucopyranosyl)amine and trimethylsilylcyanide
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A novel synthetic approach for the preparation of arylacetic acids via the reaction of aldehydes, N-(2,3,4,6-tetra-O-pivaloylated-D-glucopyranosyl)amine and trimethylsilylcyanide was developed, in which the N-(2,3,4,6-tetra-O- pivaloylated-D-glucopyranosyl)amine can be recycled conveniently and reused efficiently.
- Zhou, Guo-Bin,Zhang, Peng-Fei,Pan, Yuan-Jiang
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p. 5671 - 5677
(2007/10/03)
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- Synthesis, selective aldose reductase inhibitory profile and antihyperglycaemic potential of certain parabanic acid derivatives
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Synthesis and aldose reductase inhibitory profile of certain parabanic acid derivatives 1a-p is described. Also, the antihyperglycaemic potential of these compounds was studied. The most active inhibitors in this series were compounds 1 g, 1p, and 1o which showed inhibitory activity, 36.6, 90 and 91% respectively, at concentration 1 × 10-4. Their IC50 were 2 × 10-6, 7.5 × 10-8 and 5 × 10-8, respectively. Compound 1o exhibited pronounced antihyperglycaemic effect.
- Nabil Aboul-Enein,El-Azzounya,Maklad,Attia,Wiese
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p. 329 - 350
(2007/10/03)
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- Quinolones as gonadotropin releasing hormone (GnRH) antagonists: Simultaneous optimization of the C(3)-aryl and C(6)-substituents
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A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Young, Jonathan R.,Huang, Song X.,Chen, Irene,Walsh, Thomas F.,DeVita, Robert J.,Wyvratt Jr., Matthew J.,Goulet, Mark T.,Ren, Ning,Lo, Jane,Yang, Yi Tien,Yudkovitz, Joel B.,Cheng, Kang,Smith, Roy G.
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p. 1723 - 1727
(2007/10/03)
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- Synthesis of phenylacetic acids under rhodium-catalyzed carbonylation conditions
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Benzyl halides are efficiently carbonylated to phenylacetic acids in the presence of a catalytic amount of the dimer of chloro(1,5-cyclooctadiene)rhodium(I) in formic acid. Under these reaction conditions, sensitive functionalities such as esters and nitriles are tolerated and the phenylacetic acids are obtained in good to high yields. (C) 2000 Elsevier Science Ltd.
- Giroux,Nadeau,Han
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p. 7601 - 7604
(2007/10/03)
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- Use of antibodies to dissect the components of a catalytic event. the cyclopropenone hapten
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Antibodies elicited against the planar cyclopropenone hapten 1 efficiently catalyze ester hydrolysis, highlighting the importance of charge rather than shape complementarity as a design element of hydrolytic antibodies.
- Grynszpan, Flavio,Keinan, Ehud
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p. 865 - 866
(2007/10/03)
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- Experiments on the Chaperon effect in the nitration of aromatics
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A nitro group may be effectively delivered to the ortho position of alkylbenzenes, provided that a suitable chaperon function is located in α- position and a dilute of HNO3 in CH2Cl2 is used. The carbonyl function of an aldehyde or ketone is the best choice, but a carboxyl, alkoxycarbonyl, and amide groups all work well. The ether function showed a less pronounced ortho orientation effect, whereas the hydroxyl group was too prone to oxidation. Side reactions were minimal under the conditions employed. A para chaperon effect was seemingly at work in the CH2Cl2 nitration of benzenepropanenitrile. All the results were compared with the corresponding classical nitration in H2SO4.
- Strazzolini, Paolo,Giumanini, Angelo G.,Runcio, Antonio,Scuccato, Massimo
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p. 952 - 958
(2007/10/03)
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- A Mild Oxidation of Aromatic Amines
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Several primary aromatic amines have been converted to the corresponding nitro compounds in good yields.The oxidant was oxone (potassium peroxymonosulfate) and the reactions were performed in 5 to 20percent aqueous acetone and buffered with sodium bicarbonate.
- Webb, Kevin S.,Seneviratne, Viran
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p. 2377 - 2378
(2007/10/02)
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- Orientation Effect of Side Chain Substituents in Aromatic Substitution. Induced Ortho Nitration
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The presence of a free carboxyl or ester function on the α-carbon of toluene induces the nitration of the phenyl ring in the ortho position at or above the statistical value (chaperon effect), when pure HNO3 is used in CH2Cl2 solution.This is at variance with the results of classical nitration in H2SO4, where p-nitration predominates by far and m-nitration occurs at a remarkable extent.The new finding is explained in terms of precomplex formation.
- Strazzolini, Paolo,Verardo, Giancarlo,Gorassini, Fausto,Giumanini, Angelo G.
