- 7-Dialkylamino-1-alkylquinolinium salts: Highly versatile and stable fluorescent probes
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7-Dialkylamino- and 7-alkylsulfenyl-1-alkylquinolinium salts have been synthesized using a novel synthetic approach. The key intermediate, 7-fluoro-1-methylquinolinium iodide, was shown to possess high reactivity toward nitrogen and sulfur nucleophiles, a
- Van Den Berg, Otto,Jager, Wolter F.,Picken, Stephen J.
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- Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins
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The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral bioavailability.
- Igoe, Niall,Bayle, Elliott D.,Tallant, Cynthia,Fedorov, Oleg,Meier, Julia C.,Savitsky, Pavel,Rogers, Catherine,Morias, Yannick,Scholze, Sarah,Boyd, Helen,Cunoosamy, Danen,Andrews, David M.,Cheasty, Anne,Brennan, Paul E.,Müller, Susanne,Knapp, Stefan,Fish, Paul V.
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supporting information
p. 6998 - 7011
(2017/09/07)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula (I) and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Page/Page column 179
(2014/09/29)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula I: and compositions comprising compounds of general formula I that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Paragraph 0738; 0739
(2014/09/30)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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Compounds of general formula (I) and compositions comprising compounds of general formula (I) that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.
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Page/Page column 192; 193
(2014/09/29)
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- Pd-catalyzed nucleophilic fluorination of aryl bromides
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On the basis of mechanism-driven reaction design, a Pd-catalyzed nucleophilic fluorination of aryl bromides and iodides has been developed. The method exhibits a broad substrate scope, especially with respect to nitrogen-containing heteroaryl bromides, and proceeds with minimal formation of the corresponding reduction products. A facilitated ligand modification process was shown to be critical to the success of the reaction.
- Lee, Hong Geun,Milner, Phillip J.,Buchwald, Stephen L.
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supporting information
p. 3792 - 3795
(2014/04/03)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Page/Page column 75
(2012/07/27)
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- A novel improvement in ArLPdF catalytic fluorination of aromatic compounds
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In this study, we used reverse micellar medium for overcoming the disadvantages of ArLMF catalytic fluorination of aromatic compounds. It not only enhanced the fluorination rate, but also widened the scope of reaction for bromoaromatics with electron donating and withdrawing functionalities at ortho position. Various bromoaromatic compounds were fluorinated using the biarylphosphine ligand i.e. cyclohexyl BrettPhos ligand, along with [cinnamylPdCl]2, and CsF as the fluoride source in reverse micellar media. The anisotropic palisade layer of reverse micelles provided the active site for reaction. The most crucial factor in the critical reductive elimination step could be the spatial orientation of ArLPdF complex in the palisade layer; forming ArF as the final product in high yield with excellent selectivity.
- Samant, Bhupesh S.,Bhagwat, Sunil S.
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experimental part
p. 191 - 194
(2012/01/05)
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- Accelerating palladium-catalyzed C-F bond formation: Use of a microflow packed-bed reactor
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A flow process for Pd-catalyzed C-F bond formation is described. A microreactor with a packed-bed design allows for easy handling of large quantities of insoluble CsF with precise control over reaction times, efficient mixing, and the ability to safely handle elevated temperatures and pressures. A variety of aryl triflates, including heteroaryl ones, were converted into aryl fluorides in short reaction times (see scheme).
- Noel, Timothy,Maimone, Thomas J.,Buchwald, Stephen L.
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supporting information; experimental part
p. 8900 - 8903
(2011/10/19)
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- Formation of arf from lpdar(f): catalytic conversion of aryl triflates to aryl fluorides
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Despite increasing pharmaceutical importance, fluorinated aromatic organic molecules remain difficult to synthesize. Present methods require either harsh reaction conditions or highly specialized reagents, making the preparation of complex fluoroarenes ch
- Watson, Donald A.,Su, Mingjuan,Teverovskiy, Georgiy,Zhang, Yong,Garcia-Fortanet, Jorge,Kinzel, Tom,Buchwaldf, Stephen L.
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scheme or table
p. 1661 - 1664
(2010/06/16)
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- Elemental fluorine Part 15. Selective direct fluorination of quinoline derivatives
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Direct fluorination of various quinoline derivatives in acidic reaction media gives fluorinated quinoline products arising from electrophilic substitution processes.
