- Probing 2H-Indazoles as Templates for SGK1, Tie2, and SRC Kinase Inhibitors
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The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2-substituted aza-2H-indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so-far underrepresented aza-2H-indazole scaffold, indazoles were connected at the N2 position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza-2H-indazole derivatives showed good initial selective inhibition against SGK1, Tie2, and SRC kinases, with the best representatives having IC50 values in the range of 500 nm. In a comparative computational study, these data were analyzed and rationalized in light of docking studies.
- Schoene, Jens,Gazzi, Thais,Lindemann, Peter,Christmann, Mathias,Volkamer, Andrea,Nazaré, Marc
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p. 1514 - 1527
(2019/08/07)
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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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- BRD4-KINASE INHIBITORS AS CANCER THERAPEUTICS
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Disclosed herein are compounds that are inhibitors of BDR4 and their use in the treatment of cancer. Methods of screening for selective inhibitors of BDR4 are also disclosed. In certain aspects, disclosed are compounds of Formula I through IV.
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Page/Page column 233; 257
(2017/05/02)
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- METHODS OF INHIBITING BACTERIAL VIRULENCE AND COMPOUNDS RELATING THERETO
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The present invention relates to compounds and methods for the treatment of bacterial infections. Because their mechanism of action does not involve killing of bacteria or inhibiting their growth, the potential for these compounds to induce drug resistance in bacteria is minimized. Through inhibiting bacterial virulence, the present invention provides a novel means of treating bacterial infections.
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Paragraph 0196
(2017/01/31)
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- Potent Pan-Raf and Receptor Tyrosine Kinase Inhibitors Based on a Cyclopropyl Formamide Fragment Overcome Resistance
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While selective BRafV600E inhibitors have been proven effective clinically, acquired resistance rapidly develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway. Simultaneous targeting of multiple nodes in the pathway offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Replacement pyridine group of Y-1 by a cyclopropyl formamide group afforded I-01 as a novel multitargeted kinase inhibitor template. I-01 displayed enzyme potency against Pan-Raf and receptor tyrosine kinases (RTKs). Based on the binding mode of I-01, analogues I-02-I-18 were designed and synthesized. The most promising compound I-16 potently inhibits all subtypes of Rafs with IC50 values of 3.49 (BRafV600E), 8.86 (ARaf), 5.78 (BRafWT), and 1.65 nM (CRaf), respectively. I-16 not only exhibit comparable antiproliferative activities with positive control compounds against HepG2, SW579, MV4-11, and COLO205 cell lines, but also suppress the proliferation of melanoma SK-MEL-2 harboring overexpressed BRafWT with IC50 values of 0.93 μM. The Western blot results for the ERK inhibition in human melanoma SK-MEL-2 cell lines show that I-16 inhibits the proliferation of SK-MEL-2 cell lines without paradoxical activation of ERK, which support the hypothesis that the inhibition of Pan-Raf and RTKs might be a tractable strategy to overcome the resistance of melanoma induced by the therapy with the current selective BRafV600E inhibitors.
- Zhang, Yanmin,Wang, Lu,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Zhou, Xiang,Chen, Yadong,Lu, Tao,Tang, Weifang
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p. 1439 - 1452
(2017/06/30)
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- POTENT DUAL BRD4-KINASE INHIBITORS AS CANCER THERAPEUTICS
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Disclosed herein are compounds that are inhibitors of BRD4 and their use in the treatment of cancer. Methods of screening for selective inhibitors of BRD4 are also disclosed. In certain aspects, disclosed are compounds of Formula I-IV.
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Page/Page column 145
(2016/04/26)
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- Metal-free direct construction of sulfonamides via iodine- mediated coupling reaction of sodium sulfinates and amines at room temperature
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A simple, practical, and metal-free protocol has been developed for the synthesis of sulfonamides from sodium sulfinates and various amines through an iodine-mediated SN bond formation reaction at room temperature. This green reaction is cost-effective, operationally straightforward, and especially proceeds under very mild conditions to afford the target products in good to excellent yields (up to 98%).
- Wei, Wei,Liu, Chunli,Yang, Daoshan,Wen, Jiangwei,You, Jinmao,Wang, Hua
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supporting information
p. 987 - 992
(2015/03/30)
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- Direct conversion of thiols and disulfides into sulfonamides
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The H2O2-ZrCl4 reagent system is used as a new and efficient reagent for the conversion of thiols and disulfides into sulfonamides. The protocol offers several advantages such as excellent yields of products and extremely fast reactions at room temperature. The reagent system is very easy to handle and is environmentally safe and economical.
