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Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer's disease.
Eur J Med Chem. 2015 Apr 13; 94:348-66.EJ

Abstract

A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 16d demonstrated significant metal chelating properties, moderate acetylcholinesterase (AChE) inhibitory and anti-oxidative activity, and excellent inhibitory effects on self-induced Aβ(1-42) aggregation, Cu(2+)-induced Aβ(1-42) aggregation, human AChE-induced Aβ(1-40) aggregation and disassembled Cu(2+)-induced aggregation of the well-structured Aβ(1-42) fibrils. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that 16d binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 16d showed a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Thus, 16d was shown to be an interesting multifunctional lead compound worthy of further study.

Authors+Show Affiliations

Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China. Electronic address: tanzhh616@163.com.Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: dengyong@scu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25778991

Citation

Sang, Zhipei, et al. "Design, Synthesis and Evaluation of scutellarein-O-alkylamines as Multifunctional Agents for the Treatment of Alzheimer's Disease." European Journal of Medicinal Chemistry, vol. 94, 2015, pp. 348-66.
Sang Z, Qiang X, Li Y, et al. Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem. 2015;94:348-66.
Sang, Z., Qiang, X., Li, Y., Yuan, W., Liu, Q., Shi, Y., Ang, W., Luo, Y., Tan, Z., & Deng, Y. (2015). Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer's disease. European Journal of Medicinal Chemistry, 94, 348-66. https://doi.org/10.1016/j.ejmech.2015.02.063
Sang Z, et al. Design, Synthesis and Evaluation of scutellarein-O-alkylamines as Multifunctional Agents for the Treatment of Alzheimer's Disease. Eur J Med Chem. 2015 Apr 13;94:348-66. PubMed PMID: 25778991.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer's disease. AU - Sang,Zhipei, AU - Qiang,Xiaoming, AU - Li,Yan, AU - Yuan,Wen, AU - Liu,Qiang, AU - Shi,Yikun, AU - Ang,Wei, AU - Luo,Youfu, AU - Tan,Zhenghuai, AU - Deng,Yong, Y1 - 2015/03/04/ PY - 2014/11/09/received PY - 2015/02/27/revised PY - 2015/02/28/accepted PY - 2015/3/18/entrez PY - 2015/3/18/pubmed PY - 2015/12/29/medline KW - Acetylcholinesterase inhibitors KW - Alzheimer's disease KW - Aβ aggregation inhibitors KW - Metal-chelating agents KW - Multifunctional agents KW - Scutellarein-O-alkylamines SP - 348 EP - 66 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 94 N2 - A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 16d demonstrated significant metal chelating properties, moderate acetylcholinesterase (AChE) inhibitory and anti-oxidative activity, and excellent inhibitory effects on self-induced Aβ(1-42) aggregation, Cu(2+)-induced Aβ(1-42) aggregation, human AChE-induced Aβ(1-40) aggregation and disassembled Cu(2+)-induced aggregation of the well-structured Aβ(1-42) fibrils. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that 16d binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 16d showed a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Thus, 16d was shown to be an interesting multifunctional lead compound worthy of further study. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/25778991/Design_synthesis_and_evaluation_of_scutellarein_O_alkylamines_as_multifunctional_agents_for_the_treatment_of_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(15)00161-0 DB - PRIME DP - Unbound Medicine ER -