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Indole alkaloids from the bark of Acacia confusa and their potential antinociceptive and anti-inflammatory activities
Abstract
A pair of novel trimeric indole alkaloid enantiomers [(±)-8], five new bisindole alkaloids [4–7 and (±)-9], and three pairs of new monomeric indole alkaloid enantiomers [(±)-1–(±)-3], together with seven known alkaloids (10–16), were isolated from the bark of Acacia confusa. Their structures were determined on the basis of spectroscopic methods, especially by NMR data analyses combined with single-crystal X-ray diffraction and electronic circular dichroism analyses. Compounds 4 and 11–16 exhibited significant antinociceptive activities in an acetic acid-induced writhing test. Compounds (+)-9 and (−)-9 displayed anti-inflammatory activities through the inhibition of the NF-κB pathway, with inhibitory rates of 68.9% and 59.5%, respectively, at a concentration of 10 µM.
... Alkaloid dimers are relatively frequent (notably among Vinca alkaloids, for example), but tetra and pentamers are much rarer. A few trimeric indole alkaloids have been reported [216][217][218], but higherorder structures are extremely rare. For example, a tetramer and hexamer of the alkaloid terguride were isolated, but the oligomerization is limited and strongly reduces the high affinity of terguride for 5-HT2A receptors [219,220]. ...
The white berry bush, officially Flueggea virosa (Roxb. ex Willd.) Royle is a medicinal plant distributed throughout tropical areas and traditionally used in Africa, India and China. Root decoctions are used to treat abdominal pain, whereas extracts from the aerial parts serve to treat liver and urinary diseases, inflammatory pathologies and diabetes, among other pathologies. Plant extracts have revealed antiparasitic, antimicrobial, antiepilepsy, antidiabetic, anticancer and analgesic effects. Three main categories of phytochemicals were isolated from F. virosa: polyphenols, with the lead product bergenin; terpenoids, such as the flueggenoids and related podocarpane-type diterpenoids; and many alkaloids derived from securinine and norsecurinine. A remarkable feature of S. virosa is the production of norsecurinine oligomers, including macromolecular tetramers and pentamers, such as fluevirosinines. The most potent anticancer alkaloid in the family is the dimeric indolizidine flueggine B, which was identified as a potential binder to α/β-tubulin dimer, which is a known target for securinine. This review highlights the diversity of phytochemicals identified from S. virosa and the potential therapeutic benefits of dimeric alkaloids. Studies are encouraged to further investigate the therapeutic properties of the lead compounds but also define and finesse the nutritional profile of the edible fruit.
Plant-based indole alkaloids are very rich in pharmacological activities, and the indole nucleus is considered to contribute greatly to these activities. This review's fundamental objective is to summarize the pharmacological potential of indole alkaloids that have been derived from plants and provide a detailed evaluation of their established pharmacological activities, which may contribute to identifying new lead compounds. The study was performed by searching various scientific databases, including Springer, Elsevier, ACS Publications, Taylor and Francis, Thieme, Wiley Online Library, ProQuest, MDPI, and online scientific books. A total of 100 indole compounds were identified and reviewed. The most active compounds possessed a variety of pharmacological activities , including anticancer, antibacterial, antiviral, antimalarial, antifungal, anti-inflammatory, anti-depressant, analgesic, hypotensive, anticholinesterase, antiplatelet, antidiarrheal, spasmolytic, an-tileishmanial, lipid-lowering, antimycobacterial, and antidiabetic activities. Although some compounds have potent activity, some only have mild-to-moderate activity. The pharmacokinetic profiles of some of the identified compounds, such as brucine, mitragynine, 7-hydroxymitragynine, vindoline, and harmane, were also reviewed. Most of these compounds showed promising pharmacological activity. An in-depth pharmacological evaluation of these compounds should be performed to determine whether any of these indoles may serve as new leads.
