Two new lathyrane diterpenoids, euphanoids A and B (1 and 2), along with five known compounds (37) were isolated from the roots of Euphorbia kansuensis. Their structures were elucidated by spectroscopic analysis, and the absolute configuration of 1 was determined by single crystal X-ray diffraction. All of the isolates were screened for the inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 1 and 2 showed pronounced inhibition on NO production with IC 50 values of 4.7 and 9.5 M, respectively, being more active than the positive control, quercetin (IC 50 10.8 M).
Euphorkanlide A (1), a highly modified ingenane diterpenoid with a C 24 appendage forming an additional hexahydroisobenzofuran-fused 19-membered macrocyclic bis-lactone ring system was isolated from the roots of Euphorbia kansuensis. Its structure was determined by extensive spectroscopic analysis and quantum-chemical calculations. Compound 1 showed significant cytotoxicities against a panel of cancer cell lines (IC 50s < 5 μM). Mechanistic study revealed that 1 could induce the generation of ROS, leading to cell cycle arrest and cell apoptosis in drug-resistant cancer cell line HCT-15/5-FU.
cetane and tricyclo[8.4.1.0 3,7 ]pentadecane skeleton, respectively, were isolated from the seeds of Euphorbia lathyris. Their structures were determined by detailed spectroscopic analysis and were further confirmed by single-crystal X-ray diffraction. 1 significantly inhibited adipogenesis in 3T3-L1 adipocytes by retarding cell differentiation at the early stage.
Importins
are overexpressed in many cancers and mediate the abnormal
nuclear transport of oncogenic factors. The druggable potential of
importins still remains unclear, largely because of the lack of potent
inhibitors. Herein, the anti-castration-resistant prostate cancer
(CRPC) screening of a Euphorbiaceae diterpenoid library followed by
target fishing led to the identification of a highly potent importin-β1
inhibitor, daphnane diterpenoid DD1. DD1 selectively inhibited the growth and survival of CRPC cells at subnanomolar
concentrations and completely blocked tumor growth in preclinical
models at an extremely low dosage. Mechanistic studies revealed that
targeting of importin-β1 by DD1 significantly reduced
the nuclear accumulation of key CRPC drivers, shutting down their
downstream oncogenic signaling. Disruption of the predicted binding
sites of DD1 on importin-β1 abolished this anti-CRPC
effect. These findings suggest that importin-β1 is an effective
therapeutic target in CRPC and that DD1 as the most potent
importin-β1 inhibitor to date can be developed as therapeutics
for treatment of this disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.