- Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
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Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
- Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
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p. 4623 - 4661
(2021/05/07)
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- Sequential C-S and S-N Coupling Approach to Sulfonamides
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A one-pot three-component reaction involving nitroarenes, (hetero)arylboronic acids, and potassium pyrosulfite leading to sulfonamides was described. A broad range of sulfonamides bearing different reactive functional groups were obtained in good to excellent yields through sequential C-S and S-N coupling that does not require metal catalysts.
- Chen, Kai,Chen, Wei,Han, Bing,Chen, Wanzhi,Liu, Miaochang,Wu, Huayue
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supporting information
p. 1841 - 1845
(2020/03/04)
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- Characteristic Hydrogen Bonding Observed in the Crystals of Aromatic Sulfonamides: 1D Chain Assembly of Molecules and Chiral Discrimination on Crystallization
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N-Phenylbenzenesulfonamides exist preferentially in (+)- or (-)-synclinal conformations, which place the aromatic rings at both ends in the same direction with a twist. We have systematically analyzed the crystal structure of secondary aromatic sulfonamides bearing methyl, ethyl, and/or methoxy groups on the benzene rings. Intermolecular hydrogen bonding between the sulfonamide protons and sulfonyl oxygens was observed in 81 out of 85 crystals. The intermolecular hydrogen-bonding patterns could be classified into four types, i.e. Dimeric, Zigzag, Helical, and Straight patterns, with retention of the synclinal conformation of the sulfonamide moiety. We investigated the relationship between the hydrogen-bonding pattern and the proportion of the compounds that show chiral crystallization. On the basis of our classification of the intermolecular hydrogen bonds of aromatic sulfonamides, the crystals with Dimeric and Zigzag patterns, which both have enantiomeric synclinal conformers, intrinsically become achiral, except for kryptoracemates. In contrast, a high proportion of compounds with Helical or Straight patterns in the crystals showed chiral crystallization. Our classification is useful for discussion regarding the chirality of molecular assemblies, on the basis of the conformational chirality of the molecules in the crystal.
- Kikkawa, Shoko,Masu, Hyuma,Katagiri, Kosuke,Okayasu, Misaki,Yamaguchi, Kentaro,Danjo, Hiroshi,Kawahata, Masatoshi,Tominaga, Masahide,Sei, Yoshihisa,Hikawa, Hidemasa,Azumaya, Isao
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p. 2936 - 2946
(2019/05/10)
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- Copper-catalyzed denitrogenative N-arylation of sulfoximines and sulfonamides with arylhydrazines
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A Cu-mediated ligand-free arylation of NH-sulfoximines and sulfonamides by arylhydrazine hydrochlorides was herein demonstrated. The oxidative transformation provided an easy access towards N-aryl sulfoximines and sulfonamides in high yields (up to 93% yields) with broad functional groups tolerance (up to 36 examples). The protocol was proposed to take place through the free radical pathway based on the results of control reactions and EPR analysis.
- Dong, Wanrong,Liu, Chaoyang,Ma, Xinchi,Zhang, Yingjun,Peng, Zhihong,Xie, Dexun,An, Delie
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p. 3886 - 3893
(2019/06/18)
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- Sulfonyl imide or sulfonamide of the denitrification arylation method and product and application
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A sulfonyl imide or sulfonamide of the denitrification arylation method and product and application, sulfonimide or sulfonamide of the denitrification arylation method, comprises the following steps: to arylhydrazine and sulfonyl imide or sulfonamide as raw material, the catalyst palladium salt, alkali, solvent and oxidizing agent in the presence of, prepared N - aryl sulfonyl imide or N - aryl sulfonamides. The sulfonimide or sulfonamide of the denitrification arylation method, by adopting the arylhydrazine and sulfonimide or sulfonamide as raw materials used to prepare N - aryl sulfonyl imide or N - aryl sulfonamides, arylhydrazine because of having low cost, high reactivity and easy accessibility and the like, can make the sulfonyl imide or a sulfonamide for the arylation of the method cost is relatively low. The arylhydrazine as aryl group donor, the reaction by-product is N2 And H2 O, so it has the characteristics of green and environmental protection.
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Paragraph 0066-0073
(2019/03/31)
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- Selective cleavage of the N-propargyl group from sulfonamides and amides under ruthenium catalysis
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The selective cleavage of the N-propargyl group from sulfonamides and amides under ruthenium catalysis is described. The reaction tolerates a broad range of functional groups, and the desired products were obtained in 10–95% yield.
- Wang, Jingjing,Li, Feng,Pei, Wenlong,Yang, Mixue,Wu, Yidan,Ma, Danyang,Zhang, Furong,Wang, Jianhui
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supporting information
p. 1902 - 1905
(2018/04/19)
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- Palladium-catalyzed desulfitative arylation of sulfonamides with sodium arylsulfinates
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A Pd(II)-catalyzed desulfitative arylation protocol between sulfonamides and sodium arylsulfinates was herein reported. The direct arylation reaction was successfully achieved by a Pd(II)/Ag(I)-mediated system without participation of any external ligands with a release of SO2. And different N-aryl sulfonamides were obtained readily in up to 86% yields, exhibiting good functional groups tolerance (25 examples).