Background/Aims: Rauvolfia reflexa is a member of the Apocynaceae family. Plants from the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders Methods and Results: Two new indole alkaloids, rauvolfine C (1) and 3-methyl-10,11-dimethoxy-6-methoxycarbonyl-β-carboline (2), along with five known, macusine B (3), vinorine (4), undulifoline (5), isoresrpiline (6) and rescinnamine (7) were isolated from the bark of Rauvolfia reflexa. Cholinesterase inhibitory assay and molecular docking were performed to get insight of the inhibitory activity and molecular interactions of the compounds. The compounds showed good to moderate cholinesterase inhibitory activity with IC50 values in the range of 8.06 to 73.23 μM. Compound 7 was found to be the most potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1, 2, 5 and 6 were found to be selective towards BChE, while compounds 3, 4 and 7 were dual inhibitors, having almost equal inhibitory activity on both AChE and BChE. Molecular docking revealed that compounds 6 and 7 interacted differently on AChE and BChE, by means of hydrophobic interactions and hydrogen bonding. In AChE, the indole moiety of both compounds interacted with the residues lining the peripheral anionic site, whereas in BChE, their methoxy groups are primarily responsible for the strong inhibitory activity via interactions with residues at the active site of the enzyme. Conclusion: Two new and five known indole alkaloids were isolated from R. reflexa. Among the compounds, 7 and 6 showed the most potent and promising cholinesterase inhibitory activity, worthy for further investigations.
The indole nucleus is an important element of many natural and synthetic molecules with significant biological activity. This review covers some of the relevant and recent achievements in the biological, chemical and pharmacological activity of important indole derivatives in the areas of drug discovery and analysis.
Feeding experiments carried out with cattle and horses could prove the toxic effects of P. marcgravii (Rubiaceae) in all cases. The typical symptoms of "sudden death", however, are observed in ruminants only. This difference could not be explained so far. Apart from fluoroacetate, two more substances also have influence the toxic effects and have been isolated from P. marcgravii for the first time: N-methyltyramine and 2-methyltetrahydro-beta-carboline (2-Me THBC). Structure elucidation of these compounds is mainly accomplished by 1H-NMR, 13C-NMR and MS techniques. Due to the small quantity of fluoroacetate (5.4 micrograms/g plant), the main toxic effect obviously lies in the two discovered substances. In contrast to the slow death of horses (monogastriers), the "sudden death syndrome" of cattle (ruminants) can be explained as a result of the higher resorbility of these two substances in the gastro-intestinal system. Given orally, both substances influence the monoamine oxidase type A (MAO-A): N-methyltyramine acts as a competitive substrate, and 2-Me THBC is one of the most effective MAO-A-inhibitors. Thus, the decomposition of the specific MAO-A-substrates noradrenaline and adrenaline as well as of N-methyltyramine itself is inhibited. The alpha- and beta-receptors of the sympathetic system are stimulated more strongly, which leads to a drastic rise in blood pressure and thereby to a more rapid distribution of fluoroacetate in the body. This results in a reinforced input of fluoroacetate in the cells of especially active organs of the body (heart etc.). Thus, even smaller quantities of fluoroacetate are lethal.
Two monoterpenoid indole alkaloid erchinines A (1) and B (2), possessing unique 1,4-diazepine fused with oxazolidine architecture and three hemiaminals, were isolated from Ervatamia chinensis. Their structures were elucidated on the basis of intensive spectroscopic analysis, and a plausible biosynthetic pathway from ibogaine was proposed. Both compounds exhibited significant antimicrobial activity against Trichophyton rubrum and Bacillus subtilis, and their activities were comparable to the first line antifungal drug griseofulvin and antibiotic cefotaxime.
The rhizomes of many Atractylodes species, including A. chinensis Koidzumi, A. macrocephala Koidzumi, and A. japonica Koidzumi, are collectively termed Atractylodis Rhizoma. We prepared n-hexane extracts of the three species and evaluated their anti-inflammatory effects on lipopolysaccharide (LPS)-induced RAW 264.7 cells. Among all n-hexane extracts, those of A. japonica most strongly inhibited nitric oxide (NO) production in LPS-induced RAW 264.7 cells; five sesquiterpenes, atractylon, atractylenolide I, atractylenolide II, atractylenolide III, and 8-epiasterolid, were isolated from A. japonica. The phytochemical content of A. japonica was similar to that of A. chinensis and A. macrocephala. Moreover, the atractylon concentration was higher in A. japonica than in A. chinensis and A. macrocephala. Atractylon significantly inhibited NO and prostaglandin E2 production as well as inducible NO synthase and cyclooxygenase-2 expression in LPS-induced RAW 264.7 cells. Atractylon (40 mg/kg) also significantly reduced the acetic acid-induced writhing response, carrageenan-induced paw edema, and hot-plate latent pain response in mice. According to the results, A. japonica has anti-inflammatory and antinociceptive effects, and atractylon is the major active component of A. japonica. Therefore, atractylon can be used as a bioactivity marker in A. japonica.
