Semisynthesis and Inhibitory Effects of Solidagenone Derivatives on TLR-Mediated Inflammatory Responses

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Cuadrado Berrocal, Irene and Amesty, Ángel and Cedrón, Juan Carlos and Oberti, Juan Carlos and Estévez-Braun, Ana and Hortelano, Sonsoles and De las Heras Polo, Beatriz (2018) Semisynthesis and Inhibitory Effects of Solidagenone Derivatives on TLR-Mediated Inflammatory Responses. Molecules, 23 (12). p. 3197. ISSN 1420-3049

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Official URL: https://doi.org/10.3390/molecules23123197




Abstract

A series of nine derivatives (2–10) were prepared from the diterpene solidagenone (1) and their structures were elucidated by means of spectroscopic studies. Their ability to inhibit inflammatory responses elicited in peritoneal macrophages by TLR ligands was investigated. Compounds 5 and 6 showed significant anti-inflammatory effects, as they inhibited the protein expression of nitric oxide synthase (NOS-2), cyclooxygenase-2 (COX-2), and cytokine production (TNF-α, IL-6, and IL-12) induced by the ligand of TLR4, lipopolysaccharide (LPS), acting at the transcriptional level. Some structure–activity relationships were outlined. Compound 5 was selected as a representative compound and molecular mechanisms involved in its biological activity were investigated. Inhibition of NF-κB and p38 signaling seems to be involved in the mechanism of action of compound 5. In addition, this compound also inhibited inflammatory responses mediated by ligands of TLR2 and TLR3 receptors. To rationalize the obtained results, molecular docking and molecular dynamic studies were carried out on TLR4. All these data indicate that solidagenone derivative 5 might be used for the design of new anti-inflammatory agents.


Item Type:Article
Uncontrolled Keywords:solidagenone derivatives; diterpenes; inflammation; TLR4; molecular docking
Subjects:Medical sciences > Pharmacy > Pharmacology
Medical sciences > Pharmacy > Organic chemistry
ID Code:69189
Deposited On:15 Dec 2021 11:56
Last Modified:20 Dec 2021 08:51

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