1. Biologically active franchetine-type diterpenoid alkaloids: Isolation, synthesis, anti-inflammatory, agalgesic activities, and molecular docking.
- Author
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Xiao Y, Chang Y, Liu YY, Li TT, Qu WR, Yuan C, Chen L, Huang S, and Zhou XL
- Subjects
- Animals, Humans, Male, Mice, Aconitum chemistry, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents isolation & purification, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal isolation & purification, Dose-Response Relationship, Drug, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides pharmacology, Molecular Docking Simulation, Molecular Structure, Nitric Oxide antagonists & inhibitors, Nitric Oxide biosynthesis, Nitric Oxide metabolism, Nitric Oxide Synthase Type II antagonists & inhibitors, Nitric Oxide Synthase Type II metabolism, RAW 264.7 Cells, Structure-Activity Relationship, Alkaloids pharmacology, Alkaloids chemistry, Alkaloids isolation & purification, Alkaloids chemical synthesis, Analgesics pharmacology, Analgesics chemistry, Analgesics chemical synthesis, Analgesics isolation & purification, Diterpenes pharmacology, Diterpenes chemistry, Diterpenes isolation & purification, Diterpenes chemical synthesis
- Abstract
In this study, four franchetine-type diterpenoid alkaloids (1-4) were isolated from Aconitum sinoaxillare, and fourteen diverse franchetine analogs (5-18) were synthesized. Compounds 1, 2, 7 and 16 exhibited stronger inhibitory effects on NO production when compared to celecoxib. Among them, compound 1 had the best inhibitory effect on iNOS and COX-2 inflammatory proteins. The in vitro studies displayed that the anti-inflammatory effect of the most active compound 1 was ascribed to the inhibition of the TLR4-MyD88/NF-κB/MAPKs signalling pathway. Consequently, this led to a inhibition in the expression of inflammatory factors or mediators including NO, ROS, TNF-α, IL-6, IL-1β, iNOS, and COX-2. Additionally, compound 1 had low toxicity (LD
50 > 20 mg/kg) in mice, and it had notable analgesic effects on acetic acid-induced visceral pain (ED50 = 2.15 ± 0.07 mg/kg). Moreover, compound 1 exhibited a distinct reduction in the NaV 1.7 and NaV 1.8 channel currents during both resting and half-inactivated states at 50 μM. The present study enriches the pharmacological activities of franchetine derivatives and provides valuable insights for the development of novel anti-inflammatory and analgesic agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)- Published
- 2024
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