- Antagonizing STAT3 activation with benzo[b]thiophene 1, 1-dioxide based small molecules
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STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[b]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC50range in 0.33–0.75?μM in various cancer cell lines. The overexpressed and IL-6 induced phosphorylation levels of STAT3 were both inhibited by 15 without influencing the phosphorylation levels of the upstream kinases Src and Jak2. 15 also suppressed the expressions of STAT3 downstream gene, Bcl-2. 15 effectively increased the ROS levels of cancer cells, induced cancer cell apoptosis and abolished the colony formation ability of cancer cells without affecting bypass kinase p-Erk. Furthermore, 15 in?vivo induced significant antitumor responses, and exhibited less toxicity than Doxorubicin. Together, this study described a class of new STAT3 inhibitors as antitumor agents.
- Zhang, Wenda,Ma, Ting,Li, Shanshan,Yang, Yanwei,Guo, Jianpeng,Yu, Wenying,Kong, Lingyi
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- Lithiated benzothiophenes and benzofurans require 2-silyl protection to avoid anion migration
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2-Trimethylsilyl protection of benzothiophenes and benzofurans prevents anion migration to the 2-position when lithiated species are formed. These lithiated benzothiophenes and benzofurans provide superior results in additions to piperidones. Deprotection is conveniently achieved under acidic conditions. Direct C-7 metalation of benzothiophene is enabled by 2-triisopropylsilyl protection at C-2.
- Hansen, Marvin M.,Clayton, Marcella T.,Godfrey, Alexander G.,Grutsch Jr., John L.,Keast, Sandra S.,Kohlman, Dan T.,McSpadden, Andreea R.,Pedersen, Steven W.,Ward, Jeffrey A.,Xu, Yao-Chang
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- Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists
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N-Benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2′ and 3′-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2′-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2′-benzyl substituent were also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines.
- Hansen, Martin,Jacobsen, Stine Engesgaard,Plunkett, Shane,Liebscher, Gudrun Eckhard,McCorvy, John D.,Br?uner-Osborne, Hans,Kristensen, Jesper Langgaard
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supporting information
p. 3933 - 3937
(2015/01/30)
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- INHIBITORS OF THE KYNURENINE PATHWAY
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The present application provides novel inhibitors of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxygenase, metabolites thereof, and phannaceutically acceptable salts or prodrugs thereof. Also provided are methods for preparing these compounds. A therapeutically effective amount of one or more of the compounds of formula (I) is useful in treating diseases resulting from dysregulation of the kynurenine pathway. Compounds of formula (I) act by inhibiting the enzymatic activity or expression of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxygenase.
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Page/Page column 216; 217
(2014/12/12)
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- OLIGOMERISATION OF ETHYLENE TO MIXTURES OF 1-HEXENE AND 1-OCTENE
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A process for the otigomerisation of ethylene to predominantly 1-hexene or 1-octene or mixtures of 1-hexene and 1-octene includes contacting ethylene with a catalyst under ethylene oligomerisation conditions. The catalyst comprises a source of chromium, a diphosphine ligating compound, and optionally an activator. The diphosphine ligating compound includes at least one optionally substituted fused cyclic structure including at least two rings, the optionally substituted fused cyclic structure including a 5- to 7- membered aromatic first ring bonded to a phosphorus atom, the aromatic first ring being fused to a 4- to 8-membered heterocyclic second ring, the heterocyclic second ring including a heteroatom which is separated by two ring atoms along the shortest connecting path from the phosphorous atom that is bonded to the first aromatic ring.
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Page/Page column 26-27
(2014/12/09)
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- BENZOTHIOPHENE SULFONAMIDES AND OTHER COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN
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The present invention relates to benzothiophene sulfonamides and other compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.
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Page/Page column 104-105
(2013/12/03)
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- TRIAZOLOPYRAZINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE & INFLAMMATORY DISEASES
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Novel [1.2.4]triazolo[1,5-a]pyrazine compounds are disclosed that have a formula represented by the following (formula I). The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, arthritis, inflammation, and others.
