文献类型：期刊文献

英文题名：Design, synthesis and evaluation of diosgenin carbamate derivatives as multitarget anti-Alzheimer's disease agents

作者：Yang, Gui-Xiang[1];Huang, Yan[1];Zheng, Lu-Lu[1];Zhang, Li[1];Su, Lin[1];Wu, Yu-Hang[1];Li, Jie[1];Zhou, Li-Cheng[1];Huang, Jin[1];Tang, Yun[1];Wang, Rui[1];Ma, Lei[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China

年份：2020

卷号：187

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000510525000024)】；

基金：This work was supported by the National Natural Science Foundation of China (Grants 81973196 and 81673318), the 111 Project (Grant BP0719034) and the Natural Science Foundation of Shanghai (Grant 19ZR1413900), Overseas Expertise Introduction Project for Discipline Innovation, China, Yun Tang, (Grant BP0719034).

语种：英文

外文关键词：Alzheimer's disease; Diosgenin; Antioxidant; Anti-inflammatory; Anti-A beta activity; Multi-target-directed ligands

摘要：In order to produce an effective multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-A beta activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 +/- 2.2%,10 mu M) and cellular damage induced by H2O2 (SH-SY5Y cell protection = 75.3 +/- 3.4%, 10 mu M) or AO (astrocytes protection = 70.2 +/- 6.5%, 10 mu M). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, A beta(42) and pro-inflammatory proteins. Western blot demonstrated that MIS decreased IL-beta, IL-6 and TNF-alpha level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H2O2-inducedROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-All activities. (C) 2019 Elsevier Masson SAS. All rights reserved.