期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 44, 期 6, 页码 2523-2532出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2009.01.021
关键词
Oxoaporphine derivatives; Oxoisoaporphine derivatives; Synthesis; Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitors
资金
- Natural Science Foundation of China [20772159]
- NSFC/RGC joint Research Scheme [30731160006]
- Science Foundation of Guangzhou [2006Z2-E402]
- Science Foundation of Zhuhai [PC20041131]
- NCET
Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17, 3765-3768). In this paper, further research results were presented. A series of novel derivatives of oxoaporphine alkaloids (5a-j, 4-carboxylic amide-7-oxo-7H-dibenzo[de,g]quinoline, Ar-CONH(CH2)(n)NR) and their quaternary methiodide salts (6a-h, Ar-CONH(CH2)(n)N+(CH3)RI-) were designed and synthesized as acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) inhibitors. The AChE inhibition potency of synthetic oxoaporphine derivatives was decreased about 2-3 orders of magnitude as compared with that of oxoisoaporphine derivatives. Non-competitive binding mode was found for both kinds of derivatives. Molecular docking simulations on the oxoisoaporphine derivatives 7 series and oxoaporphine derivatives 6 series with AChE from Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme. (C) 2009 Elsevier Masson SAS. All rights reserved.
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