Choisya ternata Kunth (Rutaceae) is native to North America where it is popularly known as "Mexican orange". In this study, the anti-inflammatory effects of the essential oil (EO) obtained from the ...leaves of C. ternata, one of its minor components (ternanthranin-ISOAN) and its two synthetic analogues (methyl and propyl N-methylanthranilate--MAN and PAN) were evaluated. Mice pretreated with the EO (EO) obtained from C. ternata leaves (3-100 mg/kg, p.o.), ISOAN, MAN or PAN (1-30 mg/kg, p.o.) and the reference drugs, morphine (1 mg/kg, p.o.) and acetylsalicylic acid (ASA, 100 mg/kg, p.o.), were evaluated in inflammation models such as formalin and subcutaneous air pouch models, with measurement of cell migration, exudate volume, protein extravasation, nitric oxide and pro-inflammatory cytokines. The EO from C. ternata significantly inhibited the time that the animals spent licking the formalin-injected paw in the second phase of the model at their higher doses (30 and 100 mg/kg, respectively). An inhibition of the inflammatory reaction induced after subcutaneous carrageenan injection into air pouch was also observed. In this model, the EO significantly reduced cell migration, exudate volume, protein extravased, and the increase in levels of inflammatory mediators (nitric oxide, TNF-α and IL-1β). ISOAN, MAN and PAN behaved in the same fashion at much smaller doses. Also, these molecules were able to show significant effects in the reduction of paw edema (at all tested doses) when the phlogistic agent was carrageenan, bradykinin, 5-HT, PGE2, C48/80 or 12-O-tetradecanoylphorbol-acetate (TPA). None of the tested doses had any effect in reducing histamine-induced edema. Our results indicate that the EO from C. ternata and anthranilate derivatives demonstrates an anti-inflammatory effect.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In many countries, the leaves of Allium ursinum L. (Liliaceae) are a popular substitute for garlic and, for centuries, the herb has been taken internally to treat an array of medical conditions. ...Herein, we report the chemical composition of 12 different A. ursinum essential-oil samples (five populations; fresh/air-/oven-dried plant material; leaves/inflorescences). GC–MS/GC–FID analyses, quantitative structure–property relationship modeling (simple 0D/1D-descriptors) of retention indices and the synthesis of selected compounds, enabled the identification of >200 different constituents, mainly organo(poly)sulfides. Some of these were new compounds (allyl (methylthio)methyl, (methylthio)methyl (Z)/(E)-1-propenyl and allyl 1-(methylthio)propyl disulfides) or were previously not detected in samples of natural origin (heptyl methyl, methyl octyl, allyl hexyl (1), allyl octyl (2) and propyl (propylthio)methyl sulfides). A multivariate statistical analysis revealed the onset of significant changes in the plant material volatile profile during the drying process.
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•Allium ursinum L. (Liliaceae) is a popular substitute for garlic in many countries.•New organosulfur compounds were found during an analysis of 12 A. ursinum samples.•Their identification was based on GC–MS/NMR/IR and confirmed by synthesis and QSPR.•The volatile profile of A. ursinum changed during plant material drying.
Two volatile alkaloids, methyl (MMA) and isopropyl N-methylanthranilates (IMA), identified in the essential oil of Choisya ternata Kunth (Rutaceae), have been proven to possess polypharmacological ...properties (antinociceptive, anti-inflammatory, gastro-, hepato-, nephroprotective activities, anxiolytic and antidepressant properties, and likewise an effect on diazepam-induced sleep). In the continuation of our investigation of their urinary-metabolite profiles, we performed GC-MS analyses of the diethyl-ether extracts of selected tissues (liver, kidneys, heart, brain, lungs, quadriceps femoris muscle, and spleen) of rats intraperitoneally treated with MMA or IMA (2 g kg−1). Organ-metabolite profiles of MMA and IMA were qualitatively mutually analogous (varying only in the alcohol moiety of the metabolites), and generally analogous to their urinary-metabolite profiles. The greatest diversity and the highest overall amount of anthranilate metabolites was found in the hepatic tissue. The principal anthranilate-related compounds in the organs of rats treated with MMA, among 12 detected, were the products of ester hydrolysis, N-methylanthranilic and anthranilic acids. In the tissues of IMA-treated rats, among 16 compounds, the most abundant ones were the unmetabolized IMA and N-methylanthranilic acid. A collection of the compositional data regarding the anthranilate-related metabolites was statistically treated by multivariate statistical analysis that provided a better insight into the possible biotransformation pathways.