- Zhao, Zijian,Lian, Yan,Zhao, Chang,Wang, Bing
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supporting information
p. 1436 - 1442
(2018/06/01)
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- Sulfonamidation of Aryl and Heteroaryl Halides through Photosensitized Nickel Catalysis
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Herein we report a highly efficient method for nickel-catalyzed C?N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N-aryl and N-heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy-transfer mechanism wherein C?N bond reductive elimination occurs from a triplet excited NiII complex. Late-stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated.
- Kim, Taehoon,McCarver, Stefan J.,Lee, Chulbom,MacMillan, David W. C.
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supporting information
p. 3488 - 3492
(2018/03/05)
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- Visible Light-Induced Radical Rearrangement to Construct C-C Bonds via an Intramolecular Aryl Migration/Desulfonylation Process
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A highly efficient intramolecular selective aryl migration/desulfonylation of 2-bromo-N-aryl-N-(arenesulfonyl)amide via visible light-induced photoredox catalysis has been accomplished. This approach allows for the construction of a variety of multisubstituted N,2-diarylacetamide under mild reaction conditions.
- Li, Yuyuan,Hu, Bei,Dong, Wuheng,Xie, Xiaomin,Wan, Jun,Zhang, Zhaoguo
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p. 7036 - 7041
(2016/08/30)
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- Sulfonamide formation from sodium sulfinates and amines or ammonia under metal-free conditions at ambient temperature
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A novel, practical and highly efficient method for the construction of a variety of sulfonamides mediated by I2 was demonstrated. The reaction proceeds readily at room temperature using a variety of sodium sulfinates and amines or ammonia in water in a metal-, base-, ligand-, or additive-free protocol. Primary, secondary and tertiary sulfonamides were obtained in good to excellent yields with a broad range of functional group tolerability. This journal is
- Yang, Kai,Ke, Miaolin,Lin, Yuanguang,Song, Qiuling
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supporting information
p. 1395 - 1399
(2015/03/18)
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- Design, synthesis and structure-activity relationship of new HSL inhibitors guided by pharmacophore models
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Hormone-sensitive lipase (HSL) is a critical enzyme involved in the hormonally regulated release of fatty acids and glycerol from adipocyte lipid stores. Its inhibition may improve insulin sensitivity and blood glucose handling in type 2 diabetes. Accordingly, many small-molecule HSL inhibitors have recently been identified. In continuation of our efforts for discovery of new HSL inhibitors, we prepared a variety of esters, amides, sulfonamides and sulfonate esters capable of fitting two pharmacophore models that we developed and published earlier. The tested compounds were synthesized via coupling reactions of aroyl chlorides or sulfonyl chlorides with phenols, amines and related derivatives. Our efforts led to the identification of interesting compounds of low micromolar anti-HSL bioactivities, which have potential to be developed into effective antidiabetic agents.
- Al-Shawabkeh, Jumana D.,Al-Nadaf, Afaf H.,Dahabiyeh, Lina A.,Taha, Mutasem O.
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p. 127 - 145
(2014/03/21)
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- Copper-catalyzed N-arylation of sulfonamides with aryl bromides under mild conditions
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This Letter describes a copper catalyzed sulfonamide coupling reaction with aryl bromides to form N-aryl sulfonamides under mild conditions, including the first examples of Cu-catalyzed sulfonamide coupling at room temperature. The reaction protocol tolerates a broad range of substrates including a variety of primary and secondary sulfonamides and challenging heteroaryl bromides such as 2-bromothiazole.
- Wang, Xiang,Guram, Anil,Ronk, Michael,Milne, Jacqueline E.,Tedrow, Jason S.,Faul, Margaret M.
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supporting information; experimental part
p. 7 - 10
(2012/01/06)
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- Copper-catalysed N-arylation of arylsulfonamides with aryl bromides and aryl iodides using KF/Al2O3
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An efficient synthesis of N-arylsulfonamides with a variety of aryl bromides, aryl iodides and heteroaryl bromides using KF/Al2O 3 as a suitable base, CuI as an inexpensive catalyst and N,N′dimethylethylenediamine (N,N′-DMEDA) as an effective ligand is described. Indian Academy of Sciences.
- Hosseinzadeh, Rahman,Tajbakhsh, Mahmood,Mohadjerani, Maryam,Alikarami, Mohammad
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experimental part
p. 143 - 148
(2010/11/16)
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- Copper-catalyzed cross-coupling of sulfonamides with aryl iodides and bromides facilitated by amino acid ligands
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A highly general, convenient, and inexpensive catalyst system was developed for the N-arylation of sulfonamides with aryl iodides or bromides by using 5-20 mol % of CuI as catalyst, 20 mol % of N-methylglycine (for aryl iodides) or N,N-dimethylglycine (for aryl bromides) as ligand, and K3PO 4 as base.