- Chambers, Richard D.,Holling, Darren,Sandford, Graham,Batsanov, Andrei S.,Howard, Judith A.K.
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p. 661 - 671
(2007/10/03)
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- PURINE DERIVATIVES AS KINASE INHIBITORS
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The present invention provides kinase inhibitors of Formula I.
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Page/Page column 22
(2008/06/13)
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- Synthesis of a fluorine-18-labelled derivative of 6-nitroquipazine, as a radioligand for the in vivo serotonin transporter imaging with PET.
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Considerable efforts have been engaged in the design, synthesis and pharmacological characterization of radioligands for imaging the serotonin transporter, based on its implication in several neuropsychiatric diseases, such as depression, anxiety and schizophrenia. In the 5-halo-6-nitroquipazine series, the fluoro derivative has been designed for positron emission tomography (PET). The corresponding 5-iodo-, 5-bromo- and 5-chloro N-Boc-protected quipazines as labelling precursors, as well as 5-fluoro-6-nitroquipazine as a reference compound have been synthesized. 5-[(18)F]Fluoro-6-nitroquipazine has been radiolabelled with fluorine-18 (positron-emitting isotope, 109.8 min half-life) by nucleophilic aromatic substitution from the corresponding N-Boc protected 5-bromo- and 5-chloro-precursors using K[(18)F]F-K(222) complex in DMSO by conventional heating (145 degrees C, 2 min) or microwave activation (50 W, 30-45 s), followed by removal of the protective group with TFA. Typically, 15-25 mCi (5.5-9.2 GBq) of 5-[(18)F]fluoro-6-nitroquipazine (1-2 Ci/micromol or 37-72 GBq/micromol) could be obtained in 70-80 min starting from a 550-650 mCi (20.3-24.0 GBq) aliquot of a cyclotron [(18)F]F(-) production batch (2.7-3.8% non decay-corrected yield based on the starting [(18)F]fluoride). Ex vivo studies (biodistribution in rat), as well as PET imaging (in monkey) demonstrated that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) readily crossed the blood brain barrier and accumulated in the regions rich in 5-HT transporter (frontal- and posterial cortex, striata). However, the low accumulation of the tracer in the thalamus (rat and monkey) as well as the comparable displacement of the tracer observed with both citalopram, a -HT re-uptake inhibitor and maprotiline, a norepinephrine re-uptake inhibitor (rat), indicate that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) does not have the suggested potential for PET imaging of the serotin transporter (SERT).
- Karramkam, Mylene,Dolle, Frederic,Valette, Heric,Besret, Laurent,Bramoulle, Yann,Hinnen, Francoise,Vaufrey, Francoise,Franklin, Carine,Bourg, Sebastien,Coulon, Christine,Ottaviani, Michele,Delaforge, Marcel,Loc'h, Christian,Bottlaender, Michel,Crouzel, Christian
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p. 2611 - 2623
(2007/10/03)
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- Selective direct fluorination of quinoline derivatives
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Direct fluorination of various quinoline derivatives in acidic reaction media gives fluorinated quinoline products arising from selective, efficient electrophilic substitution processes.
- Chambers, Richard D,Holling, Darren,Sandford, Graham,Puschmann, Horst,Howard, Judith A.K
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- Dual stimulatory and inhibitory effects of fluorine-substitution on mutagenicity: An extension of the enamine epoxide theory for activation of the quinoline nucleus
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Nineteen mono- and di-fluorinated derivatives of quinoline, 1,7- phenanthroline, 1,10-phenanthroline, benzo-[h]quinoline, and benzo[f]quinoline were subjected to analysis of their structure-mutagenicity relationships. For this purpose, six new fluorinated derivatives were synthesized. The results support that the enamine epoxide structure of the pyridine moiety, as well as the bay-region epoxide structure, is responsible for mutagenicity. Formation of K-region epoxides might involve a detoxification process rather than mutagenic activation.
- Saeki, Ken-Ichi,Kawai, Hiroshi,Kawazoe, Yutaka,Hakura, Atsushi
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p. 646 - 650
(2007/10/03)
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