Chemical Constituents of Ajuga Lupulina and their Anti-Ferroptosis Activity.

Five new compounds (1, 2, 7, 12, and 16), along with fifteen known ones, were isolated from Ajuga lupulina Maxim. Their structures were revealed by analysing spectroscopic data (MS, NMR), and experimental and calculated ECD spectra was used to deduce the absolute configuration. Compound 16, with eight carbon atoms, was firstly isolated from the nature. All the isolates were evaluated for their inhibitory effect on RSL3-induced ferroptosis in HT22 mouse hippocampal neuronal cells. Among them, the abietane-type diterpenoids (7-11) significantly inhibited ferroptosis with EC50 values of 0.83 µM, 2.05 µM, 0.96 µM, 1.47 µM, and 1.19 µM, respectively.

Discovery and optimization of olanzapine derivatives as new ferroptosis inhibitors.

Ferroptosis is a new type of cell death associated with many human diseases. It is a new strategy to discover ferroptosis inhibitors for the treatment of ferroptosis-related diseases. Here the FDA-approved drug library containing 1160 molecules was screened for ferroptosis inhibitors in RSL3-induced HT22 mouse hippocampal neuronal cells. As a result, olanzapine showed potent ferroptosis inhibitory activity (EC50 = 1.18 µM). Structural optimization and the structure-activity relationships (SARs) analysis led to the synthesis of 41 new derivatives (4-44) and one known compound 45. Comparing with olanzapine, its derivative 36 showed nearly sixteen-folds improved ferroptosis inhibition and low cytotoxicity (EC50 = 0.074 µM, CC50 = 18.8 µM). Further mechanistic studies revealed that compound 36 specifically inhibited ferroptosis by its antioxidative ability. This work demonstrates that olanzapine protected RSL3-induced ferroptosis in HT22 cell, and its derivative 36 having nanomolar ferroptosis inhibitory activity merit to be developed for drugs against ferroptosis-related neurological diseases.

Diverse Sesquiterpenoids from the Roots of Croton crassifolius and Their Inhibitory Effects on Ferroptosis.

One new sesquiterpenoid, 10-epi-lochmolin F (1), together with 13 known sesquiterpenoids, was isolated from the roots of Croton crassifolius. The structures of these compounds were confirmed by UV, IR, MS, and NMR spectroscopic analysis. The absolute configuration of compound 1 was elucidated by analysis of X-ray crystallography. All the 14 isolated sesquiterpenoids were screened for their inhibitory effects on ferroptosis in HT-22 cells. Two compounds 4 and 7 showed certain inhibitory effects against RSL3-induced ferroptosis with EC50 values of 10.8±2.3 µM and 15.5±0.5 µM, respectively. Here we firstly reported the sesquiterpenoids from C. crassifolius showing inhibitory effect on ferroptosis.

Chemical constituents of Ajuga forrestii and their anti-ferroptosis activity.

Six new neoclerodane diterpenoids (1-6), along with ten known compounds (7-16), were isolated from Ajuga forrestii. Their structures were elucidated by HRESIMS, 1D and 2D NMR, ECD calculation, and single-crystal X-ray diffraction analysis. The structure of a known neoclerodane diterpene ajudecunoid C (6) was revised based on the reported NMR empirical rules. All the isolates were evaluated for their inhibitory effect on RSL3-induced ferroptosis in HT22 mouse hippocampal neuronal cells. Among them, compounds 8, 9, and 12 significantly inhibited RSL3-induced ferroptosis with EC50 values of 0.45 µM, 0.076 µM, and 0.14 µM.