Background:
Ulcerative colitis (UC) is a chronic inflammatory intestinal disease. It is necessary to find out new effective drugs for UC. In our study epicatechin extracted from grape seed by our institute for the first time could treat UC effectively. Then anti-UC mechanisms of epicatechin were elucidated in vivo and in vitro.
Methods:
Dextran sulfate sodium (DSS)-induced acute UC mice model was used to evaluate the activity of epicatechin and its properties against UC. Then its anti-inflammatory and antioxidant effects were evaluated as follows: the concentrations of TNF-α and IL-6 in the colon supernatants were determined by ELISA. NO and MPO were assayed by Griess method and commercial kit respectively. NF-κB were determined by NF-κB-Dependent Reporter Gene Expression Assay and Western Blotting respectively. Antioxidant factors such as SOD, MDA, GSH-Px and CAT were also measured in colon tissues and cell supernatant stimulated by LPS respectively.
Results:
In C57BL/6J mice model with DSS-induced UC, epicatechin was able to decrease the disease activity index and colon macroscopic damage index scores, reduce body weight loss, and significantly relieve colon contracture and crypt damage. TNF-α, IL-6, NO, MPO and MDA were reduced in the mice administered epicatechin, whereas antioxidant enzymes showed increased activity in epicatechin-treated mice and cell line respectively. Furthermore, inhibition effect on NF-κB activation by epicatechin were demonstrated in vivo and in vitro.
Conclusions:
Epicatechin has inhibitory effect on DSS-induced acute UC. This effect is mainly due to its antioxidant effect and the inhibition of inflammatory molecules related to NF-κB pathway.
Twenty‐nine compounds including three alkaloids, live triterpenoids, five coumarins, seven benzenoids, two tannins, five flavonoids, one sugar and one nucleoside are isolated from leaves of Tetradium glabrifolium. Their structures are characterized on comparison of spectral data with literature values.
New naturally occurring spirostane saponin (25S)-5β-spirostan-3β-yl-3-O-β-d-xylopyranosyl(1 → 3)-O-β-d-xylopyranosyl(1 → 4)-β-d-galactopyranoside (6) and biflavonoid glycoside myricetin-3-O-rhamnoside (C7-O-C7) myricetin-3-O-rhamnoside (4) along with a series of known compounds erythrodiol (1), 3β-O-trans-p-coumaroyl-erythrodiol (2), quercetin-3-O-α-l-rhamnoside (3) and myricetin-3-O-α-l-rhamnoside (5) were separated from the leaves of Acacia saligna (Labill.), H.L. Wendl. Compounds 1 and 2 were separated for the first time from genus Acacia. The structures of compounds 1-6 were established on the basis of extensive 1D and 2D NMR spectroscopic techniques in combination with EI-MS and HR-ESI-MS. These compounds were screened for their antioxidant and cytotoxic activities against HEPG2 (liver cancer) cell line and significant results were obtained.
Four new indole-derived metabolites (1-4), including the iodinated polyandrocarpamide B (2), have been isolated from the colonial marine ascidian Polyandrocarpa sp. collected in the Philippines. The structures of these metabolites were determined through spectral interpretation, chemical conversions and by comparisons with a synthetic phenethylamine analog.
Bark of Virola sebifera used in the preparation of hallucinogenic snuffs and drinks in Venezuela has yielded N-methyl-N-formyltryptamine and N-methyl-N-acetyltryptamine, which exist in two rotameric forms reflecting hindered rotation around the carbon—nitrogen bond of the amide function. They were detected by HPLC as well as NMR. 2-Methyl-1,2,3,4-tetrahydro-β-carboline, N,N-dimethyltryptamine, its oxide and N-monomethyltryptamine were also identified.