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•Metabolism of methyl (MMA) and isopropyl N-methylanthranilates (IMA) was investigated.•GC-MS analyses of the Et2O extracts of the homogenates of the chosen tissues of MMA/IMA-treated rats were performed.•Organ-metabolite profiles of MMA and IMA were qualitatively analogous and analogous to their urinary-metabolite profiles.•Products of ester group hydrolysis and the unmetabolized compounds were the major anthranilates detected in the organs.•Multivariate statistical analysis pinpointed to specific connections between the analyzed xenobiotic metabolites.
Two volatile alkaloids, isopropyl N-methylanthranilate (IMA) and methyl N-methylanthranilate (MMA), present in the human diet and cosmetic products, were recently demonstrated to possess important ...pharmacological activities. While MMA is considered to be phototoxic, there is scarce data on the toxicity of IMA. Herein, we analyzed urinary metabolites of IMA and MMA in rats (200 mg kg−1, i.p., 7 days) by combining three different approaches: 1) preparative chromatography, 2) synthesis, and 3) SPR. The preparative approach, Sephadex LH-20 chromatography of the extract of urine samples of IMA treated animals, in conjunction with NMR, enabled the identification of 16 different anthranilate derivatives, among which products of aromatic core hydroxylation (isopropyl 5-hydroxy-N-methylanthranilate, isopropyl 5-hydroxyantranilate, isopropyl 3-hydroxyantranilate) were the major ones. The first application of the synthetic/combinatorial approach led to a successful identification of MMA metabolites, where 2-(methylamino)benzamide and N-methylanthranilic acid were the principal ones, among 14 others. Generally, MMA and IMA undergo analogous biotransformation pathways; however, MMA predominantly underwent chemical conversions of the ester group, i.e. transformation into derivatives of anthranilamide and anthranilic acid, while the major metabolic pathway of IMA was hydroxylation of the aromatic core. Additionally, pathohistological examinations revealed no signs of liver toxicity, or other signs of toxicity.
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•Metabolism and hepatotoxicity of two pharmacologically active N-methylanthranilates were investigated.•Urinary metabolites of the anthranilates, in rats, were analyzed by 3 approaches: preparative, synthetic and combinatorial.•Aromatic core hydroxylation was the principal metabolic pathway of isopropyl N-methylanthranilate.•Products of ester group transformation into an amide or acid were the major metabolites of methyl N-methylanthranilate.•The novel combination of the identification approaches allows implementation of the 3R-strategy in metabolite analysis.
To complement the knowledge on the anti‐inflammatory activity of methyl and isopropyl N‐methylanthranilates, two natural products with panacea‐like properties, we investigated their effects on ...thioglycolate‐elicited macrophages by evaluating macrophage ability to metabolize MTT, macrophage membrane function, and macrophage myeloperoxidase and phagocytic activities. Moreover, two additional aspects of the inflammatory response of these compounds, their inhibitory activity on xanthine oxidase and catalase, were studied. It was found that these two compounds regulate elicited macrophage functions, most probably by interfering with the function of cell membranes and changing the reducing cellular capacity or enzyme activity of macrophages. Nonetheless, no significant inhibitory action either towards xanthine oxidase or catalase was found, suggesting that the inhibition of these enzymes is not involved in the anti‐inflammatory mode of action of these two esters.
