- P(III)-Assisted Electrochemical Access to Ureas via in situ Generation of Isocyanates from Hydroxamic Acids
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An external oxidant-free protocol for the generation of isocyanates from hydroxamic acids assisted by trivalent phosphine under mild electrochemical conditions was reported. The process started with the anodic oxidation of hydroxamic acids, followed by reacting with phosphine to form corresponding alkoxyphosphoniums and subsequent rearrangement with the release of tri-substituted phosphine oxide as the driving force to give isocyanates, which were trapped by N-based nucleophiles to produce various ureas. This method provides a broadly applicable procedure to access isocyanate intermediates under mild electrochemical conditions.
- Meng, Haiwen,Sun, Kunhui,Xu, Zhimin,Tian, Lifang,Wang, Yahui
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supporting information
p. 1768 - 1772
(2021/03/26)
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- Thioether-Directed NiH-Catalyzed Remote γ-C(sp3)-H Hydroamidation of Alkenes by 1,4,2-Dioxazol-5-ones
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A NiH-catalyzed thioether-directed cyclometalation strategy is developed to enable remote methylene C-H bond amidation of unactivated alkenes. Due to the preference for five-membered nickelacycle formation, the chain-walking isomerization initiated by the NiH insertion to an alkene can be terminated at the γ-methylene site remote from the alkene moiety. By employing 2,9-dibutyl-1,10-phenanthroline as the ligand and dioxazolones as the reagent, the amidation occurs at the γ-C(sp3)-H bonds to afford the amide products in up to 90% yield (>40 examples) with remarkable regioselectivity (up to 24:1 rr).
- Chen, Qishu,Du, Bingnan,Ouyang, Yuxin,Yu, Wing-Yiu
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supporting information
p. 14962 - 14968
(2021/09/29)
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- Molecular simulation and activity studies of oxametacin as an HDAC inhibitor
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Background: Oxametacin is a non-steroidal anti-inflammatory drug with pharmacophores of classic histone deacetylase inhibitors. To evaluate the histone deacetylase enzymatic inhibition and antitumor potential of Oxametacin, molecular docking, molecular dynamic simulation and in vitro activity assay processes were performed in the present study. Methods: In the docking study, multiple π - π stacking and H-bond interactions were discovered to play significant roles in the Oxametacin-HDAC3 bindings. Results: Such interactions were proved to be stable by the molecular dynamic simulation. Enzymatic inhibition assay showed potent inhibitory activity of Oxametacin (IC50 value of 0.18 μM) against Hela cell nucleus extract compared with SAHA (0.21 μM). Conclusion: In the isoform selectivity assay, Oxametacin exhibited selectivity for HDAC3 (0.13 μM) over HDAC6 (0.46 μM). In the antiproliferative test, Oxametacin exhibited leukemic cell lines selectivity against the solid tumor cell lines. Current studies reveal that Oxametacin can be used as a lead compound in further development of histone deacetylase inhibitors for the anticancer therapy.
- Jing, Fanbo,Zhang, Lei,Luan, Yepeng,Bian, Jiang
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p. 1277 - 1282
(2017/11/14)
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- 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2-hydrogen-indole-3-yl)-N-hydroxyacetamide adopted as histone deacetylase inhibitor and preparation method and application thereof
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The invention belongs to the technical field of medicinal chemistry, particularly relates to a histone deacetylase inhibitor and a preparation method and application thereof, provides an efficient histone deacetylase inhibitor, relates to a compound of the formula (I), further relates to a pharmaceutical acceptable salt, a solvate and a prodrug of the compound, and further relates to a pharmaceutical composition containing the compound of the formula (I) and pharmaceutical application of the pharmaceutical composition. The histone deacetylase inhibitor can effectively treat diseases caused by histone deacetylase abnormal activity expression.
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Paragraph 0030
(2016/10/31)
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- Structure-based design, synthesis, and biological evaluation of indomethacin derivatives as cyclooxygenase-2 inhibiting nitric oxide donors
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Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a nitric oxide donor. A human whole-blood COX assay shows the modifications on the 3-acetic acid part of the indomethacin yielding an amide-nitrate derivative 32 and a sulfonamide-nitrate derivative 61 conferred COX-2 selectivity. Along with their respective des-nitrate analogs, for example, 31 and 62, the nitrates 32 and 61 were effective antiinflammatory agents in the rat air-pouch model. After oral dosing, though, only 32 increased nitrate and nitrite levels in rat plasma, indicating that its nitrate tether served as a nitric oxide donor in vivo. In a rat gastric injury model, examples 31 and 32 both show a 98% reduction in gastric lesion score compared to that of indomethacin. In addition, the nitrated derivative 32 inducing 85% fewer gastric lesions when coadministered with aspirin as compared to the combination of aspirin and valdecoxib.
- Wey, Shiow-Jyi,Augustyniak, Michael E.,Cochran, Edward D.,Ellis, James L.,Fang, Xinqin,Garvey, David S.,Janero, David R.,Letts, L. Gordon,Martino, Allison M.,Melim, Terry L.,Murty, Madhavi G.,Richardson, Steward K.,Schroeder, Joseph D.,Selig, William M.,Trocha, A. Mark,Wexler, Roseanne S.,Young, Delano V.,Zemtseva, Irina S.,Zifcak, Brian M.
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p. 6367 - 6382
(2008/03/27)
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- 2-METHYL INDOLE CYCLOOXYGENASE-2 SELECTIVE INHIBITORS, COMPOSITIONS AND METHODS OF USE
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The invention describes compositions and kits comprising 2-methyl indole cyclooxygenase 2 (COX-2) selective inhibitors or pharmaceutically acceptable salts thereof, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The 2-methyl indole cyclooxygenase 2 selective inhibitors can be optionally substituted with at least one nitric oxide enhancing group. The invention also provides methods for (a) treating inflammation, pain and fever; (b) treating gastrointestinal disorders and/or improving the gastrointestinal properties of COX-2 selective inhibitors; (c) facilitating wound healing; (d) treating renal and/or respiratory toxicities; (e) treating disorders resulting from elevated levels of cyclooxygenase-2; (f) improving the cardiovascular profile of COX-2 selective inhibitors; (g) treating diseases resulting from oxidative stress; (h) treating endothelial dysfunctions; (j) treating diseases caused by endothelial dysfunctions; (k) treating inflammatory disease states and/or disorders; (1) treating ophthalmic disorders; and (m) treating peripheral vascular diseases. The nitric oxide enhancing groups are organic nitrates, organic nitrites, nitrosothiols, thionitrites, thionitrates, NONOates, heterocyclic nitric oxide donors and/or nitroxides. The heterocyclic nitric oxide donors are furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.
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Page/Page column 81-82
(2010/11/23)
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- METHOD FOR THE PROPHYLAXIS OR TREATMENT OF CARCINOMAS
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There are described methods for the prophylaxis or treatment of carcinomas in a mammalian subject comprising administering a metal complex having anti-inflammatory activity to the mammal. Typically, the complex is a complex of at least one metal and at least one non-steroidal anti-inflammatory drug (NSAID). Suitable complexes include a complex of a metal and a carboxylate, or a derivative of a carboxylate, having anti-inflammatory activity.
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Page/Page column 58-59
(2010/11/24)
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