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p. 1155 - 1161
(2007/10/02)
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- Diphosphonic acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
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Diphosphonate compounds, processes for their preparation and pharmaceutical compositions containing them and being useful for treating calcium metabolism disorders. The diphosphonates are of the formula STR1 wherein R1 and R2 are hydrogen, acyl or alkyl which can be substituted by aryl, R3 and R4 are hydrogen or alkyl or R3 and R4 together represent lower alkylene, R5 is a hydrogen atom or alkyl, X is a valency bond or alkylene, Y is a valency bond, alkylene or substituted alkylene, Z is hydrogen, hydroxyl or amino group optionally substituted by alkyl and n is 1, 2 or 3; and including the pharmacologically acceptable salts thereof.
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- Ru(III) Catalysed Oxidation of Aryl Styryl Ketones by Periodate in Acid Medium: A Kinetic Study
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Oxidation of unsubstituted and substituted phenyl styryl ketones by periodate in the presence of Ru(III) is first order each in and and fractional order in .The rate of reaction increases with decrease in .Each mol of aryl styryl ketone consumes two mol of periodate for complete oxidation and the products have been identified as the corresponding substituted benzoic acids and phenylacetic acids.A probable mechanism involves the formation of a 1:1 complex between Ru(III) and the substrate which is oxidised by periodate to Ru(V) complex in rate-determining step which later dissociates to give products.
- Swarnalakshmi, N.,Uma, V.,Sethuram, B.,Navaneeth Rao, T.
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p. 386 - 388
(2007/10/02)
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- Hydrolysis of 3-Nitrophenyl Acetate by β-Cyclodextrin in Sustituted Imidazole Buffers
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In order to examine the effects of substituted imidazoles upon cyclodextrin esterolysis, the title hydrolysis has been carried out at 30 deg C using imidazole, 2-methyl-, 2-isopropyl-, 2,4,5-trimethyl-, and 2-(1,1-dimethyl-2-hydroxyethyl)-imidazole.Observed pseudo-first-order rate constants (kobs) are analysed in terms of a Lineweaver-Burk-type equation to give the first-order rate constant (kcat) for a cyclodextrinester complex (CD-S) and an apparent dissociation constant (Kapp).The latter gives the dissociation constants (Kd and Ki) for CD-S and a cyclodextrin-imidazole complex.Using the equation kcat=kcat-OH + kcat-Imf, the second-order rate constants for CD-S due to hydroxide ion (kcat-OH) and due to an imidazole base (kcat-Im) are determined.A plot of kcat-Im versus pKa of the imidazoles gives β 0.62, and solvent D2O effects upon kcat-Im for 2-isopropyl- and 2,4,5-trimethyl-imidazole are estimated to be ca. 2.From these results, it is suggested that the imidazoles used here act as a general base catalyst for the cyclodextrin esterolysis.
- Akiyama, Masayasu,Ohmachi, Tadatoshi,Ihjima, Masao
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p. 1511 - 1516
(2007/10/02)
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- Hypertensive phenylalkylamines and salts thereof
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Compounds of the formula STR1 wherein R1 is hydrogen, --(CH2)n --R4 or --CO--R5, where n is 1 or 2, R4 is hydrogen, cyano or benzoyl, and R5 is hydrogen, lower alkoxy, benzyloxy, --CH2 --NH2, --CH(CH3)--NH2, --CH2 --NH--CH2 --C6 H5 or --CH(CH3)--NH--CH2 --C6 H5, R2 is hydrogen or methyl, and R3 is amino, nitro, --NH--CO--R6 or --NH--A--R7, where R6 is hydrogen, methyl, methoxy, ethoxy, methylthio or ethylthio, R7 is amino, methylamino or dimethylamino, and A is --CO-- or --SO2 --, provided, however, that R1 and R4 are other than hydrogen and R2 is other than hydrogen or methyl when R6 is hydrogen or methyl, and non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as hypertensives.
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- Phenylalkylamines and salts thereof
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Compounds of the formula STR1 wherein R1 is hydrogen, --(CH2)n --R4 or --CO--R5, where n is 1 or 2, R4 is hydrogen, cyano or benzoyl, and R5 is hydrogen, lower alkoxy, benzyloxy, --CH2 --NH2, --CH(CH3)--NH2, --CH2 --NH--CH2 --C6 H5 or --CH(CH3)--NH--CH2 --C6 H5, R2 is hydrogen or methyl, and R3 is amino, nitro, --NH--CO--R6 or --NH--A--R7, where R6 is hydrogen, methyl, methoxy, ethoxy, methylthio or ethylthio, R7 is amino, methylamino or dimethylamino, and A is --CO-- or --SO2 --, and non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as hypertensives.
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