A review on β-carboline alkaloids and their distribution in foodstuffs: A class of potential functional components or not?

Pentavalent antimonials and amphotericin B remain as the main drugs to treat human leishmaniasis. However, the high toxicity and variable efficacy of treatment have stimulated the search for novel drug candidates. Naturally occurring alkaloids have a long history of antileishmanial activity. Here, we investigate the effects of the β-carboline-1-propionic acid alkaloid isolated from Quassia amara L., Simaroubaceae, against Leishmania amazonensis and Leishmania infatum. The alkaloid was isolated after liquid-liquid fractionation followed by chromatographic purification of the Q. amara methanol extract. The antileishmanial activity was evaluated by the microdilution method, using resazurin as the viability indicator. In addition, annexin and propidium iodide were used to detect parasites undergoing apoptosis. The anti-amastigote activity of the β-carboline-1-propionic acid alkaloid was determined by the infection of RAW 264.7 macrophages. The alkaloid displayed leishmanicidal activity against Leishmania amazonensis and L. infantum promastigotes and intracellular amastigotes with 50% inhibitory concentration ranging from 2.7 ± 0.82 to 9.4 ± 0.5 μg/ml and selectivity indexes >10. Moreover, apoptotic Leishmania amazonensis (19.5%) and L. infantum (40.4%) promastigotes were detected after 5 h incubation with the alkaloid. Finally, the β-carboline-1-propionic acid alkaloid inhibited the production of NO of infected macrophages, suggesting that the intracellular amastigote elimination occurs in a nitrosative stress-independent way. The results shown here suggest that the β-carboline-1-propionic acid alkaloid has potential as an antileishmanial agent.

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β-Carboline-1-propionic acid alkaloid: antileishmanial and cytotoxic effects

Three new quassinoids, javanicinols A and B (1 and 2) and 4-keto-(16S)-methoxyjavanicin B (3), together with three known quassinoids (4-6) were isolated from the chloroform-soluble fraction of the methanol extract of the Picrasma javanica wood. The structures of 1-3 were determined by spectroscopic analyses, including 1D and 2D NMR, HRESIMS, and CD. The anti-HIV-1 viral protein R (Vpr) assay revealed that 1 and 2 exhibited potent anti-Vpr activities at 1.25 μM. Furthermore, the assay also revealed the potent anti-Vpr activities of (16R)-methoxyjavanicin B (7) and (16S)-methoxyjavanicin B (8), which were previously isolated from the Picrasma javanica wood.

Three new quassinoids isolated from the wood of Picrasma javanica and their anti-Vpr activities.

Lots of studies have demonstrated that anterior cingulate cortex plays important roles in the pain perception and pain modulation. The present study explored the role of mu-opioid receptor in nociceptive modulation in anterior cingulate cortex of rats with neuropathic pain. Neuropathic pain model was set up by chronic constriction injury of the left sciatic nerve of rats. The hindpaw withdrawal latency to thermal and mechanical stimulation, by hot plate and Randall Selitto Test respectively, was used to evaluate the rat's responses to noxious stimulation. Results showed that intra-anterior cingulate cortex injection of morphine could induce the antinociception dose-dependently. By intra-anterior cingulate cortex injection of opioid receptor antagonist, the morphine-induced antinociception could be attenuated by naloxone, as well as much significantly by the selective mu-opioid receptor antagonist β-funaltrexamine, indicating that mu-opioid receptor is involved in the morphine-induced antinociception in anterior cingulate cortex of rats with neuropathic pain. The morphine-induced antinociception was much more decreased in rats with neuropathic pain than that in normal rats, and there was a significant decrease in mu-opioid receptor messenger RNA levels in anterior cingulate cortex of rats with neuropathic pain, indicating that there may be a down-regulation in mu-opioid receptor expression in anterior cingulate cortex of rats with neuropathic pain. To further confirm the role of mu-opioid receptor in morphine-induced antinociception in anterior cingulate cortex, normal rats were received intra-anterior cingulate cortex administration of small interfering RNA targeting mu-opioid receptor and it was found that there was a down-regulation in mu-opioid receptor messenger RNA levels, as well as a down-regulation in mu-opioid receptor expression in anterior cingulate cortex tested by real-time polymerase chain reaction and western blotting. Furthermore, the morphine-induced antinociceptive effect decreased significantly in rats with small interfering RNA targeting mu-opioid receptor, which indicated that knockdown mu-opioid receptor in anterior cingulate cortex could also attenuate morphine-induced antinociceptive effect. These results strongly suggest that mu-opioid receptor plays a significant role in nociceptive modulation in anterior cingulate cortex of rats.