- Bahrami, Kiumars,Khodaei, Mohammad M.,Soheilizad, Mehdi
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supporting information; experimental part
p. 4843 - 4846
(2010/10/02)
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- Solvent hydrogen bonding and structural effects on nucleophilic aromatic substitution reactions. Part-2: Reaction of benzenesulphonyl chloride with anilines in propan-2-ol/2-methylpropan-2-ol mixtures
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Substitution reactions of fourteen para- and meta-substituted anilines with benzenesulphonyl chloride in different mole fractions of propan-2-ol in 2-methylpropan-2-ol have been investigated conductometrically. The second order rate constants correlates satisfactorily with pKa values of the anilines and also with the Hammett's substituent constant. The para-substituted anilines shows a satisfactory correlation with Charton's LDR equation. The results of these correlations indicate the formation of an electron deficient transition state. The rate data correlate satisfactorily with macroscopic solvent parameters such as relative permittivity, εr and polarity, ETN. Multiple correlation analysis of the rate data via Kamlet-Taft's solvatochromic parameters reveals that the solvent dipolarityfpolarizability plays a dominant role in governing the reactivity.
- Bhuvaneshwari,Elango
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experimental part
p. 233 - 241
(2010/04/05)
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- Solvent hydrogen bonding and structural effects on nucleophilic substitution reactions: Part 3. Reaction of benzenesulfonyl chloride with anilines in benzene/ propan-2-ol mixtures
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Substitution reactions of 13 para- and meta-substituted anilines with benzene-sulfonyl chloride in varying mole fractions of benzene in propan-2-ol have been investigated conductometrically, The second-order rate constants correlate well with pKa values of anilines and with the Hammett's equation. The negative Hammett reaction constant indicates the formation of an electron-deficient transition state. The rate data correlate satisfactorily with macroscopic solvent parameters such as relative permittivity, εr, and polarity, ETN. Correlation of rate data with Kamlet-Taft solvatochromic parameters (α, β, π*) suggests that both the specific and nonspecific solute-solvent interactions influence the reactivity.
- Bhuvaneshwari,Elango
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p. 657 - 663
(2008/09/17)
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- Solvent hydrogen bonding and structural effects on nucleophilic substitution reactions. Part-1: Reaction of benzenesulphonyl chloride with anilines in benzene/2-methylpropan-2-ol-mixtures
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Substitution reactions of eleven para- and meta-substitutcd anilines with benzencsulphonyl chloride in different mole fractions of benzene in 2-methylpropan-2-ol have been investigated conductometrically. The second order rate constants don't correlate either with pK values of the anilines or with the Hammett's and its modified equations. The para-substituted anilines shows a satisfactory correlation with Charton's LDR equation and the results indicate the formation of an electron deficient transition state. The rate data correlate satisfactorily with macroscopic solvent parameters such as relative permittivity, εr, and polarity, ETN. Multiple correlation analysis of the rate data via Kamlet-Taft's solvatochromic parameters reveals that the solvent hydrogen bond donor property plays a dominant role in governing the reactivity.
- Bhuvaneshwari,Elango
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experimental part
p. 1227 - 1233
(2009/12/31)
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- Amidino protease inhibitors
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Amidino and benzamidino compounds, including compounds of the formula: wherein R1-R4, R6-R9, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit a number of proteolytic enzymes are described. Also described are methods for preparing the compounds of Formula I.
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- GUANIDINO PROTEASE INHIBITORS
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Compounds of the formula: STR1 wherein R 1--R 4, R. sup.7--R 8, R a, R b, R c, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit a number of proteolytic enzymes are described. Also described are methods for preparing the compounds of Formula I.
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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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- ANALYSIS OF SUBSTITUENT AND SOLVENT EFFECTS ON DISSOCIATION OF N-PHENYLBENZENESULPHONAMIDES
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The potentiometric titration in water, methanol, dimethyl sulphoxide, dimethylformamide, and acetonitrile has been used for determination of pK values of 13 N-arylbenzenesulphonamides.The validity of the Hammett and Yukawa-Tsuno models using several sets of substituent constants has been evaluated by the test to check adequacy of the regression function and by the factor analysis.It has been found that the substituent effects in solvents must be interpreted with regard to the experimental method used, solvent, set of the substituent constants, as well as the model equation ETR.The dependence of the Hammett reaction constants on the solvent has been analyzed and reveals a preferred stabilization of the conjugated base through hydrogen bonds.Direct conjugation of the reaction centre with the substituent and with different extent of the solvent-dependence with the 4-CN and 4-NO2 derivatives have been observed.
