- Multiprotein Dynamic Combinatorial Chemistry: A Strategy for the Simultaneous Discovery of Subfamily-Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3
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Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biomolecules. To date, most, if not all, biologically templated DCC systems employ only a single biomolecule to direct the self-assembly process. To expand the scope of DCC, herein, a novel multiprotein DCC strategy has been developed that combines the discriminatory power of a zwitterionic “thermal tag” with the sensitivity of differential scanning fluorimetry. This strategy is highly sensitive and could differentiate the binding of ligands to structurally similar subfamily members. Through this strategy, it was possible to simultaneously identify subfamily-selective probes against two clinically important epigenetic enzymes: FTO (7; IC50=2.6 μm) and ALKBH3 (8; IC50=3.7 μm). To date, this is the first report of a subfamily-selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins; thus it is of broad scientific interest.
- Das, Mohua,Yang, Tianming,Dong, Jinghua,Prasetya, Fransisca,Xie, Yiming,Wong, Kendra H. Q.,Cheong, Adeline,Woon, Esther C. Y.
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Read Online
- Meta -Non-flat substituents: A novel molecular design to improve aqueous solubility in small molecule drug discovery
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Aqueous solubility is a key requirement for small-molecule drug candidates. Here, we investigated the regioisomer-physicochemical property relationships of disubstituted benzenes. We found that meta-isomers bearing non-flat substituents tend to possess the lowest melting point and the highest thermodynamic aqueous solubility among the regioisomers. The examination of pharmaceutical compounds containing a disubstituted benzene moiety supported the idea that the introduction of a non-flat substituent at the meta position of a benzene substructure would be a promising approach for medicinal chemists aiming to improve the thermodynamic aqueous solubility of drug candidates, even though it might not be universally effective. This journal is
- Ichikawa, Yuki,Hiramatsu, Michiaki,Mita, Yusuke,Makishima, Makoto,Matsumoto, Yotaro,Masumoto, Yui,Muranaka, Atsuya,Uchiyama, Masanobu,Hashimoto, Yuichi,Ishikawa, Minoru
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supporting information
p. 446 - 456
(2021/01/29)
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- Electrochemically generatedN-iodoaminium species as key intermediates for selective methyl sulphonylimination of tertiary amines
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Reported herein is a straightforward protocol for approachingN-sulphonylamidinesviaan electricity-driven, iodine-mediated cross dehydrogenative condensation (CDC) between sulphonamides and tertiary amines, which features exclusive N-CH3selectivity for the amine partners. Mechanistic studies indicate that anin situgeneratedN-iodoaminium species serves as the key intermediate.
- Huang, Binbin,Yang, Chao,Zhou, Jia,Xia, Wujiong
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supporting information
p. 5010 - 5013
(2020/05/18)
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- Primary Sulfonamide Synthesis Using the Sulfinylamine Reagent N-Sulfinyl- O-(tert-butyl)hydroxylamine, t-BuONSO
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Sulfonamides have played a defining role in the history of drug development and continue to be prevalent today. In particular, primary sulfonamides are common in marketed drugs. Here we describe the direct synthesis of these valuable compounds from organometallic reagents and a novel sulfinylamine reagent, t-BuONSO. A variety of (hetero)aryl and alkyl Grignard and organolithium reagents perform well in the reaction, providing primary sulfonamides in good to excellent yields in a convenient one-step process.
- Davies, Thomas Q.,Hall, Adrian,Skolc, David,Tilby, Michael J.,Willis, Michael C.
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supporting information
p. 9495 - 9499
(2020/12/21)
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- Manganese-Catalyzed N-Alkylation of Sulfonamides Using Alcohols
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An efficient manganese-catalyzed N-alkylation of sulfonamides has been developed. This borrowing hydrogen approach employs a well-defined and bench-stable Mn(I) PNP pincer precatalyst, allowing benzylic and simple primary aliphatic alcohols to be employed as alkylating agents. A diverse range of aryl and alkyl sulfonamides undergoes mono-N-alkylation in excellent isolated yields (32 examples, 85% average yield).
- Reed-Berendt, Benjamin G.,Morrill, Louis C.
