Active Transport of Hepatotoxic Pyrrolizidine Alkaloids in HepaRG Cells

1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites occurring as food contaminants that can cause severe liver damage upon metabolic activation in hepatocytes. However, it is yet unknown how these contaminants enter the cells. The role of hepatic transporters is only at the beginning of being recognized as a key determinant of PA toxicity. Therefore, this study concentrated on assessing the general mode of action of PA transport in the human hepatoma cell line HepaRG using seven structurally different PAs. Furthermore, several hepatic uptake and efflux transporters were targeted with pharmacological inhibitors to identify their role in the uptake of the PAs retrorsine and senecionine and in the disposition of their N-oxides (PANO). For this purpose, PA and PANO content was measured in the supernatant using LC-MS/MS. Also, PA-mediated cytotoxicity was analyzed after transport inhibition. It was found that PAs are taken up into HepaRG cells in a predominantly active and structure-dependent manner. This pattern correlates with other experimental endpoints such as cytotoxicity. Pharmacological inhibition of the influx transporters Na⁺/taurocholate co-transporting polypeptide (SLC10A1) and organic cation transporter 1 (SLC22A1) led to a reduced uptake of retrorsine and senecionine into HepaRG cells, emphasizing the relevance of these transporters for PA toxicokinetics.     

Hit to Leads with Cytotoxic Effect in Leukemic Cells: Total Synthesis Intermediates as a Molecule Treasure Chest

A previously designed and developed 12-step total synthesis that includes [1,1′-biphenyl]-2-amine and carbazole intermediates and that ultimately produces the carbazole alkaloid carbazomycin G was exploited as a screening compound library with the goal of identifying potential lead compound(s) with cytotoxic effect. These compounds were investigated by using in-vitro tests involving the two human cell lines HL-60 and MOLM-13, which both model acute myeloid leukaemia (AML). The in-vitro biological test results were used together with the molecular structures of the various intermediates in a concise SAR analysis. Several of the intermediates revealed cytotoxicity (IC₅₀<10⁻⁴ M), although the final natural product carbazomycin G did not reveal cytotoxicity versus the two said human cell lines.     

RFA—300型自动分析仪检测总植物碱的改进

对连续流动法测定烟草及烟草制品中总植物碱的各影响因素进行了试验研究,并根据试验结果对仪器管路进行相应的改造。实验结果表明,烟草制品中总植物碱的连续流动法测定,改进后方法的回收收率高、重现性好。     

Asymmetric Hydrogenation of Activated Ketones on Platinum: Relevant and Spectator Species

The heterogeneous enantioselective hydrogenation of activated ketones over chirally modified platinum is reviewed with emphasis on identifying the role of the various species observed in this catalytic system. The past years have witnessed a continuous broadening of the scope of this catalytic system including new reactants and modifiers affording over 97% ee. New reaction pathways have been uncovered and the kinetic and mechanistic studies have been faced with a number of complicating factors caused by spectator species and interactions in solution and on the Pt surface. The previously proposed mechanistic models are critically assessed in the light of these new findings.     

Effects ofSolanum glycoalkaloids on chemosensilla in the Colorado potato beetle

Steroidal glycoalkaloids, found in species of the Solanaceae, elicit bursting activity in galeal and tarsal chemosensilla of adult Colorado potato beetles. The effect has an average latency of 6–12 sec, depending on the sensillum/alkaloid combination. A 20-sec alkaloid treatment is often suffficient to render galeal sensilla unresponsive to gamma-aminobutyric acid, normally an effective stimulant. The alkaloids have similar effects on galeal sensilla of larval Colorado potato beetles and on labellar chemosensilla of the blowfly. It is concluded that these compounds act independently of any specialized chemoreceptor in the Colorado potato beetle, and that association of the Colorado potato beetle with solanaceous plants has not led to evolution of a specific receptor forSolanum glycoalkaloids.     

Nutritive quality of the alkaloid-poor Washington lupin (Lupinus polyphyllus lindl var SF/TA) as a potential protein crop

Abstract : An alkaloid-poor line of Washington lupin (Lupinus polyphyllus Lindl var SF/TA) was developed in an experiment started in 1982. The nutritive quality (alkaloid content, protein and amino acids, fat and fatty acids. macro- and micronutrients, fibre, sugars) yields, and seed quality of this line were studied. The results show that the total alkaloid content was low and varied in different seeds from 226 μg g^?1 to 366 μg g^?1 of dry matter. The main alkaloid was lupanine, but 16 other alkaloids (including sparteine and gramine) were also present. The var SF/TA cannot yet be used for human nutrition without processing although it would be a valuable protein crop. The results confirm that seeds which look different also vary in chemical composition.     

Stereoselective Synthesis and Antiallodynic Activity of 3-Hydroxylated Paroxetines

The design, stereoselective synthesis and in vivo antiallodynic activity of four novel paroxetine analogs, named 3-hydroxy paroxetines (3HPXs), is reported herein. Among the novel synthesized compounds, three showed an antiallodynic effect, while (R,R)-3HPX was found to be 2.5 times more bioactive than (-)-paroxetine itself in neuropathic rats. Consequently, the current investigation not only discloses a novel promising analgesic drug, but also reveals that functionalization at the C3 position of paroxetine could be as effective as the common functionalization at either C4 or within the sesamol group.     

Ergovaline and peramine production in endophyte-infected tall fescue: Independent regulation and effects of plant and endophyte genotype

Peramine and ergovaline have ecological and economical significance because they possess insect and/or mammalian toxicity properties. The relationship between these endophytically derived alkaloids in tall fescue (Festuca arundinacea Schreb.) is unknown. Seasonal and plant tissue effects on the concentration of peramine and ergovaline was investigated in field and greenhouse experiments. The relationship between the alkaloids and the regulatory effects of endophyte and plant on their content were investigated among progeny of reciprocal crosses between high- and low-ergovaline and peramine plant-endophyte combinations. Variation in peramine concentration ranged from 750 to 1742 µg/kg in greenhouse-grown plants, and there was no seasonal trend in peramine content. There was a correlation (r=0.69) between peramine and ergovaline content among leaf tissues of field-grown plants, but there was no correlation between the alkaloids in the culm (r=0.20) or panicle (r=0.17) tissues. Mean leaf ergovaline concentration of progeny derived from the low-ergovaline parent (163 µg/kg) was less than the midparent value (228 µg/kg), but mean of progeny from the high-ergovaline parent was not different from the mid-parent value. Ranges within each progeny set were approximately double their mean. Mean leaf peramine concentrations of the progeny sets were similar to the mid-parent value (3354 µg/kg) but ranges were from 1716 to 8753 µg/kg. There was no correlation between leaf peramine and ergovaline (r=0.01). These data suggest that endophytically produced alkaloids are independently regulated and are controlled by both plant and endophyte genotype.     

Structures and allelopathic effects ofNuphar alkaloids: Nupharolutine and 6,6′-dihydroxythiobinupharidine

Two of the majorNuphar alkaloids, nupharolutine and 6,6-dihydroxythiobinupharidine, were isolated from the aquatic perennial herbNuphar lutea (L.) Sibth. & Sm., yellow water lily. In a lettuce seedling bioassay of the two pure compounds, the former was inactive and the latter was highly inhibitory of radicle elongation at concentrations greater than 2 ppm. Structures and stereochemistry of the two compounds were confirmed by DEPT,¹H-¹H COSY,¹H-¹³C COSY, and¹H-¹H NOESY experiments.