Recently, we identified a new natural antinociceptive alkaloid ternanthranin, isopropyl N-methylanthranilate (ISOAN), from the plant species Choisya ternata Kunth (Rutaceae). In this work we ...concentrated on the elucidation of its mechanism of action in comparison with two other esters of this acid (methyl (MAN) and propyl (PAN)). Mice orally pre-treated with ISOAN, MAN or PAN (at 0.3, 1 and 3mg/kg) were less sensitive to chemical or thermal stimuli in different nociception models (formalin-, capsaicin- and glutamate-induced licking response, tail flick and hot plate). All compounds (1 and 3mg/kg) showed significant activity in the peripheral nociception models, as well as a dose-dependent spinal antinociceptive effect in the tail flick model. We observed that glibenclamide was able to reverse the antinociceptive effect of ISOAN in the hot plate model suggesting the involvement of K+ATP channels. The antinociceptive effect of MAN and PAN may be related to adrenergic, nitrergic and serotoninergic pathways. In addition, the antinociception of PAN was reverted by naloxone implying that the opioid pathway participates in its activity. The cholinergic and cannabinoid systems were found not be involved in the onset of the antinociceptive effects of any of the esters. In conclusion, isopropyl, methyl and propyl N-methylanthranilates produced significant peripheral and central antinociception at doses lower than that of morphine, the classical opioid analgesic drug, without causing toxicity.
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Mexican people employed infusion of leaves of
Choisya ternata Kunth for their antispasmodic and “simulative properties”.
In the present study the detailed GC and GC–MS analyses of the essential oil ...of
Choisya ternata Kunth (Rutaceae) were performed. The presence of a minor constituent isopropyl
N-methylanthranilate (
1) was revealed among other identified volatiles. A synthesis of
1 was undertaken in order to corroborate this find and obtain gram quantities that would allow the testing of its biological activity (peripheral and central antinociceptive activity).
The oils were investigated by GC and GC–MS. Synthesized compounds were spectrally characterized (UV–Vis, IR, 1D and 2D NMR, MS). The obtained synthetic samples of compounds were assayed for peripheral and central antinociceptive activity in two models (effects on acetic acid induced writhing in mice and the hot plate test for nociception).
Detailed GC and GC–MS analyses of the essential oil of
Choisya ternata Kunth (Rutaceae) among 157 other identified volatiles revealed the presence of a minor constituent isopropyl
N-methylanthranilate (
1). Compound
1, named ternanthranin, is therefore detected as a natural product for the first time with a very restricted occurrence (samples of several citrus oils were screened for the presence of
1). The antinociceptive activities were assayed for ternanthranin, the two other synthetic analogs, methyl and propyl
N-methylanthranilate, as well as the essential oil and the crude ethanol extract of the leaves. The results clearly demonstrate a very high (even significant at 0.3
mg/kg) dose dependent activity for the anthranilates (and the extracts). Isopropyl
N-methylanthranilate showed the highest, while methyl
N-methylanthranilate showed the lowest activity (with the methyl ester at 3
mg/kg still better than acetylsalicylic acid, at 200
mg/kg, in the first, or comparable with morphine, at 5
mg/kg, in the second test).
This study once again revealed that detailed investigations of plant species with ethnopharmacologically documented activity may yield new natural compounds—a new alkaloid (ternanthranin), a volatile simple anthranilate that can be considered responsible for the antinociceptive activity of the crude plant extracts.
Herein we investigated the potential protective effects of methyl N-methylanthranilate (MA) and isopropyl N-methylanthranilate (IA), two naturally occurring plant constituents from Rutaceae taxa, in ...a rat model of acute intoxication with carbon tetrachloride (CCl4) by tracking changes in kidney tissue morphology and function.
The antioxidant capacity of IA and MA was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid radical cation (ABTS+) assays and superoxide-scavenging test. Wistar rats were treated daily with MA and IA for seven days in a dose of 200mg/kg. Twenty-four hours after a CCl4 injection, rats were sacrificed and blood samples were used for the evaluation of urea and creatinine. Kidney tissue specimens were stained with hematoxylin and eosin, periodic acid-Schiff and Jones stain and evaluated for morphological changes. Quantification of structural changes determined by histological analysis of kidney tissue was assessed by a morphometric analysis of glomeruli using ImageJ software.
IA and MA applied in high doses on their own did not cause any significant damage to kidney tissue. A pretreatment with MA prior to the administration of CCl4 significantly prevented the increase of serum levels of decreased kidney function markers, while that of IA did not. Histopathological evaluation of the kidneys also revealed that MA reduced the incidence of kidney lesions.
Our experiments showed that methyl-, and not isopropyl-, N-methylanthranilate possesses a protective potential against CCl4-induced kidney damage in rats. The results are of interest due to the presence of natural or synthetic methyl N-methylanthranilate in the human diet and their potent analgesic properties.
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