Fritaipaines A − J, isosteroidal alkaloids with anti-neuroinflammatory activity from the bulbs of Fritillaria taipaiensis

Abstract

Ten new isosteroidal alkaloids, fritaipaines A − J (1−10), and six known congeners (11–16) were isolated from the bulbs of Fritillaria taipaiensis. The planar structure of these compounds as well as the absolute configuration, were fully elucidated based on spectroscopic and single-crystal X-ray diffraction data analysis and electronic circular dichroism (ECD) methods. Fritaipaines A (1) and B (2) are rare C₂₆ cevanine-type alkaloids having C-18 nor carbon skeleton. Fritaipaines C − F (3–6) are the first examples of jervine-type alkaloids featuring an inversed E/F ring moiety. The characteristic ¹³C NMR data for judging E/F rings-inversion of jervine-type alkaloids were summarized. Compounds 5, 9, and 16 exhibited potent nitric oxide (NO) inhibitory activity in lipopolysaccharide (LPS) stimulated BV-2 cells with IC₅₀ values of 3.7 ± 0.4, 10.3 ± 1.1, and 6.9 ± 0.7 μM, respectively. All compounds showed weak or no acetylcholinesterase (AChE) inhibition as determined by the Ellman's method. The results of network pharmacology experiments predicted that the anti-Alzheimer's disease (AD) effect of fritaipaine E (5) was related to 9 signaling pathways and 5 core targets, including SRC, PIK3CA, AKT1, EGFR, and IGF1R. Molecular docking simulations highlighted interactions between 5 and core targets, showing inhibitory effects on AD.