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

Chemical Research in Chinese Universities ›› 2017, Vol. 33 ›› Issue (4): 611-622.doi: 10.1007/s40242-017-6465-7

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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

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）.

Abstract

Abstract:

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.

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]. Chemical Research in Chinese Universities, 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

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