- Ludwig, Miroslav,Pytela, Oldrich,Javurkova, Helena,Vecera, Miroslav
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p. 2900 - 2908
(2007/10/02)
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- THE "ANOMALOUSLY" HIGH CATALYTIC ACTIVITY OF PYRIDINE N-OXIDES IN ACYL TRANSFER REACTIONS IN PROTON-INERT MEDIA
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The kinetics of the slow stage of nucleophilic catalysis by 4-dimethylaminopyridine N-oxide (III) in the aminolysis of derivatives of benzenesulfonic acid C6H5SO2X (X = Cl, Br, SO3C6H5) by 3-nitroaniline in methylene chloride at 25 deg C were studied.The intermediate nucleophilic catalysis products 1-phenylsulfonyloxy-4-dimethylaminopyridinium salts +C5H4N(CH3)2-4>*X- were isolated and studied by UV and PMR spectroscopy.The equilibrium in the formation of these salts (X- = Cl-) was studied.By analysis of the obtained data it was concluded that the higher catalytic activity of pyridine N-oxides in acyl transfer processes in proton-inert media in relation to the corresponding pyridines (in spite of the substantially lower basicity of the former) is due to two factors, i.e., the higher thermodynamic stability of the salt-like intermediates and their higher reactivity in relation to neural nucleophiles (arylamines).The relationships and the possible mechanisms of the effect of the anion X- in the composition of the ion-pair intermediate products on the formal kinetics of the slow stage of nucleophilic catalysis and on the reactivity of the intermediates are discussed.
- Litvineko, L. M.,Savelova, V. A.,Belousova, I. A.
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p. 1326 - 1335
(2007/10/02)
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- VARIATION OF TRANSITION STATE IN REACTIONS OF BENZENSULFONYL CHLORIDES WITH ANILINES IN MeOH-MeCN SOLVENTS
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Kinetic studies of nucleophilic substitution reactions of substituted benzenesulfonyl chlorides with anilines were conducted at 35 deg C in a range of methanol-acetonitril solvent mixtures.Results showed that (i) the magnitudes of ρN and β associated with a change of substituent in the nucleophile are large and indicate a relatively advanced bond-formation in the transition state, (ii) maximum size of ρN, ρS and β at the solvent composition of the maximum ionizing power, together with a positive cross-interaction coefficient, suggest SN2 transition state of a "synchronous push-pull" type, and (iii) the potential energy surface model is unstable to predict the transition state variation to a more product-like transition state, where bond formation is much more progressed and bond-breaking is slightly more advanced, upon changing the solvent to a more ionizing one enhancing leaving ability.In this respect the quantum mechanical model is superior to the potential energy surface model.
- Lee, Ikchoon,Koo, In Sun
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p. 1803 - 1808
(2007/10/02)
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- KINETICS OF THE REACTION OF N-ARYLSULFONYL-4-(DIMETHYLAMINO)PYRIDINIUM SALTS WITH 3-NITROANILINE IN METHYLENE CHLORIDE
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The kinetics were investigated for the slow stage of nucleophilic catalysis by 4-(dimethylamino)pyridine in the aminolysis of derivatives of arenesulfonic acids RC6H4SO2X (R=H, X=Cl, Br, SO3C6H5; R=4-CH3, X= Cl) by 3-nitroaniline in methylene chloride at 25 deg C.It was shown that the reaction of N-arylsulfonyl-4-(dimethylamino)pyridinium salts +C5H4N(CH3)2-4>.X- (I), i.e., the intermediate catalysis products, with arylamine takes place in three parallel kinetically independent directions: bimolecular reaction of the salt (I) with the amine (kpp); trimolecular processes, involving catalysis by a second molecule of the salt (I) (kppS) and by 4-dimethylaminopyridine (kppm).In addition, the reaction of the initial derivative RC6H4SO2X with the arylamine, catalyzed by the salts (I) (k0S) leads to the same final products.The reactivity of the substrates (I), which exist in the form of ion pairs in methylene chloride, is controlled by the nature of the anion X- and decreases in the order C6H5SO3- > Br- Cl-.The effectiveness of catalysis by a second molecule of the salt (I) and by 4-dimethylaminopyridine increases in the same order.The observed relationships indicate that electrostatic cation-anion interaction in the ion pair has a determining effect on the reactivity of N-arylsulfonylpyridinium salts as electrophilic reagents.
- Savelova, V. A.,Belousova, I. A.,Litvinenko, L. M.
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p. 1333 - 1339
(2007/10/02)
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- Substituted 2H-pyran-2,6 (3H)-dione derivatives useful in treatment of allergic reactions
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Substituted 2H-pyran-2,6(3H)-dione derivatives useful in the treatment of allergic conditions are prepared by reaction of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with an appropriate aniline.
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