- Structure-activity relationship study of E6 as a novel necroptosis inducer
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Necroptosis inducers represent a promising potential treatment for drug-resistant cancer. We herein describe the structure modification of E6, which was identified recently as a potent and selective necroptosis inducer. The studies described herein demonstrate for the first time that functionalized biphenyl derivatives possess necroptosis inducer activity. Furthermore, these studies have led to the identification of two promising compounds (5h and 5j) that can be used for further optimization studies as well as mechanism of action investigations.
- Mou, Jianfeng,Park, Ann,Cai, Yu,Yuan, Junying,Yuan, Chengye
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supporting information
p. 3057 - 3061
(2015/06/22)
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- NAPHTHALENE DERIVATIVE
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The present invention provides compounds which can regulate VCP activity. The present invention provides the compound of formula (I) (R is as defined in the description) or oxides, esters, prodrugs, pharmaceutically acceptable salts or solvates thereof. The compounds can regulate VCP activity, and thus are useful for treating VCP-mediated diseases such as neurodegenerative diseases.
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Paragraph 0584
(2013/06/27)
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- MODULATORS OF HISTONE METHYLTRANSFERASE, AND METHODS OF USE THEREOF
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Disclosed are compounds, pharmaceutical compositions containing the compounds, and the uses of the compounds and compositions as modulators of histone methyltransferases, and for treating diseases influenced by modulation of histone methyltransferase activity.
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Page/Page column 148
(2012/06/30)
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- NOVEL HETEROCYCLIC AMIDE DERIVATIVES HAVING DIHYDROOROTATE DEHYDROGENASE INHIBITING ACTIVITY
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Novel heterocyclic amide derivatives having pharmacological effects, that is, compounds represented by the general formula (1) or salts thereof: (1) wherein X1-X2 is S-CH2 or the like; R1 is alkyl or the like; p is 0 to 7; R2 is hydrogen, alkyl, or the like; R3 is hydrogen, alkyl, or the like; Y1-Y2 is CH=CH or the like; R4 is halogeno, alkyl, or the like; q is 0 to 4; and R5 is halogeno, hydrogen, alkyl, or the like.
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Page/Page column 51; 53
(2010/10/20)
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- Transformation of mutagenic aromatic amines into non-mutagenic species by alkyl substituents: Part II: Alkylation far away from the amino function
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Alkyl and trifluoromethyl derivatives of 4-aminobiphenyl (1) (4ABP) and 2-aminofluorene (7) (2AF) were synthesised and assayed for mutagenicity using Salmonella typhimurium tester strains TA98 and TA100 with and without the addition of S9 mix. Modification of 1 was achieved by attachment of alkyl groups (methyl, ethyl, iso-propyl, n-butyl, tert-butyl) and a trifluoromethyl group (CF3) in the 4′-position, the 3′-position (Me, CF3) and the 3′-, 5′-positions (DiMe, DiCF3). Compound 7 was modified by introduction of alkyl groups (methyl, tert-butyl, adamantyl) and a trifluoromethyl group (CF3) in the 7-position. The derivatives of 1 and 7 show for groups with growing steric demand decreased mutagenic activity. The bulkiest groups (CF3, tert-butyl and adamantyl) induce the strongest effects on the mutagenicity. It was even possible to eliminate the mutagenicity of 1 and 7 by introduction of such substituents. In the last part of the work, we compared the experimental mutagenicities with calculated values derived from QSAR correlations. Our findings show that the predictions for aromatic amines with bulky substituents were generally too high. The strongest deviations were observed in the case of the CF3-, tert-butyl- and the adamantyl-group. Only the parent compounds and derivatives with small alkyl groups were predicted well. These investigations show that "large" substituents have an influence on the mutagenicity caused by their steric demand. To predict the correct mutagenicities of such compounds, it is necessary to introduce steric parameters in the respective QSAR equations which will be done in a forthcoming paper.
- Glende, Carsten,Klein, Markus,Schmitt, Heimo,Erdinger, Lothar,Boche, Gernot
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- Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1
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Thrombosis is a major cause of mortality in the industrialized world. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly re
- Quan, Mimi L.,Liauw, Ann Y.,Ellis, Christopher D.,Pruitt, James R.,Carini, David J.,Bostrom, Lori L.,Huang, Peggy P.,Harrison, Kimberly,Knabb, Robert M.,Thoolen, Martin J.,Wong, Pancras C.,Wexler, Ruth R.
