- Diastereoselective Photoredox-Catalyzed [3 + 2] Cycloadditions of N-Sulfonyl Cyclopropylamines with Electron-Deficient Olefins
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A highly diastereoselective, visible-light-induced [3 + 2] cycloaddition between N-sulfonyl cyclopropylamines and electron-deficient olefins is reported. The reactions proceed via the oxidation of a sulfonamide aza-anion by an organic photocatalyst to generate a nitrogen-centered radical. Strain-induced ring opening and intermolecular addition to the olefin generate an intermediate carbon-centered radical that is reduced to an anion prior to 5-exo cyclization. This enables a highly diastereoselective construction of trans-cyclopentanes possessing synthetically useful functional groups.
- White, Dawn H.,Noble, Adam,Booker-Milburn, Kevin I.,Aggarwal, Varinder K.
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supporting information
p. 3038 - 3042
(2021/05/04)
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- Rational Design, Optimization, and Biological Evaluation of Novel MEK4 Inhibitors against Pancreatic Adenocarcinoma
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Growth, division, and development of healthy cells relies on efficient response to environmental survival cues. The conserved mitogen-activated protein kinase (MAPK) family of pathways interface extracellular stimuli to intracellular processes for this purpose. Within these pathways, the MEK family has been identified as a target of interest due to its clinical relevance. Particularly, MEK4 has drawn recent attention for its indications in pancreatic and prostate cancers. Here, we report two potent MEK4 inhibitors demonstrating significant reduction of phospho-JNK and antiproliferative properties against pancreatic cancer cell lines. Furthermore, molecular inhibition of MEK4 pathway activates the MEK1/2 pathway, with the combination of MEK1/2 and MEK4 inhibitors demonstrating synergistic effects against pancreatic cancer cells. Our inhibitors provided insight into the crosstalk between MAPK pathways and new tools for elucidating the roles of MEK4 in disease states, findings which will pave the way for better understanding of the MAPK pathways and development of additional probes.
- Kwong, Ada J.,Munshi, Hidayatullah G.,Oelschlager, Hannah E.,Pham, Thao N. D.,Scheidt, Karl A.
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supporting information
p. 1559 - 1567
(2021/10/04)
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- STK4 INHIBITORS FOR TREATMENT OF HEMATOLOGIC MALIGNANCIES
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The application relates to compounds of Formula (I'): which modulate the activity of a kinase (e.g., STK4), a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease or disorder associated with the modulation of a kinase, such as STK4.
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Paragraph 00690
(2017/01/09)
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- PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
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The present invention relates to 6-amino-7-deaza-purine derivatives which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular RET family kinases. The present
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Page/Page column 52
(2014/12/12)
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- SUBSTITUTED PYRIMIDINYL AND PYRIDINYL-PYRROLOPYRIDINONES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
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The present invention relates to substituted pyrimidinyl- and pyridinylpyrrolopyridinone compounds which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular RET family kinases. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions containing these compounds.
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Page/Page column 60; 61
(2014/05/24)
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- Fragment-based discovery of bromodomain inhibitors part 2: Optimization of phenylisoxazole sulfonamides
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Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.
- Bamborough, Paul,Diallo, Hawa,Goodacre, Jonathan D.,Gordon, Laurie,Lewis, Antonia,Seal, Jonathan T.,Wilson, David M.,Woodrow, Michael D.,Chung, Chun-Wa
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supporting information; experimental part
p. 587 - 596
(2012/03/26)
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