Inubritantrimers A-D: Trimerized Sesquiterpenoid [4 + 2] Adducts Featuring a Distinctive Spiro-Polycyclic Scaffold from Inula britannica.

Inubritantrimer A (1), a trace trimerized sesquiterpenoid [4 + 2] adduct featuring an unusual exo-exo type spiro-polycyclic scaffold, together with three new endo-exo [4 + 2] adducts, inubritantrimers B-D (2-4), were discovered from the flowers of Inula britannica. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, and ECD approaches. 1 is characterized as a novel exo-exo trimer, synthesized biogenetically from three sesquiterpenoid monomers, featuring a unique linkage of C-11/C-1', C-13/C-3' and C-13'/C-3″, C-11'/C-1″ through a two-step exo [4 + 2] cycloaddition process. Compounds 1-4 exhibited modest cytotoxicity against breast cancer cells with IC50 values in the range of 5.84-12.01 µM.

Sesquiterpenoids from Inula britannica and Their Potential Effects against Triple-Negative Breast Cancer Cells.

Flowers of Inula britannica commercially serve as pharmaceutical herbs in the manufacturing of medicinal products. In the current study, sesquiterpenoids of I. britannica flowers' extract and their potential effects against triple-negative breast cancer (TNBC) cells were investigated. Eight structurally diverse sesquiterpenoids, including one sesquiterpenoid dimer (1) and seven sesquiterpenoid monomers (2−8) were isolated from this source. The structures of all compounds were elucidated by 1D/2D NMR data, and their absolute configurations were discerned by single crystal X-ray diffraction. All of the compounds were tested for their potential effects against TNBC. Specifically, 5 displayed strong antiproliferative potency against TNBC cells with a high selective index (SI) on MCF-7 cells (SI > 4 of IC50 on MDA-MB-468/IC50 on MCF-7), and dimer 1 (IC50 = 8.82 ± 0.85 µM) showed better antiproliferative potency against MCF-7 cells than the other monomers did (2−8) (IC50 > 20 µM). To our best knowledge, compound 5 is the first sesquiterpenoid targeting TNBC cells.

A new neuroprotective candidate TJ1 targeting amyloidogenesis in 5xFAD Alzheimer's disease mice.

As one of the main pathmechanisms of Alzheimer's disease (AD), amyloid-ß (Aß) is widely considered to be the prime target for the development of AD therapy. Recently, imidazolylacetophenone oxime ethers or esters (IOEs) have shown neuroprotective effects against neuronal cells damage, suggesting their potential use in the prevention and treatment of AD. Thirty IOEs compounds from our lab in-house library were constructed and screened for the inhibitory effects on Aß42-induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aß42-induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aß42 aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aß42-stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H2O2- and RSL3-stimulated PC12 cells. The cognitive improvement of TJ1 was assessed in 5xFAD (C57BL/6J) transgenic mouse. These results showed that TJ1 had strong neuroprotective effects and high blood-brain barrier (BBB) permeability without obvious cytotoxicity. TJ1 impeded the self-accumulation process of Aß42 by acting on Aß oligomerization and fibrilization. Besides, TJ1 reversed Aß-, H2O2- and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aß42 and Aß plaques, and attenuated the glia reactivation and inflammatory response in the brain,. Taken together, our results demonstrate that TJ1 improves cognitive impairments as a new neuroprotective candidate via targeting amyloidogenesis, which suggests the potential of TJ1 as a treatment for AD.