- Computer-assisted designed "selenoxy-chinolin": A new catalytic mechanism of the GPx-like cycle and inhibition of metal-free and metal-associated Aβ aggregation
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Using support from rational computer-assisted design, a novel series of hybrids (selenoxy-chinolin) designed by fusing the metal-chelating agent CQ and the antioxidant ebselen were synthesized and evaluated as multitarget-directed ligands. Most of the hybrids demonstrated significant ability to mimic GPx, which is highly consistent with the prediction results of DFT studies for the selenenyl sulfide intermediates in the computational design. Using 77Se, 1H and 13C NMR spectroscopy and high-resolution mass spectroscopy (HRMS), a novel catalytic mechanism, including a new selenium quinone active species, was first demonstrated. 2D NMR studies indicated that the typical hybrid has an effective interaction with Aβ. In addition, the optimal compound 12k was found to possess an excellent ability to scavenge peroxide and to inhibit self- and metal-induced Aβ aggregation, and an ability to disassemble preformed self- and metal-induced Aβ aggregates effectively. Furthermore, 12k was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg-1. Overall, we demonstrated that hybrid 12k, through rational structure-based computational design, shows a potential for development as a therapeutic agent in AD.
- Wang, Zhiren,Wang, Yali,Li, Wenrui,Liu, Zhihong,Luo, Zonghua,Sun, Yang,Wu, Ruibo,Huang, Ling,Li, Xingshu
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- Ebselen as a peroxynitrite scavenger in vitro and ex vivo
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We have previously shown that peroxynitrite (PN) selectively impaired prostacyclin (PGI2)-dependent vasorelaxation by tyrosine nitration of PGI2 synthase in an in situ model (Zou MH, Jendral M and Ullrich V, Br J Pharmacol 126: 1283-
- Daiber, Andreas,Zou, Ming-Hui,Bachschmid, Markus,Ullrich, Volker
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- Antioxidant activity of the anti-inflammatory compound ebselen: A reversible cyclization pathway via selenenic and seleninic acid intermediates
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A revised mechanism that accounts for the glutathione peroxidase (GPx)-like catalytic activity of the organoselenium compound ebselen is described. It is shown that the reaction of ebselen with H2O2 yields seleninic acid as the only oxidized product. The X-ray crystal structure of the seleninic acid shows that the selenium atom is involved in a noncovalent interaction with the carbonyl oxygen atom. In the presence of excess thiol, the Se-N bond in ebselen is readily cleaved by the thiol to produce the corresponding selenenyl sulfide. The selenenyl sulfide thus produced undergoes a disproportionate in the presence of H2O2 to produce the diselenide, which upon reaction with H2O2, produces a mixture of selenenic and seleninic acids. The addition of thiol to the mixture containing selenenic and seleninic acids leads to the formation of the selenenyl sulfide. When the concentration of the thiol is relatively low in the reaction mixture, the selenenic acid undergoes a rapid cyclization to produce ebselen. The seleninic acid, on the other hand, reacts with the diselenide to produce ebselen as the final product. DFT calculations show that the cyclization of selenenic acids to the corresponding selenenyl amides is more favored than that of sulfenic acids to the corresponding sulfenyl amides. This indicates that the regeneration of ebselen under a variety of conditions protects the selenium moiety from irreversible inactivation, which may be responsible for the biological activities of ebselen.
- Sarma, Bani Kanta,Mugesh, Govindasamy
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experimental part
p. 10603 - 10614
(2009/12/31)
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- MECHANISM OF THE CATALYTIC REDUCTION OF HYDROPEROXIDES BY EBSELEN : A SELENIUM - 77 NMR STUDY
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Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one 1, a non-toxic selenium containing heterocyclic compound has been shown to display both anti-inflammatory activity in vivo and GSH-Px-like activity in vitro.Using (1)H and (77)Se NMr we investigated the mechanism of reduction of hydroperoxides by thiols in the presence of 1.A catalytic cycle depending on the formation of diselenides and selenylsulfides was found.The selenic acid oxidation level present in compound 1 is particularly stable because of the intermolecular cyclisation.This contracts with previously reported results concerning the oxidation of organoselenium compounds.
- Fisher, Hartmut,Dereu, Norbert
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p. 757 - 768
(2007/10/02)
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