Bicyclic polyprenylated acylphloroglucinol-related meroterpenoids as potent DRAK2 inhibitors from Hypericum patulum

Jin-Chang Huang; Xin-Yu Jia; Yi-Fan Lv; Hong-Hong Xu; Ming Han; Qiang-Qiang Yu; Yu-Ting Lu; Hong-Xun Yang; Yang Yang; Jing-Ya Li; Ai-Jun Hou

doi:10.1016/j.phytochem.2024.114375

Bicyclic polyprenylated acylphloroglucinol-related meroterpenoids as potent DRAK2 inhibitors from Hypericum patulum

Phytochemistry. 2024 Dec 27:114375. doi: 10.1016/j.phytochem.2024.114375. Online ahead of print.

Authors

Jin-Chang Huang¹, Xin-Yu Jia², Yi-Fan Lv¹, Hong-Hong Xu³, Ming Han³, Qiang-Qiang Yu¹, Yu-Ting Lu³, Hong-Xun Yang⁴, Yang Yang⁵, Jing-Ya Li⁶, Ai-Jun Hou⁷

Affiliations

¹ Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
² School of Pharmacy, Fudan University, Shanghai, 201203, China.
³ State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁴ Sinopharm Chemical Reagent Co., Ltd. Shanghai, 200002, China.
⁵ State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
⁶ State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address: jyli@simm.ac.cn.
⁷ Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: ajhou@sjtu.edu.cn.

PMID: 39733941
DOI: 10.1016/j.phytochem.2024.114375

Abstract

As a both edible and medicinal plant, Hypericum patulum (Hypericaceae) is used as a natural herbal tea, scented tea, and folk medicine. In this study, eight undescribed bicyclic polyprenylated acylphloroglucinol-related meroterpenoids named hyperpatins A-H, along with eight known ones, were isolated from this plant. Their structures were elucidated on the basis of spectroscopic techniques, chemical method, X-ray crystallographic experiments, and electronic circular dichroism analyses. Hyperpatins A-H possess a characteristic pyran ring system diversely fused with the bicyclo[3.3.1]nonane-2,4,9-trione core, and hyperpatins C and D incorporate a unique α,β-unsaturated aldehyde moiety. Some of the isolates exhibited potent inhibitory effects on death-associated protein kinase-related apoptosis-inducing kinase 2 with IC₅₀ values ranging from 2.60 ± 0.29 to 17.93 ± 3.08 μM. This is the first report of DRAK2 inhibitory activity for acylphloroglucinol-related meroterpenoids. The most active molecule hyperpatins C showed binding affinity with DRAK2 by hydrogen-bond and hydrophobic interactions in molecular docking and promoted the glucose-stimulated insulin secretion ability of primary islets.

Keywords: Death-associated protein kinase-related apoptosis-inducing kinase 2; Glucose-stimulated insulin secretion; Hypericaceae; Hypericum patulum; Hyperpatins A–H; Meroterpenoids.