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p. 2752 - 2759
(2007/10/03)
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- Carbocation-like reactivity patterns in X′-substituted-4-biphenylylnitrenium ions
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4-Azido-X′-substituted biphenyls (X′ = 4′-MeO, 4′-Me, 4′-F, 3′-Me, 4′-Cl, H, 3′-MeO, 3′-Cl, 4′-CF3) have been prepared and subjected to 248 nm flash photolysis irradiation in 20:80 acetonitrile:water. Transient X′-substituted 4-biphenylylnitrenium ions 10 (Ar-C6H4-N+H) are observed, with lifetimes ranging from 0.6 ms (4′-MeO) to 26 ns (4′-CF3). These cations are quenched by azide ion, with values of kaz ranging from 6 to 10×109 M-1 s-1, with the majority in the range (9-10)×109. This near constant kaz provides further evidence that arylnitrenium ions are quenched by azide ion at the diffusion limit. The solvent reactivities, plotted in a single-parameter Hammett plot against σ+(X), exhibit a poor correlation, with the points for the para π-electron donors deviating from the correlation line based on the other substituents in the direction of requiring a more negative substituent parameter. The data are more satisfactorily fit to the two-parameter Yukawa-Tsuno equation; the parameter r+ obtained in this fit is 2.8. Thus the resonance interaction of the para π-donor X′-substituents with the positive charge of the cation is underestimated by σ+, a situation that has previously been observed with benzylic-type carbenium ions. The conclusion is made that, in their reaction with water, 4-biphenylylnitrenium ions behave like benzyl cations bearing two additional stabilizing vinyl groups, i.e., as if they had the structure Ar-C+(C-to-C)2 double bond. The inherent reactivity and the pattern of the aryl substituent effects are in fact similar to those in the carbocation series Ar-C+(Ph)2.
- Ren,McClelland
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- Design and synthesis of non-peptide Ras CAAX mimetics as potent farnesyltransferase inhibitors
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Cysteine farnesylation of the ras oncogene product Ras is required for its transforming activity and is catalyzed by farnesyltransferase (FTase). The Ras carboxyl terminal tetrapeptide CAAX (C is cysteine, A is any aliphatic amino acid, X is methionine or serine) is the minimum sequence for FTase recognition. We report here the design, synthesis, and biological characterization of Ras CAAX non-peptide mimetics in which the cysteine is linked through a reduced pseudopeptide bond to 4-amino-3'-carboxybiphenyl. These non-peptide mimetics are potent inhibitors of FTase (IC50 = 40 nM for the most potent inhibitor) and are highly selective for FTase over GGTase I (geranylgeranyltransferase I). They are not substrates for farnesylation, do not have peptidic features, and have no hydrolyzable bonds. Structure- activity studies reveal the importance of the position of the carboxylic acid on the aryl ring as well as the reduction of the cysteine amide bond. Substitution at the 2-position of 4-amino-3'-carboxybiphenyl increases inhibitory potency, while the removal of the carboxylic acid results in a 10- fold loss of inhibitory activity.
- Qian, Yimin,Vogt, Andreas,Sebti, Sa?d M.,Hamilton, Andrew D.
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p. 217 - 223
(2007/10/03)
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- Acid-Catalyzed Reactions of N-Arylhydroxylamines and Related Compounds with Benzene. Iminium-Benzenium Ions
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N-Arylhydroxylamines react with benzene in the presence of trifluoroacetic acid (TFA) at room temperature to give diphenylamines.When TFA was replaced by a strong acid, trifluoromethanesulfonic acid (TFSA), the major products were aminobiphenyls.The nature of the reaction was explored by reactions of 4-substituted phenylhydroxylamines and dialkylaniline N-oxides with benzene.Thus, it was demonstrated that the reactive intermediates are onium-benzenium dications which are trapped by benzene to give aminobiphenyls by a mechanism similar to the Friedel-Krafts alkylation.Further evidence for the proposed reaction mechanism was the observation that nitrosobenzene and azoxybenzene reacted with benzene to give analogous products in the presence of the stronger acid.
- Shudo, Koichi,Ohta, Toshiharu,Okamoto, Toshihiko
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p. 645 - 653
(2007/10/02)
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