- Flavone inspired discovery of benzylidenebenzofuran-3(2H)-ones (aurones) as potent inhibitors of human protein kinase CK2
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In this work, we describe the design, synthesis and SAR studies of 2-benzylidenebenzofuran-3-ones (aurones), a new family of potent inhibitors of CK2. A series of aurones have been synthesized. These compounds are structurally related to the synthetic flavones and showed nanomolar activities towards CK2. Biochemical tests revealed that 20 newly synthesized compounds inhibited CK2 with IC50 values in the nanomolar range. Further property-based optimization of aurones was performed, yielding a series of CK2 inhibitors with enhanced lipophilic efficiency. The most potent compound 12m (BFO13) has CLipE = 4.94 (CLogP = 3.5; IC50 = 3.6 nM) commensurable with the best known inhibitors of CK2.
- Bdzhola, V. G.,Bilokin, Y. V.,Borysenko, I. P.,Lukashov, S. S.,Protopopov, M. V.,Prykhod'ko, A. O.,Starosyla, S. A.,Vdovin, V. S.,Yarmoluk, S. M.
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- An Intramolecular Wittig Approach toward Heteroarenes: Synthesis of Pyrazoles, Isoxazoles, and Chromenone-oximes
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α-Halohydrazones/ketoximes are transformed into trisubstituted pyrazoles/disubstituted isoxazoles by treatment with phosphine, acyl chloride, and a base. Mechanistic investigations revealed the in situ formation of azo/nitroso olefin intermediates which underwent a tandem phospha-Michael/N- or O-acylation/intramolecular Wittig reaction to afford the heteroarenes in moderate to good yields. Further, proper functionalization of α-haloketoximes and a change of conditions allowed the chemoselective synthesis of chromenone-oximes as well as rearranged isoxazoles, thereby realizing a diversity-oriented synthesis.
- Khairnar, Pankaj V.,Lung, Tsai-Hui,Lin, Yi-Jung,Wu, Chi-Yi,Koppolu, Srinivasa Rao,Edukondalu, Athukuri,Karanam, Praneeth,Lin, Wenwei
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supporting information
p. 4219 - 4223
(2019/06/17)
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- Structure-based design leads to the identification of lithium mimetics that block mania-like effects in rodents. Possible new GSK-3β therapies for bipolar disorders
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More than two million American adults, or approximately one percent of the population 18 years or older, suffer from bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3β (GSK-3β) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective GSK-3β inhibitors. The best ligand in this series (having a Ki value of 4.6 nM against GSK-3β) was studied in a novel mouse model of mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3β inhibitor in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted kinase in both physiological and pathophysiological events.
- Kozikowski, Alan P.,Gaisina, Irina N.,Yuan, Hongbin,Petukhov, Pavel A.,Blond, Sylvie Y.,Fedolak, Allison,Caldarone, Barbara,McGonigle, Paul
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p. 8328 - 8332
(2008/02/09)
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- Ortho-Coordinated Acylation on Phenol Systems
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The ortho-coordinated acylation of phenol salts reported in recent synthetic applications has been extensively investigated.The data obtained support the hypothesis that formation of an organized complex between the phenol salts and the acylating agents may strongly influence the reaction pathway, depending on the nature of the specific cation, phenol, and acyl chloride involved in the process.The structural factors which control the formation of the reacting complex 3 have been extensively investigated; the results obtained allow us to discuss the possibilities and limitations of this methodology in selective o-acylphenol synthesis.The present methodology is the procedure of choice for ortho-functionalization of phenols with electrophilic reagents such as phosgene, oxaloyl chlorides, polyunsaturated acid chlorides, phthalic dichlorides, and, in general, acid chlorides α-functionalized with an electron-withdrawing group.
- Sartori, Giovanni,Casnati, Giuseppe,Bigi, Franca
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p. 4371 - 4377
(2007/10/02)
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- α-Chlorination of Aromatic Acetyl Derivatives with Benzyltrimethylammonium Dichloroiodate
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Reaction of aromatic acetyl derivatives with benzyltrimethylammonium dichloroiodate in refluxing dichloroethane/methanol for several hours gave α-chloroacetyl derivatives in good yields.
- Kajigaeshi, Shoji,Kakinami, Takaaki,Moriwaki, Masayuki,Fujisaki, Shizuo,Maeno, Kimihiro,Okamoto, Tsuyoshi
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p. 545 - 546
(2007/10/02)
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- INVESTIGATIONS ON REACTIONS OF CHLORINE DIOXIDE AND SODIUM CHLORITE WITH ORGANIC COMPOUNDS. PART XXXV. REACTIONS OF CHLORINE DIOXIDE WITH RING-SUBSTITUTED STYRENES
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Reactions of chlorine dioxide with ring substituted styrenes (1a-n) in carbon tetrachloride at 52-54 deg C were studied.The reaction products were isolated and characterised.It has been found that methyl-, chloro-, nitrostyrenes and 4-methoxystyrene are attacked by chlorine dioxide exclusively on the vinyl group, to yield the corresponding α-chloroacetophenones (2), diastereoisomers of β-chlorostyrene (6,7), oxidation products (8,9) and some polymers.Oxidation of its phenolic hydroxyl groups and vinyl polymerization took place in hydroxystyrenes.
- Kwiecien, Halina,Jalowiczor, Jozef
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p. 811 - 824
(2007/10/02)
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- Process for production of 2-haloacetylphenols
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A new process for production of 2-haloacetylphenols having the general formula STR1 (wherein, Y is halogen atom; m is an integer of 0-2, X and n have the same meaning as mentioned below), which comprises reacting phenols having the general formula STR2 (w
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