AUTHOR=Hu Xiaoyu , Liu Chan , Wang Kaichun , Zhao Lanxue , Qiu Yu , Chen Hongzhuan , Hu Jiangmiao , Xu Jianrong 

TITLE=Multifunctional Anti-Alzheimer’s Disease Effects of Natural Xanthone Derivatives: A Primary Structure-Activity Evaluation

JOURNAL=Frontiers in Chemistry

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2022.842208

DOI=10.3389/fchem.2022.842208

ISSN=2296-2646

ABSTRACT=<p><bold>Background:</bold> A series of α-Mangostin (α-M) derivatives were designed and synthesized. α-M and four analogues were evaluated for their multifunctional anti-Alzheimer’s disease (anti-AD) effects on fibrillogenesis, microglial uptake, microglial degradation, and anti-neurotoxicity of Aβ, as well as LPS-induced neuroinflammation. The differences in bioactivities were analyzed to understand the structure-activity relationship for further modifications.</p><p><bold>Purpose:</bold> This study aims to investigate the anti-AD effects of α-M and elucidate its structure-activity relationship by comparing difference between α-M and several analogues.</p><p><bold>Methods:</bold> Aβ fibrillogenesis was detected by Thioflavin T fluorometric assay. The levels of Aβ<sub>1-42</sub> and inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay. Neuron viability was examined by the CCK-8 assay. The morphology of ZO-1 of bEnd.3 cultured in BV-2-conditioned medium was evaluated by immunofluorescence staining.</p><p><bold>Results:</bold> Aβ fibrillogenesis was significantly inhibited by co-incubation with α-M, Zcbd-<bold>2</bold> or Zcbd-<bold>3</bold>. α-M, Zcbd-<bold>2</bold>, Zcbd-<bold>3,</bold> and Zcbd-<bold>4</bold> decreased the levels of Aβ<sub>1-42</sub> and inflammatory cytokines, and promoted Aβ uptake, degradation and anti-inflammation effects inflammation in microglia. α-M and Zcbd-<bold>3</bold> protected neuron viability from Aβ-induced neurotoxicity, and preserved tight junction integrity of bEnd.3 against LPS-induced neuroinflammation.</p><p><bold>Conclusion:</bold> Zcbd-<bold>3</bold> acted as α-M almost in all effects. The structure-activity analysis indicated that the 3-methyl-2-butenyl group at C-8 is essential for the bioactivity of α-M, while modifying the double hydroxylation at the C-2 position may improve the multifunctional anti-AD effects.</p>