Bioassay-guided isolation of dehydrocostus lactone from Saussurea lappa: A new targeted cytosolic thioredoxin reductase anticancer agent

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 (1–10). 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.

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Ethaselen: a novel organoselenium anticancer agent targeting thioredoxin reductase 1 reverses cisplatin resistance in drug-resistant K562 cells by inducing apoptosis

Journal of Zhejiang University SCIENCE B ◽

10.1631/jzus.b1600073 ◽

2017 ◽

Vol 18 (5) ◽

pp. 373-382 ◽

Cited By ~ 9

Author(s):

Suo-fu Ye ◽

Yong Yang ◽

Lin Wu ◽

Wei-wei Ma ◽

Hui-Hui Zeng

Keyword(s):

Anticancer Agent ◽

Cisplatin Resistance ◽

Thioredoxin Reductase ◽

K562 Cells ◽

Drug Resistant ◽

Thioredoxin Reductase 1

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Ethaselen: a potent mammalian thioredoxin reductase 1 inhibitor and novel organoselenium anticancer agent

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2011.11.034 ◽

2012 ◽

Vol 52 (5) ◽

pp. 898-908 ◽

Cited By ~ 64

Author(s):

Lihui Wang ◽

Zhiyu Yang ◽

Jianing Fu ◽

Hanwei Yin ◽

Kun Xiong ◽

...

Keyword(s):

Anticancer Agent ◽

Thioredoxin Reductase ◽

Thioredoxin Reductase 1

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A New Sesquiterpene and other Constituents from Saussurea Lappa Root

Natural Product Communications ◽

10.1177/1934578x1000501002 ◽

2010 ◽

Vol 5 (10) ◽

pp. 1934578X1000501 ◽

Cited By ~ 2

Author(s):

Jin-ao Duan ◽

Pengfei Hou ◽

Yuping Tang ◽

Pei Liu ◽

Shulan Su ◽

...

Keyword(s):

Acid Derivative ◽

Artemisia Annua ◽

Saussurea Lappa ◽

Artemisinic Acid ◽

Structural Skeleton ◽

Dehydrocostus Lactone

Five sesquiterpenes, dehydrocostus lactone (1), santamarine (5), β-cyclocostunolide (6), 4α-hydroxy-4β-methyldihydrocostol (7) and 10α-hydroxyl-artemisinic acid (9), along with four other compounds, β-sitosterol (2), daucosterol (3), 5-hydroxy-methyl-furaldehyde (4), and trans-syingin (8), were isolated and identified from the roots of Saussurea lappa (Compositae). Based on previous reports and our study, sesquiterpene derivatives are common and characteristic constituents of the genus Saussurea. Among the nine compounds obtained, 9 is a new sesquiterpene. It is an artemisinic acid derivative, whose structural skeleton has not been reported for Saussurea species before, but artemisinic acid is a common compound in another Compositae species, Artemisia annua. Dehydrocostus lactone (1) is present in high-content and is a possible bioprecursor of 10α-hydroxyartemisinic acid (9).

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