Cruciferous phytoalexin related metabolites, (−)-dioxibrassinin (1) and (−)-3-cyanomethyl-3-hydroxyoxindole (2) were prepared from isatin as racemates and were resolved by chiral HPLC. Their absolute configurations were determined by the new chiroptical technique, vibrational circular dichroism (VCD), as well as by the conventional electronic circular dichroism (ECD). It is concluded that the absolute configurations of the naturally occurring (−)-1 and (−)-2 are both S.
Little is known about the chemistry of most species of the genus Acacia, although the genus is quite large and widespread in the warm subarid and arid portions of the world. As presently defined, Acacia is a cosmopolitan genus containing in excess of 1350 species. Taxonomic relationships and identification of Acacia species are difficult; new studies of the genus confirm that Acacia is an agglomeration of at least five discrete groups. The major elements of this ‘genus’ are the groups now recognized as the subgenus Acacia, the genus Faidherbia, the subgenus ‘Aculeiferum’, relatives of Acaciacoulteri, Bentham’s series Filicinae, the subgenus Phyllodineae, and possibly others, each with somewhat distinct chemistry. A number of secondary metabolites have been reported from various Acacia species including amines and alkaloids, cyanogenic glycosides, cyclitols, fatty acids and seed oils, fluoroacetate, gums, non-protein amino acids, terpenes (including essential oils, diterpenes, phytosterol and triterpene genins and saponins), hydrolyzable tannins, flavonoids and condensed tannins. The most evident and best known are polysaccharides (gums) and complex phenolic substances (condensed tannins).
Four vobasinyl-ibogan type bisindole alkaloids, ervachinines A-D (1-4), along with 12 known terpenoid indole alkaloids, were isolated from the whole plant of Ervatamia chinensis. Their structures were elucidated by analysis of spectroscopic data, including 1D and 2D NMR, and the absolute configurations of 1-4 were determined by CD exciton chirality method. All of the compounds were evaluated for in vitro cytotoxicity against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480. Bisindole alkaloids 1-6 exhibited inhibitory effects, with IC(50) values comparable to those of cisplatin.
The antioxidant and anti-quorum sensing activities of eight extracts were studied in green pods of Acacia nilotica. The specific phenolic compositions and their quantifications were performed by HPLC and MS/MS, which showed that the HEF (pH 4) was higher in gallic acid, ellagic acid, epicatechin, rutin, and GTs. In order to find antioxidant potential of various extracts, their activities were studied for TPC, AOA, FRSA, RP, inhibition of LPO, FIC activity, HO* and O(2)(-) scavenging activities. Among them HEF (pH 4) has shown potent antioxidant activity. HEF (pH 4) was also found effective in protecting plasmid DNA and HAS protein oxidation induced by HO*. Pre-treatment of HEF (pH 4) at 75 and 150 mg/kg body weight for 6 days caused a significant increase in the levels of CAT and SOD and decrease in the level of MDA content in liver, lungs, kidneys and blood when compared to CCl(4)-intoxicated rats. Eventually, the extracts were also screened for anti-QS activity. Of these extracts two showed QS inhibition: HEF (pH 4) and HCE. The results obtained strongly indicate that green pod of A. nilotica are important source of natural antioxidants.
Twenty-two plant organs from eleven plants comprising five families were extracted and screened for antiplasmodial activity in vitro against Plasmodium falciparum 3D7 (chloroquine sensitive) and Dd2 (chloroquine resistant and pyrimethamine sensitive). Fifty nine percent of plant extracts from 22 extracts exerted activity on P. falciparum strain 3D7 with an IC(50) less than 50 microg/mL, whereas 43% of plant extracts showed an IC(50) value within 50 microg/mL on Dd2 strains. Plant extracts from Gardenia lutea, Haplophyllum tuberculatum, Cassia tora, Acacia nilotica and Aristolochia bracteolata possessed IC(50) values less than 5 microg/mL on both tested strains. Bioassay guided fractionation of A. nilotica revealed that the ethyl acetate extract possessed the highest activity (IC(50) = 1.5 microg/mL). Fraction 2 (R(f) = 0.75) prepared by preparative chromatography showed the highest activity on P. falciparum (IC(50) = 1.7 microg/mL). Phytochemical analysis indicated that the most active phase contained terpenoids and tannins and was devoid of alkaloids and saponins. The effect of plant extracts on lymphocyte proliferation showed low toxicity to the human cells. This plant has been subjected to long term clinical trials in folk medicine and is a promising plant.