https://journals.sagepub.com/doi/pdf/10.1177/1744806920966144

Role of mu-opioid receptor in nociceptive modulation in anterior cingulate cortex of rats.

Two new canthin-6-one alkaloids, 4,9-dimethoxy-5-hydroxycanthin-6-one (1) and 9-methoxy-(R/S)-5-(1-hydroxyethyl)-canthin-6-one (2), together with fifteen known ones were isolated from the roots of Thailand Eurycoma longifolia Jack. Among the known canthin-6-one alkaloids, compounds 9 and 16 were isolated from the Eurycoma genus for the first time. Meanwhile, the nitric oxide (NO) inhibitory activities of all isolates were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 cells at 50 µM. Moreover, a dose-dependent experiment was conducted for active compounds 1, 2, 4, 6, 7, 10, 12–17 at the concentration of 10, 25, and 50 µM, respectively. Consequently, compounds 1, 4, 6, 7, 12, 14, 15, as well as 17 were found to inhibit NO release from RAW264.7 cells in a dose-dependent manner. 




Two new canthin-6-one alkaloids, 4,9-dimethoxy-5-hydroxycanthin-6-one (1) and 9-methoxy-(R/S)-5-(1-hydroxyethyl)-canthin-6-one (2), together with fifteen known ones were isolated from the roots of Thailand Eurycoma longifolia Jack. Among them, 1, 4, 6, 7, 12, 14, 15, as well as 17 were found to inhibit NO release from RAW264.7 cells in a dose-dependent manner at the concentration of 10, 25, and 50 µM.

Anti-inflammatory canthin-6-one alkaloids from the roots of Thailand Eurycoma longifolia Jack

A compound library, which consists of 75 natural β-carboline-type or canthinone-type alkaloids from Simaroubaceae plants and their chemical synthetic analogues, was screened for the anti-inflammatory activity by inhibition of the overproduction of inflammatory mediator nitric oxide (NO) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophage cells. Six compounds, namely, benzalharman (23), kumujian (27), 1-ethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (37), 1-acetophenone-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (42), cathin-6-one (46), and 9-methoxy-cathin-6-one (57), exhibited significant inhibitory activity on the overproduction of NO with good dose dependency. Further investigation demonstrated that all of the six compounds down-regulated the high expression of inducible nitric oxide synthase (iNOS) protein. Among them, two canthinone-type alkaloids (46 and 57) potently down-regulated cyclooxygenase-2 (COX-2) protein expression in a dose-dependent manner and also inhibited the overproduction of inflammatory mediator prostaglandin E2 (PGE2). However, the β-carboline-type alkaloids (23, 27, 37, and 42) exhibited no obvious inhibition on the overproduction of PGE2 and the expression of COX-2 protein. The results suggested that β-carboline-type alkaloids and canthinone-type alkaloids may exert an anti-inflammatory effect through different mechanism.

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Identification of β-carboline and canthinone alkaloids as anti-inflammatory agents but with different inhibitory profile on the expression of iNOS and COX-2 in lipopolysaccharide-activated RAW 264.7 macrophages.

Linyu Li

Papers

Identification of β-carboline and canthinone alkaloids as anti-inflammatory agents but with different inhibitory profile on the expression of iNOS and COX-2 in lipopolysaccharide-activated RAW 264.7 macrophages.