Spiro-Polycyclic Polyprenylated Acylphloroglucinols from Hypericum monogynum and Their anti-Alzheimer’s Disease Effects
Wenjing Tian, Shoulun He, Tingjiya Wang, Shengfei Zhong, Jingyu Sun, Junjie Chen, Xiaoyi Wang, Chunchun Du, Yuhang You, Yingting Lin, Ye Wang, Guanghui Wang, Xiaobin Li, Haifeng ChenAbstract
Eight undescribed spiro-polycyclic polyprenylated acylphloroglucinols (PPAPs) with a 6/6/5 tricyclic architecture (1−8), together with eight known analogues (9−16), were isolated from Hypericum monogynum L. Their structures including absolute configurations were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Biological evaluation revealed that compounds 4 and 16 showed potential as dual-target anti-Alzheimer’s disease (AD) lead compounds, as they not only exhibited potent acetylcholinesterase (AChE) inhibitory activities but also induced peroxisome proliferator-activated receptor-γ transactivation and upregulated ATP-binding cassette transporter A1 expression. The in vivo anti-AD effects of 4 and 16 were evaluated by the zebrafish behavioral experiments. Compound 16 exhibited anti-AD effects with no detectable toxicity or teratogenicity, whereas 4 exhibited toxicity to zebrafish at 10 μM. These findings not only expand the chemical diversity of spiro-PPAPs but also underscore their potential as dual-target agents for AD treatment.