NDLI: Computer-assisted designed “selenoxy–chinolin”: a new catalytic mechanism of the GPx-like cycle and inhibition of metal-free and metal-associated Aβ aggregation

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Luo, Zonghua Wu, Ruibo Wang, Yali Li, Wenrui Huang, Ling Sun, Yang Li, Xingshu Liu, Zhihong Wang, Zhiren
Description	Author Affiliation: Wang Z ( School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. huangl72@mail.sysu.edu.cn lixsh@mail.sysu.edu.cn.)
Abstract	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 $^{77}Se,$ $^{1}H$ and $^{13}C$ 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.
ISSN	14779226
Issue Number	48
Volume Number	44
e-ISSN	13645447
Journal	Dalton Trans.
Language	English
Publisher	Royal Society of Chemistry
Publisher Date	2015-12-28
Publisher Place	Great Britain (UK)
Access Restriction	Subscribed
Subject Keyword	Amyloid Beta-Peptides Chemistry Antioxidants Biocompatible Materials Hydroxyquinolines Metals Organoselenium Compounds Selenium Alzheimer Disease Drug Therapy Metabolism Animals Chemical Synthesis Therapeutic Use Azoles Blood-Brain Barrier Catalysis Chelating Agents Clioquinol Glutathione Peroxidase Magnetic Resonance Spectroscopy Mice Journal Article Research Support, Non-U.S. Gov't
Content Type	Text
Resource Type	Article
Subject	Inorganic Chemistry

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