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Molecules 2018, 23(12), 3197; https://doi.org/10.3390/molecules23123197

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

1
Departamento de Farmacología, Farmacognosia y Botánica. Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal s/n. 28040 Madrid, Spain
2
Departamento de Química Orgánica, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna. Avda. Astrofísico Fco. Sánchez 2. La Laguna, 38206 Tenerife, Spain
3
Facultad de Ciencias Químicas, Universidad de Córdoba and IMBIV (UNC−CONICET), Avenida Haya de la Torre y M. Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina
4
Unidad de Terapias Farmacológicas. Área de Genética Humana. Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Carretera de Majadahonda-Pozuelo Km 2, 28220 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Received: 5 November 2018 / Revised: 25 November 2018 / Accepted: 3 December 2018 / Published: 4 December 2018
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Abstract

A series of nine derivatives (210) 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.
Keywords: solidagenone derivatives; diterpenes; inflammation; TLR4; molecular docking solidagenone derivatives; diterpenes; inflammation; TLR4; molecular docking
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Cuadrado, I.; Amesty, Á.; Cedrón, J.C.; Oberti, J.C.; Estévez-Braun, A.; Hortelano, S.; Heras, B. Semisynthesis and Inhibitory Effects of Solidagenone Derivatives on TLR-Mediated Inflammatory Responses. Molecules 2018, 23, 3197.

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