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p. 3715 - 3724
(2019/03/30)
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- Highly Chemoselective NH- and O-Transfer to Thiols Using Hypervalent Iodine Reagents: Synthesis of Sulfonimidates and Sulfonamides
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Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with three new S-X connections being made selectively in one pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product distribution, converting the sulfonimidate to the sulfonamide. Studies into the possible intermediate species are presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species forming the same products.
- Tota, Arianna,St John-Campbell, Sahra,Briggs, Edward L.,Estévez, Gala Ogalla,Afonso, Michelle,Degennaro, Leonardo,Luisi, Renzo,Bull, James A.
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supporting information
p. 2599 - 2602
(2018/05/22)
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- N-acyl sulfamide FBPase inhibitor, preparation method thereof, drug composition and application
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The invention discloses an N-acryl sulfamide FBPase inhibitor of a novel structure, and a preparation method thereof, a drug composition and an application, and particularly relates to an N-acryl sulfamide FBPase inhibitor shown in the formula I, a salt thereof for medicine, a preparation method, a composition comprising one or more compounds, an application of the compound in preparing the FBPase inhibitor or a drug for treating FBPase-related diseases, and an application in preparing a drug for preventing and/or treating diabetes. The formula is shown in the description.
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Paragraph 2483; 2485; 2486
(2017/09/08)
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- Cu(II)-catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids to primary aryl sulfonamides
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A novel protocol for CuO-catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids was developed. It is the first example of using an accessible amino acid as an ammonia synthetic equivalent for the synthesis of primary aryl sulfonamides via oxidative decarboxylation/elimination reactions. The present protocol shows excellent functional group tolerance and provides an efficient method for the synthesis of primary aryl sulfonamides in excellent yields.
- Zhou, Liandi,Li, Xiaokang,Liu, Wei,Zhao, Yongli,Chen, Junmin
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p. 1299 - 1306
(2016/08/16)
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- A general iodine-mediated synthesis of primary sulfonamides from thiols and aqueous ammonia
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A general and efficient methodology for preparing primary sulfonamides has been developed. In the presence of iodine as the catalyst and TBHP (70% in water) as the oxidant, a wide range of primary sulfonamides were prepared from the corresponding thiols and aqueous ammonia in moderate to good yields.
- Feng, Jian-Bo,Wu, Xiao-Feng
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supporting information
p. 6951 - 6954
(2016/07/30)
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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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p. 1395 - 1399
(2015/03/18)
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- Orally active aminopyridines as inhibitors of tetrameric fructose-1,6-bisphosphatase
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A novel sulfonylureido pyridine series exemplified by compound 19 yielded potent inhibitors of FBPase showing significant glucose reduction and modest glycogen lowering in the acute db/db mouse model for Type-2 diabetes. Our inhibitors occupy the allosteric binding site and also extend into the dyad interface region of tetrameric FBPase.
- Hebeisen, Paul,Haap, Wolfgang,Kuhn, Bernd,Mohr, Peter,Wessel, Hans Peter,Zutter, Ulrich,Kirchner, Stephan,Ruf, Armin,Benz, J?rg,Joseph, Catherine,Alvarez-Sánchez, Rubén,Gubler, Marcel,Schott, Brigitte,Benardeau, Agnes,Tozzo, Effie,Kitas, Eric
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scheme or table
p. 3237 - 3242
(2011/07/07)
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- PYRAZINE DERIVATIVES AND USE AS PI3K INHIBITORS
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The present invention is related to pyrazine derivatives of Formula (I) in particular for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung injuries.
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Page/Page column 41
(2008/06/13)
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- Acyl sulfonamide anti-proliferatives: Benzene substituent structure-activity relationships for a novel class of antitumor agents
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Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.
