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Increasing evidence suggests the significant contribution of high levels of thioredoxin reductase (TrxR) in various stages of tumorigenesis and resistance to tumor chemotherapy. Thus, inhibition of TrxR with small molecules is an attractive strategy for cancer therapy. Eriocalyxin B (EriB), a naturally occurring diterpenoid extracted from Isodon eriocalyx, has reflected potential anticancer activities through numerous pathways. Here, we describe that EriB covalently modifies GSH and selectively inhibits TrxR activity by targeting the Sec residue of the enzyme. Pharmacological inhibition of TrxR by EriB results in elevated ROS levels, reduced total GSH and thiols content, which ultimately induced potent RKO cell apoptosis mediated by oxidative stress. Importantly, EriB indicates potent synthetic lethality with GSH inhibitors, BSO, in RKO cells. In summary, our results highlight that targeting TrxR by EriB explores a novel mechanism for the biological action of EriB. This opened up a new therapeutic indication for using EriB to combat cancers.

Elevated expression of thioredoxin reductase (TrxR) is associated with the tumorigenesis and resistance to cancer chemoradiotherapy, highlighting the potential of TrxR inhibitors as anticancer drugs. Deoxyelephantopin (DET) is the major active ingredient of Elephantopus scaber and reveals potent anticancer activity. However, the potential mechanism of action and the cellular target of DET are still unknown. Here, we found that DET primarily targets the Sec residue of TrxR and irreversibly prohibits enzyme activity. Suppression of TrxR by DET leads to accumulation of reactive oxygen species and dysregulation in intracellular redox balance, eventually inducing cancer cell apoptosis mediated by oxidative stress. Noticeably, down-regulation of TrxR1 by shRNA increases cell sensitivity to DET. Collectively, targeting of TrxR1 by DET uncovers a novel mechanism of action in DET and deepens the understanding of developing DET as a potential chemotherapeutic agent for treating cancers.

One new flavone hydrate named lobatflavate (1), one new chromone named lobatchrosin (2), and one new isoflavone named 3S,4R-tuberosin (3), along with four known isoflavone analogues (4-7), were isolated from the traditional Chinese medicinal plant of Pueraria lobata (Willd.) ohwi. Their structures were elucidated by extensive spectroscopic methods of IR, UV, HR-ESI-MS, 1D and 2D NMR. The absolute configuration of 3 was determined by CD spectrum associated with TD-DFT calculation analysis. All compounds except for 2 were assayed the inhibitory activity against α-glucosidase. Every tested compound was proved to be more active than positive control of acarbose. Of which 1 and 4 showed significant activity with IC50 value of 1.79μM and 23.01μM (IC50 of acarbose was 1998.79μM). Enzyme kinetic experiments revealed that 1 was irreversible whereas 4 was reversible and non-competitive α-glucosidase inhibitors. Moreover, structure-activity relationship was discussed and the docking studies of 1, 3 and 4 were also carried out.

A pair of new neo-clerodane diterpenoid epimers, 3S-methoxyl-teucvin (1) and 3R-methoxyl-teucvin (2), were isolated from the Roots of Croton crassifolius. Their structures were completely established on the basis of spectroscopic methods, and the absolute configurations were determined by analysis of electronic circular dichroism (ECD) spectroscopy and X-ray diffraction analysis. Compounds 1 and 2 exhibited anti-inflammatory activities with IC50 values of 0.82 and 0.54 μM, respectively, while the IC50 value of dexamethasone as a positive control was found to be 0.14 μM.

The present work describes modifications to an existing TLC bioautographic method for detecting acetylcholinesterase inhibitors from plant extracts. The basic principle of the method is that the enzyme converts 1-naphthyl acetate into naphthol which reacts with Fast Blue B salt to make a purple-colored background on the TLC plates. Inhibitors of acetylcholinesterases produced white spots on the background. Our modifications involve changes in the concentration of the enzyme, the reagents, and the time of the reaction. With these changes, the consumption of the enzyme was reduced by 85% and the detection limits were decreased remarkably.

Aims Inhibition of acetylcholinesterase (AChE) is still considered as a strategy for the treatment of neurological disorders such as Alzheimer's disease (AD). Many plant derived alkaloids (such as huperzine A, galanthamine and rivastigmine) are known for their AChE inhibitory activity. The aim of the present work was to isolate and identify new AChE inhibitors from Holarrhen antidysenterica . Main methods These compounds were tested for AChE inhibiting activity by the Ellman's method in 96-well microplates. In addition, molecular modeling was performed to explore the binding mode of inhibitors 1 – 5 at the active site of AChE, and the preliminary structure–activity relationships (SARs) were discussed. Key findings In the course of searching for AChE inhibitors from herb medicines, the total alkaloidal extract from the seeds of H. antidysenterica was found having potent AChE inhibitory activity with an IC 50 value of 6.1 μg/mL. Further bioactivity-guided chromatographic fractionation afforded five steroidal alkaloids, conessine 1 , isoconessimine 2 , conessimin 3 , conarrhimin 4 and conimin 5 . All the isolated compounds, except for 2 , showed strong AChE inhibiting activity with IC 50 values ranging from 4 to 28 μM. The most active inhibitor is compound 3 with an IC 50 value of 4 μM. The mode of AChE inhibition by 3 was reversible and non-competitive. Significance The results suggest that these alkaloids could be potential candidates for further development of new drugs against AD.

Geissoschizine methyl ether (1), a newly discovered strong acetylcholinesterase (AChE) inhibitor, along with six weakly active alkaloids, vallesiachotamine (2), hisuteine (3), hirsutine (4), isorhynchophylline (5), cisocorynoxeine (6) and corynoxeine (7) have been isolated from Uncaria rhynchophylla. Geissoschizine methyl ether (1) inhibited 50% of AChE activity at concentrations of 3.7 ± 0.3 µg mL(-1) while the IC(50) value of physostigmine as a standard was 0.013 ± 0.002 µg mL(-1). The mode of AChE inhibition by 1 was reversible and non-competitive. In addition, molecular modelling was performed to explore the binding mode of inhibitor 1 at the active site of AChE.