Discovery of neo-Clerodane Diterpenoids from Ajuga campylantha as Neuroprotective Agents against Ferroptosis and Neuroinflammation

  • J Nat Prod. 2023 Aug 25;86(8):2006-2021. doi: 10.1021/acs.jnatprod.3c00447.
Xing Peng  1 ,  Qingyun Tan  1 ,  Zhikang Zhang  1 ,  Deyin Wu  1 ,  Jun Xu  1 ,  Huihao Zhou  1 ,  Qiong Gu  1
Affiliations
  • 1. Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
PMID: 37566645 DOI: 10.1021/acs.jnatprod.3c00447
Abstract

Twelve new neo-clerodane Diterpenoids, eight undescribed methoxy/ethoxy acetal analogues, and one new nor-iridane monoterpenoid were isolated from Ajuga campylantha. Their structures were elucidated using a combination of spectroscopic data, quantum chemical calculations, and X-ray crystallography. This research reveals the distinctive structural features of A. campylantha diterpenes, including distinct C rings and 4,18-double bonds, distinguishing them from diterpenes of other Plants in the Ajuga genus. Compound 2 represents the first example of a 19(5→6)-abeo-clerodane formed through a Wagner-Meerwein rearrangement. The isolated compounds were assessed for their neuroprotective effects against RSL3-induced Ferroptosis in HT22 cells and LPS-induced neuroinflammation in BV-2 cells. Notably, compound 7 inhibits Ferroptosis (EC50 = 10 μM) with a potentially new mechanism of action. The preliminary structure-activity relationship studies revealed that the furan-clerodane Diterpenoids possess potential Ferroptosis inhibitory activity, while the lactone-clerodanes do not. This study represents the first report of furan-containing clerodanes within the Ajuga genus, providing fresh insights into the phytochemistry and pharmacological potential of A. campylantha.

Products