- Lobb, Karen L.,Hipskind, Philip A.,Aikins, James A.,Alvarez, Enrique,Cheung, Yiu-Yin,Considine, Eileen L.,De Dios, Alfonso,Durst, Gregory L.,Ferritto, Rafael,Grossman, Cora Sue,Giera, Deborah D.,Hollister, Beth A.,Huang, Zhongping,Iversen, Philip W.,Law, Kevin L.,Li, Tiechao,Lin, Ho-Shen,Lopez, Beatriz,Lopez, Jose E.,Martin Cabrejas, Luisa M.,McCann, Denis J.,Molero, Victoriano,Reilly, John E.,Richett, Michael E.,Shih, Chuan,Teicher, Beverly,Wikel, James H.,White, Wesley T.,Mader, Mary M.
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p. 5367 - 5380
(2007/10/03)
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- Excitatory amino acid receptor antagonists
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The present invention provides compounds of Formula I or Formula II, or the pharmaceutically acceptable salts or prodrugs thereof, pharmaceutical compositions comprising compounds or Formula I or Formula II, and methods for treating neurological disorders and neurodegenerative diseases, particularly migraine.
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- Unconventional Regiospecific Syntheses of Aromatic Carbonamides and Thiocarbonamides by Means of Tin-Mediated Friedel-Crafts Reactions
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Friedel-Crafts reactions of stannylarenes 1 with tosyl isocyanate (TsNCO, 2) give N-tosylcarbonamides 3 via ipso substitution of the stannyl group.Thus, unconventionally substituted aromatic carbonamides can be obtained.The combination of the reaction of 1 and 2 with that of 1 and chlorosulfonyl isocyanate (14) allows one-pot syntheses of N-(arylsulfonyl)-substituted aromatic carbonamides with optional substitution patterns on both aromatic rings.The known ipso-specific substitutions of stannylarenes with 14 are extended to bi- and tricyclic arenes as well as to thiophenes 6 and 22.One stannyl group can serve as a leaving group for two aromatic systems, as shown with diaryldialkyltins 29.Also, stannylalkanes such as 27 react with 14 to afford alkylsulfonyl isocyanates and products of further reactions, such as 28.From the reactions of 1 with ethoxycarbonyl isocyanate (32), ortho- and meta-substituted aromatic thiocarbonamides 33 which are potential precursors for further syntheses, are accessible.The scope, limitations, and mechanism of these electrophilic substitutions are outlined.
- Arnswald, Martin,Neumann, Wilhelm P.
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p. 7022 - 7028
(2007/10/02)
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- Mild and Efficient Synthesis of Aromatic Sulfonamides by in situ Preparation of the Corresponding Sulfonyl Isothiocyanates
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A new reaction between chlorosulfonyl isocyanate (1) and trialkylstannyl-substituted arenes 2a-k, 7, 9 is described.It provides the aromatic sulfonyl isocyanates 3 or their derivatives, the sulfonamides 4a-j, the sulfonylcarbamates 5a-b, or sulfonylureas 6, respectively.The trialkylstannyl group as an efficient leaving group allows mild reaction conditions to be applied and unusual substitution patterns to be obtained, normally not accessible by electrophilic aromatic substitutions.Thus, sulfonamidation can be achieved in meta position to a trifluoromethyl group. Key words: Electrophilic aromatic substitution; sulfodestannalytion; isocyanates, sulfonyl, aromatic; sulfonyl compounds; trialkylarylstannanes, application of
- Arnswald, Martin,Neumann, Wilhelm P.
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p. 1997 - 2000
(2007/10/02)
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- DISSOCIATION OF SUBSTITUTED BENZENESULPHONAMIDES IN WATER, METHANOL AND ETHANOL
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Thirteen monosubstituted arylsulphonamides (XC6H4SO2NH2) and two 3,4-disubstituted arylsulphonamides (X2C6H3SO2NH2) have been synthetized and their dissociation constants have been measured by potentiometric titration in water, methanol, and ethanol.The Hammett substitution dependences have been calculated for all the media, and changes in the reaction constants due to transition from water to alcohols are discussed in confrontation with analogous dependences of benzoic acids.The reaction constant ρ found in methanol is lower than that in water.The dissociation constants have been treated by the method of the principal components and by multiple linear regression.
- Ludwig, Miroslav,Pytela, Oldrich,Kalfus, Karel,Vecera, Miroslav
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p. 1182 - 1192
(2007/10/02)
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