- Rate and Yield Enhancements in Nucleophilic Aromatic Substitution Reactions via Mechanochemistry
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A variety of nucleophilic aromatic substitution reactions were carried out mechanochemically to great advantage. On average, reactions rates were nine-times faster. The corresponding kinetic studies presented provide the clearest head-to-head kinetic comparisons between mechanochemical and conventional systems at identical temperatures. Attempts are provided at classifying the kinetics of one example. Removal of polar, protic solvents from these reactions presents environmental benefits to a reaction class whose kinetics are heavily dependent on such solvents.
- Andersen, Joel M.,Starbuck, Hunter F.
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p. 13983 - 13989
(2021/04/02)
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- SUBSTITUTED 3-((3-AMINOPHENYL)AMINO)PIPERIDINE-2,6-DIONE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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Provided herein are piperidine dione compounds having the following structure (I) wherein RN, R1, R2, R3, R4, L,V, m, and n are as defined herein, compositions comprising an effective amount of a piperidine dione compound, and methods for treating or preventing an androgen receptor mediated disease.
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Paragraph 00373
(2020/07/14)
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- SUBSTITUTED 3-((3-AMINOPHENYL)AMINO)PIPERIDINE-2,6-DIONE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
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Provided herein are piperidine dione compounds having the following structure: wherein RN, R1, R2, R3, R4, X, L, V, m, and n are as defined herein, compositions comprising an effective amount of a piperidine dione compound, and methods for treating or preventing an androgen receptor mediated disease.
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Paragraph 0485; 0486
(2020/07/14)
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- Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the N-Terminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype
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The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects.
- Wellaway, Christopher R.,Bamborough, Paul,Bernard, Sharon G.,Chung, Chun-Wa,Craggs, Peter D.,Cutler, Leanne,Demont, Emmanuel H.,Evans, John P.,Gordon, Laurie,Karamshi, Bhumika,Lewis, Antonia J.,Lindon, Matthew J.,Mitchell, Darren J.,Rioja, Inmaculada,Soden, Peter E.,Taylor, Simon,Watson, Robert J.,Willis, Rob,Woolven, James M.,Wyspiańska, Beata S.,Kerr, William J.,Prinjha, Rab K.
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p. 9020 - 9044
(2020/08/24)
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- Inhibition of mutated isocitrate dehydrogenase 1 in cancer
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Background: R132H mutation of isocitrate dehydrogenase 1 (IDH1) is found in ~75% of low-grade gliomas and secondary glioblastomas as well as in several other types of cancer. More chemotypes of inhibitors of IDH1(R132H) are therefore needed. Objective: The study aimed to develop a new class of IDH1(R132H) inhibitors as potent antitumor agents. Method: A biochemical assay was developed to find inhibitors of IDH1(R132H) mutant enzyme. Chemical synthesis and structure-activity relationship studies were used to find compounds with improved potency. Antitumor activities of selected compounds were evaluated. Results: A series of aromatic sulfonamide compounds was found to be novel, potent inhibitors of IDH1(R132H) with Ki values as low as 0.6 μM. Structure-activity relationships of these compounds are discussed. Enzyme kinetics studies showed that one compound is a competitive inhibitor against the substrate α-KG and a non-competitive inhibitor against the cofactor NADPH. Several inhibitors were found to have no activity against wild-type IDH1, showing a high selectivity. Two potent inhibitors exhibited strong activity against proliferation of BT142 glioma cells with IDH1 R132H mutation, while these compounds did not significantly affect the growth of glioma cells without IDH1 mutation. Conclusion: This novel series of IDH1(R132H) inhibitors have potential to be further developed for the treatment of glioma with IDH1 mutation.
- Wu, Fangrui,Cheng, Gang,Yao, Yuan,Jiang, Hong,Song, Yongcheng,Kogiso, Mari,Li, Xiao-Nan
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p. 715 - 724
(2018/11/21)
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- IMIDAZOQUINOLINE COMPOUNDS AS BROMODOMAIN INHIBITORS
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The present invention provides compound of formula (I), or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, a polymorph, a prodrug, N-oxide or S-oxide thereof; and processes for their preparation. The invention further relates to pharmaceutical compositions containing said compounds and their use in the treatment of diseases or disorders mediated by bromodomain containing proteins, particularly cancer.
