ABSTRACT
Isolation and identification of natural products from plants is an essential approach for discovering drug candidates. Herein we report the characterization of three sesquiterpene lactones from a new genus Shangwua, e.g. onopordopicrin (ONP), C2, and C3, and evaluation of their pharmacological functions in interfering cellular redox signaling. Compared to C2 and C3, ONP shows the most potency in killing cancer cells. Further experiments demonstrate that ONP robustly inhibits thioredoxin reductase (TrxR), which leads to perturbation of cellular redox homeostasis with the favor of oxidative stress. Knockdown of the TrxR sensitizes cells to the ONP treatment while overexpression of the enzyme reduces the potency of ONP, underpinning the correlation of TrxR inhibition to the cytotoxicity of ONP. The discovery of ONP expands the library of the natural TrxR inhibitors, and the disclosure of the action mechanism of ONP provides a foundation for the further development of ONP as an anticancer agent.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Asteraceae/chemistry , Enzyme Inhibitors/pharmacology , Lactones/pharmacology , Sesquiterpenes/pharmacology , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Humans , Lactones/chemistry , Lactones/isolation & purification , Molecular Docking Simulation , Molecular Structure , Oxidative Stress/drug effects , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Structure-Activity Relationship , Thioredoxin-Disulfide Reductase/metabolism , Tumor Cells, CulturedABSTRACT
Heliaquanoid A (1), the first exo-2,4-linked Diels-Alder adduct between a pseudoguaianolide dienophile and a guaianolide diene, and heliaquanoids B-E (2-5), four new 2,4-linked Diels-Alder adducts between a xanthanolide dienophile and a guaianolide diene, were isolated from stems and leaves of Inula helianthus-aquatica. Their structures were determined by NMR spectroscopy, a modified Mosher's method, electronic circular dichroism, and X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate cytotoxic activities against HL-60 cells with IC50 values of 7.5 and 4.9 µM, respectively.
Subject(s)
Inula/chemistry , Sesquiterpenes/chemistry , A549 Cells , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Dimerization , Drug Screening Assays, Antitumor , HL-60 Cells , Helianthus/chemistry , Humans , MCF-7 Cells , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacologyABSTRACT
Thirteen new ent-isopimarane-type diterpenoids, 1-10 and 14-16, and seven known diterpenoids, 11-13 and 17-20, were isolated from the roots of Euphorbia hylonoma. Among these compounds, four pairs of C-12 epimers (1 vs 2, 4 vs 5, 12 vs 13, and 14 vs 15) were identified. The structures of the new diterpenoids were elucidated using spectroscopic data analyses, electronic circular dichroism, and single-crystal X-ray diffraction data. The phytotoxic effects of compounds 1-20 on the growth of the roots and shoots of Poa annua and Festuca arundinacea seedlings were evaluated. Among the tested diterpenoids, 18 was the most active for inhibiting the growth of P. annua seedlings, and this compound was as active as glyphosate.
