Incorporation of Dihydroartemisinin into Memantine Through a Propriate Spacer to Make Hybrid with Enhanced Effects to Protect PC12 Cells from Corticosterone-caused Impairments

doi:10.1007/s40242-017-6465-7

高等学校化学研究 ›› 2017, Vol. 33 ›› Issue (4): 611-622.doi: 10.1007/s40242-017-6465-7

Incorporation of Dihydroartemisinin into Memantine Through a Propriate Spacer to Make Hybrid with Enhanced Effects to Protect PC12 Cells from Corticosterone-caused Impairments

ZHANG Lei¹, ZHOU Fan¹, ZHANG Laitao¹, PENG Lizhi¹, GUO Cuiping¹, LUO Cheng², CHEN Heru^1,2,3

1. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China;
2. State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China;
3. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, P. R. China

收稿日期:2016-11-23 修回日期:2017-05-04 出版日期:2017-08-01 发布日期:2017-05-15
通讯作者: CHEN Heru E-mail:thrchen@jnu.edu.cn
基金资助:
Supported by the National Natural Science Foundation of China（No.81172982），the Natural Science Foundation of Guangdong Province of China（No.2015A030311012） and the Fundamental Research Funds for the Central Universities of China（No.11615323）.

Incorporation of Dihydroartemisinin into Memantine Through a Propriate Spacer to Make Hybrid with Enhanced Effects to Protect PC12 Cells from Corticosterone-caused Impairments

ZHANG Lei¹, ZHOU Fan¹, ZHANG Laitao¹, PENG Lizhi¹, GUO Cuiping¹, LUO Cheng², CHEN Heru^1,2,3

1. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China;
2. State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China;
3. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, P. R. China

Received:2016-11-23 Revised:2017-05-04 Online:2017-08-01 Published:2017-05-15
Contact: CHEN Heru E-mail:thrchen@jnu.edu.cn
Supported by:
Supported by the National Natural Science Foundation of China（No.81172982），the Natural Science Foundation of Guangdong Province of China（No.2015A030311012） and the Fundamental Research Funds for the Central Universities of China（No.11615323）.

摘要/Abstract

摘要：

Ten memantine(Mema)-dihydroartemisinin(DHA) ligands were designed and synthesized. Three types of isomers including α,β, and a defined γ isomer were found in each intermediates(1a-1e). Type γ isomer was firstly reported here and confirmed as a less stable eclipsed conformation. The bonding of Mema with DHA through different carbon chains generally makes the new entities more cytotoxic than either Mema or artemisinin(Arte). The β Mema/DHA ligands are a little bit more cytotoxic than α ligands. By applying corticosterone(Cort)-impaired PC12 cells models, it was found that Mema and those ligands with more than 3 carbon chains showed weak or no neur oprotective activities against the insults. However, two ligands, 2a(β) and 2b(β) showed better effects than either Arte or their combination(Mema/Arte in 1:1 molar ratio) at a dose of 5 μmol/L. Furthermore, ligands 2a(β), 2b(β) and 2c(β) were confirmed as mild N-methyl-D-aspartate(NMDA) antagonists, and their corresponding α isomers are weak NMDA antagonists. All the data indicate that the bonding of Mema/DHA in compacted β conformation mode results in enhanced effects against Cort-induced insults in PC12 cells and might reverse memantine as an anti-depression NMDA antagonist.

关键词: Artemisinin, Memantine, Neuroprotection, N-Methyl-D-aspartate(NMDA) receptor, Depression

Abstract:

Key words: Artemisinin, Memantine, Neuroprotection, N-Methyl-D-aspartate(NMDA) receptor, Depression

ZHANG Lei, ZHOU Fan, ZHANG Laitao, PENG Lizhi, GUO Cuiping, LUO Cheng, CHEN Heru. Incorporation of Dihydroartemisinin into Memantine Through a Propriate Spacer to Make Hybrid with Enhanced Effects to Protect PC12 Cells from Corticosterone-caused Impairments[J]. 高等学校化学研究, 2017, 33(4): 611-622.

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Incorporation of Dihydroartemisinin into Memantine Through a Propriate Spacer to Make Hybrid with Enhanced Effects to Protect PC12 Cells from Corticosterone-caused Impairments

Incorporation of Dihydroartemisinin into Memantine Through a Propriate Spacer to Make Hybrid with Enhanced Effects to Protect PC12 Cells from Corticosterone-caused Impairments

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