- Deng, Wei,Liu, Lei,Zhang, Chen,Liu, Min,Guo, Qing-Xiang
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p. 7295 - 7298
(2007/10/03)
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- Ortho effect in dissociation of substituted N-phenylbenzenesulfonamides
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Twenty-five 2,2′-disubstituted N-phenylbenzenesulfonamides (2-X-C6H4SO2NHC6H4-Y-Z′) were synthesised and their purity checked by elemental analysis. This set of model substrates involved all possible combinations of methoxy, methyl, hydrogen, chloro, and nitro substituents. The dissociation constants of the sulfonamides were determined by potentiometric titration in methanol, pyridine, dimethyl sulfoxide, N,N-dimethylformamide, acetone, and acetonitrile. The dissociation constants pKHA obtained were correlated with various sets of substituent constants describing electronic and steric effects of the substituents, and the statistically treated data were used to discuss the contribution of the substituent effects in the dissociation and the difference between the effects transmitted from the two rings. A linear regression model explaining 99% of the variability of experimental data in all the solvents has been found and discussed. Moreover, the experimental data were also interpreted by the methods using latent variables, the principal component analysis (PCA) and conjugated deviation analysis (CDA), and two latent variables were shown to be statistically significant in the description of dissociation. The first obviously describes common action of electronic and steric effects of substituents; the other probably concerns a combined effect of substituent and solvent on the position of acid-base equilibrium.
- Nadvornik, Jiri,Ludwig, Miroslav
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p. 1380 - 1392
(2007/10/03)
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- N- and 2-Substituted N-(Phenylsulfonyl)glycines as Inhibitors of Rat Lens Aldose Reductase
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A variety of N-(phenylsulfonyl)-N-phenylglycines 5, N-(phenylsulfonyl)-2-phenylglycines 6, and N-(phenylsulfonyl)anthranilic acids 7 were prepared as analogues of the N-(phenylsulfonyl)glycine 1 aldose reductase inhibitors.In the rat lens assay, several derivatives of 5 display greater inhibitory activity than the corresponding glycines 1, suggesting that N-phenyl substitution enhances affinity for aldose reductase.Enzyme kinetic evaluations of the 4-benzoylamino analogues of 5 and 1 demonstrate that these compounds produce inhibition by the same mechanism.However, the significant differences in relative inhibitory potencies between compounds of series 5 and 1 may indicate that these compounds do not interact with the inhibitor binding site in precisely the same manner.Evaluation of the individual enantiomers of series 6 reveals that the S isomers are substantially more active than the corresponding R isomers.Also, with the exception of the naphthalene analogue 6n, the S stereoisomers of this series display greater inhibitory potencies than the glycines 1.The anthranilates 7 generally are less active than the glycines 1, demonstrating that direct incorporation of an aromatic ring in the glycine side chain may result in a decrease in affinity for aldose reductase.
- DeRuiter, Jack,Borne, Ronald F.,Mayfield, Charles A.
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p. 145 - 151
(2007/10/02)
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- Possibilities and Limits of the Carbanionically Induced Sulfonamide-Aminosulfone Rearrangement
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When transfering the title reaction to the 2- and 1-naphthyltoluenesulfonamides 5 and 10, the -shift of the arylsulfonyl group proceeds into the 3- and 2-position (to give 9 and 12, respectively), which is in full compliance with optimal conjugative and steric conditions for the relevant intermediates 8 and 11.Attemps to initiate comparable -rearrangements through the o-lithiated biphenyl derivative 17 and the p-lithiated N-phenyltoluenesulfonamide 23 led again, after extended transmetalation cascades, to the conventional -rearrangement products 22 and 32, respectively.In attempting to cause in the o-tolylbenzenesulfonamide 49 an anionically induced -sulfonyl shift into the benzyl position, two fragments of the starting molecule combined to give the novel heteropolycycle 51.Finally, it could be shown that contrary to the literature, the sulfonamides 46 and 57 rearrange also photolytically to the o-aminosulfones 45 and 58.
- Hellwinkel, Dieter,Lenz, Ruediger
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- Kinetische Verfolgung der Sulfamidbildung mittels quantitativer Differentialthermoanalyse
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Die Reaktion zwischen Benzolsulfochlorid und einigen Anilinderivaten kann im Bereich oberchalb 200 K mit der dynamischen Technik der DTA untersucht werden, wobei sich eine Reaktion 2.Ordnung ergibt.Aktivierungsparameter und Reaktionsenthalpien werden durch die Anilinsubstituenten beeinflusst.
- Anderson, H.,Hoffmann, U.,Haberland, D.
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p. 639 - 648
(2007/10/02)
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