To further understand the purpose of the traditional processing method of the seeds of Strychnos nux-vomica L. (Loganiaceae) as well as analgesic and anti-inflammatory activities of brucine and brucine N-oxide extracted from this medicinal plant, various pain and inflammatory models were employed in the present study to investigate their pharmacological profiles. Both brucine and brucine N-oxide revealed significant protective effects against thermic and chemical stimuli in hot-plate test and writhing test. However, on different phases they exerted analgesic activities in formalin test. Brucine N-oxide showed stronger inhibitory effect than brucine in carrageenan-induced rat paw edema, both of them significantly inhibited the release of prostaglandin E2 in inflammatory tissue, reduced acetic acid-induced vascular permeability and the content of 6-keto-PGF1a in Freund's complete adjuvant (FCA) induced arthritis rat's blood plasma. In addition, brucine and brucine N-oxide were shown to reduce the content of 5-hydroxytryptamine (5-HT) in FCA-induced arthritis rat's blood plasma, while increase the content of 5-hydroxytryindole-3-acetic acid (5-HIAA) accordingly. These results suggest that central and peripheral mechanism are involved in the pain modulation and anti-inflammation effects of brucine and brucine N-oxide, biochemical mechanisms of brucine and brucine N-oxide are different even though they are similar in chemical structure.
The butanolic fraction of dried leaves of Acacia pennata (Mimosaceae) was tested for analgesic and anti-inflammatory activities in animal models. It showed significant protective effects against chemical stimuli (acetic acid and formalin) in the mouse. It also produced a significant increase of the threshold of sensitivity to pressure-induced pain in the rats. The extract revealed an inhibitory effect in carrageenin-induced rat paw oedema in the late phase. The results suggested that a peripheral mechanism is involved in the analgesic, associated to anti-inflammatory effect (NSAIDs-like). Among the class of compounds characterized in this fraction, flavonoids may be mainly responsible for the pharmacological activities.
In the present study, the ethanolic extracts from the heartwood of Acacia confusa, a species indigenous to Taiwan, exhibit strong antioxidant effects. Among all the fractions from ethanolic extracts of heartwood, the EtOAc soluble fraction exhibits the best antioxidant activity. The 80% 1,1-diphenyl-2-picrylhydrazyl radical inhibitory activity by the EtOAc extract was observed at a concentration of 5 mug/mL, and at the same dosage there was a similar free radical scavenging activity for (-)-ascorbic acid and (+)-catechin, both of which are well-known antioxidants. In addition, the EtOAc extract also protects PhiX174 supercoiled DNA against strand scission induced by hydroxyl radical. Furthermore, following by column chromatography and reverse-phase high-performance liquid chromatorgrapy, 10 pure phenolic compounds, including three major antioxidants (3,7,8,3',4'-pentahydroxyflavone, 7,8,3',4'-tetrahydroxy-3-methoxyflavone, and 3,4,2',3',4'-pentahydroxy-trans-chalcone) and a new flavonoid (3,7,8,3'-tetrahydroxy-4'-methoxyflavone), were isolated from the ethanolic extracts of A. confusa heartwood.
A new chlorotryptamine alkaloid, N-chloromethyl-N,N-dimethyltryptamine, was isolated from a methanol extract of the Chinese shrub Acacia confusa Merr., together with its known hallucinogenic analogues, N-methyltryptamine, N,N-dimethyltryptamine and N,N-dimethyltryptamine-N-oxide. The new compound was an artefact of the isolation conditions. The complete H-1 and C-13 NMR assignments for these compounds were carried out using H-1, C-13, DEPT, gCOSY, gHSQC and gHMBC NMR experiments. Copyright (C) 2007 John Wiley & Sons, Ltd.
- Li Z.
- Z Li
- C J Zhang
- D B Zhang
- J Wen
- X W Zhao
- Y Li
- K Gao