2. Academic Validation
  3. Semi-synthesis and biological evaluation of flavone hybrids as multifunctional agents for the potential treatment of Alzheimer's disease

Semi-synthesis and biological evaluation of flavone hybrids as multifunctional agents for the potential treatment of Alzheimer's disease

  • Bioorg Chem. 2020 Jul;100:103917. doi: 10.1016/j.bioorg.2020.103917.
Shaochun Shi 1,  Huibin Wang 2,  Jian Wang 2,  Yvxi Wang 1,  Xiaobian Xue 1,  Zilin Hou 1,  Guo-Dong Yao 1,  Xiao-Xiao Huang 1,  Hongwei Zhao 3,  Qingbo Liu 4,  Shao-Jiang Song 5
Affiliations

Affiliations

  • 1 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 2 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, PR China.
  • 3 Jilin Yizheng Pharmaceutical Group Co., Ltd., Jilin Province, Siping 136001, People's Republic of China.
  • 4 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Jilin Yizheng Pharmaceutical Group Co., Ltd., Jilin Province, Siping 136001, People's Republic of China. Electronic address: [email protected].
  • 5 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address: [email protected].
PMID: 32442817 DOI: 10.1016/j.bioorg.2020.103917
Abstract

7-O-galloyltricetiflavan (GTF), a natural flavonoid, is known to exert anti-oxidation and neuroprotective activity, which are related to the prevention of Alzheimer's disease (AD). In this study, three series of GTF hybrids have been designed, synthesized and evaluated as multifunctional agents for treatment AD. The biological assays indicated that most of them showed strong inhibitory effect on self-induced β-amyloid (Aβ) aggregation, and a significant ability to inhibit ChEs. Among them, compound A15 exhibited best inhibition of Aβ aggregation (78.81% at 20 μM), potent AChE inhibitory potencies (IC50, 0.56 μM), and compound C4 presented the highest ability to inhibit BuChE (IC50, 5.77 μM). Furthermore, kinetic, molecular modeling and molecular dynamics studies revealed that A15 and C4 could interact with the catalytic active site of AChE and BuChE, respectively. In addition, compounds A15 and C4 could cross the blood-brain barrier in vitro. More importantly, A15 and C4 also showed excellent neuroprotective activities against H2O2-induced human neuroblastoma SH-SY5Y cells damage and nearly no toxicity on SH-SY5Y cells. All of these outstanding in vitro results indicated A15 and C4 as the leading structure worthy of further investigation.

Keywords

7-O-galloyltricetiflavan; Alzheimer's disease; Multifunctional agents; Neuroprotective activities; inhibition of Aβ aggregation.

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