Planta Med 2018; 84(05): 329-335
DOI: 10.1055/s-0043-120115
Natural Product Chemistry and Analytical Studies
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Inhibition of TNF-α-Induced Inflammation by Sesquiterpene Lactones from Saussurea lappa and Semi-Synthetic Analogues

Siwattra Choodej
The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan
Khanitha Pudhom
Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
Tohru Mitsunaga
The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan
› Author Affiliations
Further Information

Publication History

received 28 July 2017
revised 30 August 2017

accepted 16 September 2017

Publication Date:
29 September 2017 (eFirst)


We investigated the tumor necrosis factor-alpha (TNF-α) inhibitory activity of sesquiterpenes from Saussurea lappa root extracts. According to the hexane and EtOAc extracts showing significant activity with IC50 values of 0.5 and 1.0 µg/mL, respectively, chromatographic fractionation of the extracts was performed and led to the isolation of 10 sesquiterpenes (110). Costunolide (1), a major compound, and dehydrocostus lactone (4) exhibited high efficiency in decreasing TNF-α levels, with IC50 values of 2.05 and 2.06 µM, respectively. In addition, sesquiterpene analogues were synthesized to establish their structure-activity relationship (SAR) profile. Among the semi-synthetic analogues, compounds 6a and 16 showed the most potent activity with IC50 values of 1.84 and 1.97 µM, respectively. More importantly, compound 6a showed less toxicity than costunolide and 16. These results provided the first SAR profile of sesquiterpene lactones and indicated that the α-methylene-γ-lactone moiety plays a crucial role in TNF-α inhibition. Additionally, the epoxide derivative 6a might represent a lead compound for further anti-TNF-α therapies, owing to its potent activity and reduced toxicity.

Supporting Information