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Page/Page column 85
(2008/06/13)
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- FUSED HETEROCYCLE DERIVATIVE, MEDICINAL COMPOSITION CONTAINING THE SAME, AND MEDICINAL USE THEREOF
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The present invention provides nitrogen-containing fused cyclic derivatives represented by the following general formula or pharmaceutically acceptable salts thereof, or prodrugs thereof, which exhibit an excellent inhibitory activity in human SGLT and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, postprandial hyperglycemia, impaired glucose tolerance, diabetic complications or obesity, in the formula one of R1 and R4 represents a group represented by the following general formula (S) (in which R5 and R6 represent H, OH, a halogen atom, etc.; Q represents an alkylene group etc.; and ring A represents an aryl group etc.), and the other represents H, OH, an amino group, etc.; R2 and R3 represent H, OH, an amino group, a halogen atom, and an optionally substituted alkyl group, etc.; A1 represents O, S, etc.; A2 represents CH or N; G represents a group represented by the following general formula (G-1) or (G-2) (E1 represents H, F or OH; and E2 represents H, F, a methyl group, etc.), and pharmaceutical compositions comprising the same, and pharmaceutical uses thereof.
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Page/Page column 29
(2010/11/24)
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- ARYL-CARBALDEHYDE OXIME DERIVATIVES AND THEIR USE AS ESTROGENIC AGENTS
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This invention provides estrogen receptor modulators having the structure (I) where R1-R5 are as defined in the specification; or a pharmaceutically acceptable salt thereof.
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- Piperidine derivatives having effects on serotonin related systems
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The present invention provides the compounds of the following formula: Wherein the variables are as defined in the specification and a method for inhibiting the reuptake of seretonin, antagonizing the 5-HT1Areceptor and antagonizing the 5-HT2Areceptor which comprises administering to a subject in need of such treatment an effective amount of the compound of above formula.
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- Azepine derivatives having effects on serotonin related systems
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The present invention provides compounds of formula I and a method of inhibiting the reuptake of serotonin, antagonizing the 5-HT1Areceptor and antagonizing the 5-HT2Areceptor which comprises administering to a subject in need of suc
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- Pyrrolidine and pyrroline derivatives having effects on serotonin related systems
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The present invention provides the compounds of the following formula (I): and a method for inhibiting the reuptake of seretonin, antagonizing the 5-HT1Areceptor and antagonizing the 5-HT2Areceptor which comprises administering to a subject in need of such treatment an effective amount of formula (I).
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Page column 26
(2010/02/05)
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- Electrophilic Aromatic Substitution. Part 33. Partial Rate Factors for Protiodetritiation of Benzothiophen; the Resonance-dependent Reactivity of the Ring Positions
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Rate coefficients for detriation of benzothiophen, specifically labelled with tritium at each position, have been measured in anhydrous trifluoroacetic acid, and, for benzothiophen, in a range of trifluoroacetic acid-acetic acid mixtures, all at 70 deg C.The dependence of rate upon acidity is consistent with the effect of hydrogen bonding between sulphur and trifluoroacetic acid, as found previously for other sulphur-containing heterocycles.Partial rate factors, corrected for the effect of hydrogen bonding are (positions in parentheses): 8.84 * 105 (2); 1.18 * 106 (3); 360 (4); 13200 (5); 16200 (6); and 26.2 (7); the corresponding ?+ values are -0.68, -0.695, -0.29, -0.47, -0.48, and -0.16.The positional reactivity order is the same as found in pyrolysis of 1-arylethyl acetates, and solvolysis of 1-arylethyl chlorides, but the ?+ values are more negative due to the greater demand for resonance stabilization of the transition states in hydrogen exchange.Comparison of the 2- : 3-isomer ratios in various substitutions leads to the unexpected conclusion that substitution at the 2-position is subject to steric effects, probably due to the proximity of the sulphur d-orbitals.
- Amin, Hassan B.,Awad, Amin A.,Archer, William J.,Taylor, Roger
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p. 1489 - 1492
(2007/10/02)
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