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Page/Page column 123; 124
(2015/04/22)
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- Nucleophilic Aromatic Substitution Reactions in Water Enabled by Micellar Catalysis
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Given the huge dependence on dipolar, aprotic solvents such as DMF, DMSO, DMAc, and NMP in nucleophilic aromatic substitution reactions (SNAr), a simple and environmentally friendly alternative is reported. Use of a "benign-by-design" nonionic surfactant, TPGS-750-M, in water enables nitrogen, oxygen, and sulfur nucleophiles to participate in SNAr reactions. Aromatic and heteroaromatic substrates readily participate in this micellar catalysis, which takes place at or near ambient temperatures.
- Isley, Nicholas A.,Linstadt, Roscoe T. H.,Kelly, Sean M.,Gallou, Fabrice,Lipshutz, Bruce H.
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supporting information
p. 4734 - 4737
(2015/10/12)
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- A practical nickel-catalyzed reductive alkylation of amidophenyl bromides
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A modified Weix's reductive coupling for alkylation of amidoaryl bromides based on Ni(COD)2 precatalyst and 2,2′-dipyridyl ligand was developed. This reaction is reliable for amidophenyl bromides and gives yields up to 87%, and is potentially useful in the synthesis of amidophenyl-containing molecules.
- Liu, Xuge,Yang, Zhilin,Li, Ya-Min,Yang, Fan,Feng, Liang,Wang, Nengzhong,Ma, Debiao,Chang, Kwen-Jen,Shen, Yuehai
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p. 9522 - 9529
(2015/03/04)
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- Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: Effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and inhibition of Src homology 2 domain-containing protein tyrosine phosphatase-2 activity
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(E)-4-[3-(1-Adamantyl)-4′-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure-anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3′-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.
- Dawson, Marcia I.,Xia, Zebin,Jiang, Tao,Ye, Mao,Fontana, Joseph A.,Farhana, Lulu,Patel, Bhaumik,Li, Ping Xue,Bhuiyan, Mohammad,Pellicciari, Roberto,Macchiarulo, Antonio,Nuti, Roberto,Zhang, Xiao-Kun,Han, Young-Hoon,Tautz, Lutz,Hobbs, Peter D.,Jong, Ling,Waleh, Nahid,Chao, Wan-Ru,Feng, Gen-Sheng,Pang, Yuhong,Su, Ying
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supporting information; experimental part
p. 5650 - 5662
(2009/08/09)
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- PYRROLIDINE DERIVATIVES AS ERK INHIBITORS
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Disclosed are the ERK inhibitors of Formula (1.0): and the pharmaceutically acceptable salts and solvates thereof. Q is a piperidine or piperazine ring that can have a bridge or a fused ring. The piperidine ring can have a double bond in the ring. All other substitutents are as defined herein. Also disclosed are methods of treating cancer using the compounds of Formula (1.0).
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Page/Page column 175-176
(2010/11/28)
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- Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series
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Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.
- Petrov, Kimberly G.,Zhang, Yue-Mei,Carter, Malcolm,Cockerill, G. Stuart,Dickerson, Scott,Gauthier, Cassandra A.,Guo, Yu,Mook Jr., Robert A.,Rusnak, David W.,Walker, Ann L.,Wood, Edgar R.,Lackey, Karen E.
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p. 4686 - 4691
(2007/10/03)
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- Anilinoquinazolines as protein tyrosine kinase inhibitors
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Heteroaromatic compounds are described, methods for their preparation, pharmaceutical compositions containing them, methods of use, and their use in medicines. In particular, the invention relates to quinazoline and pyridopyrimidine derivatives which exhibit protein tyrosine kinase inhibition.
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Page/Page column 74
(2008/06/13)
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- Anilinoquinazaolines as protein tyrosine kianse inhibitors
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Heteroaromatic compounds are described, methods for their preparation, pharmaceutical compositions containing them, methods of use, and their use in medicines. In particular, the invention relates to quinazoline and pyridopyrimidine derivatives which exhibit protein tyrosine kinase inhibition.
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Page/Page column 46
(2008/06/13)
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