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Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors

文献类型：期刊论文

作者Shi, Yu-fang1; Zhang, Hai-yan2; Wang, Wei2; Fu, Yan2; Xia, Yu1; Tang, Xi-can2; Bai, Dong-lu1; He, Xu-chang1
刊名ACTA PHARMACOLOGICA SINICA
出版日期2009-08
卷号30期号:8页码:1195-1203
关键词Alzheimer's disease huperzine B acetylcholinesterase butyrylcholinesterase cholinesterase inhibitors
ISSN号1671-4083
DOI10.1038/aps.2009.91
文献子类Article
英文摘要Aim: To design novel bifunctional derivatives of huperzine B (HupB) based on the concept of dual binding site of acetylcholinesterase (AChE) and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer's disease (AD). Methods: Novel 16-substituted bifunctional derivatives of HupB were synthesized through chemical reactions. The inhibitory activities of the derivatives toward AChE and butyrylcholinesterase (BuChE) were determined in vitro by modified Ellman's method. Cell viability was quantified by the reduction of MTT. Results: A new preparative method was developed for the generation of 16-substituted derivatives of HupB, and pharmacological trials indicated that the derivatives were multifunctional cholinesterase inhibitors targeting both AChE and BuChE. Among the derivatives tested, 9c, 9e, 9f, and 9i were 480 to 1360 times more potent as AChE inhibitors and 370 to 1560 times more potent as BuChE inhibitors than the parent HupB. Further preliminary pharmacological trials of derivatives 9c and 9i were performed, including examining the mechanism of AChE inhibition, the substrate kinetics of the enzyme inhibition, and protection against hydrogen peroxide (H2O2)-induced cytotoxicity in PC12 cells. Conclusion: Preliminary pharmacological evaluation indicated that 16-substituted derivatives of HupB, particularly 9c and 9i, would be potentially valuable new drug candidates for AD therapy, and further exploration is needed to evaluate their pharmacological and clinical efficacies.
WOS关键词ALZHEIMERS-DISEASE ; HIGHLY POTENT ; ACETYLCHOLINESTERASE INHIBITORS ; INDUCED INJURY ; DESIGN ; DRUGS ; SITE ; BUTYRYLCHOLINESTERASE ; MEDICINE ; PROGRESS
资助项目National Natural Science Foundation of China[30472067] ; Shanghai SK Foundation for Research and Development[2004010-h]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:3653588
WOS记录号WOS:000269016100016
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/279164]  
专题药理学第二研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药物化学研究室
通讯作者Zhang, Hai-yan
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Neuropharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Shi, Yu-fang,Zhang, Hai-yan,Wang, Wei,et al. Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2009,30(8):1195-1203.
APA Shi, Yu-fang.,Zhang, Hai-yan.,Wang, Wei.,Fu, Yan.,Xia, Yu.,...&He, Xu-chang.(2009).Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors.ACTA PHARMACOLOGICA SINICA,30(8),1195-1203.
MLA Shi, Yu-fang,et al."Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors".ACTA PHARMACOLOGICA SINICA 30.8(2009):1195-1203.

入库方式： OAI收割

来源：上海药物研究所

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