Β-carboline Alkaloids Research Articles

Is the NMDA Receptor of the CA1 Region Participated in the Amnesic Effect of Harmane?

Aims: In the present study, we investigated the influence of NMDA receptor agonist (N-methyl-d-aspartate) and antagonist (D-AP7) on amnesia induced by a β-carboline alkaloid, harmane. Methodology: Animals implanted with bilateral cannulae at the CA1 regions of the dorsal hippocampus and microinjected with glutamatergic drugs. One-trial step-down was used to assess memory acquisition and then, the hole-board method to assess exploratory behaviors in adult male NMRI mice. Results: The results revealed that pre-training intra-CA1 administration of NMDA (0.5 ng/mouse) and D-AP7 (0.25 and 0.5 ng/mouse) improved and impaired memory acquisition, respectively. Also, pre-training intra-peritoneal (i.p.) administration of harmane (12 mg/kg) decreased memory acquisition. Furthermore, pre-training intra-CA1 injection of sub-threshold dose of NMDA (0.02 ng/mouse) reversed, while non-significant dose of D-AP7 (0.125 ng/mouse) did not change impairment of memory acquisition induced by harmane (12 mg/kg, i.p.). Conclusion: In addition, all above doses of drugs did not alter locomotor activity. These results suggest that the CA1 NMDA receptors are involved in harmane-induced amnesia.

A microbial model of mammalian metabolism: biotransformation of 4,5-dimethoxyl-canthin-6-one using Cunninghamella blakesleeana CGMCC 3.970

1. A filamentous fungus, Cunninghamella blakesleeana CGMCC 3.970, was applied as a microbial system to mimic mammalian metabolism of 4,5-dimethoxyl-canthin-6-one (1). Compound 1 belongs to canthin-6-one type alkaloids, which is a major bioactive constituent of a traditional Chinese medicine (the stems of Picrasma quassioides).2. After 72 h of incubation in potato dextrose broth, 1 was metabolized to seven metabolites as follows: 4-methoxyl-5-hydroxyl-canthin-6-one (M1), 4-hydroxyl-5-methoxyl-canthin-6-one (M2), canthin-6-one (M3), canthin-6-one N-oxide (M4), 10-hydroxyl-4,5-dimethoxyl-canthin-6-one (M5), 1-methoxycarbonl-β-carboline (M6), and 4-methoxyl-5-O-β-D-glucopyranosyl-canthin-6-one (M7).3. The structures of metabolites were determined using spectroscopic analyses, chemical methods, and comparison of NMR data with those of known compounds. Among them, M7 was a new compound.4. The metabolic pathways of 1 were proposed, and the metabolic processes involved phase I (O-demethylation, dehydroxylation, demethoxylation, N-oxidation, hydroxylation, and oxidative ring cleavage) and phase II (glycosylation) reactions.5. This was the first research on microbial transformation of canthin-6-one alkaloid, which could be a useful microbial model for producing the mammalian phase I and phase II metabolites of canthin-6-one alkaloids.6. 1, M1−M5, and M7 are canthin-6-one alkaloids, whereas M6 belongs to β-carboline type alkaloids. The strain of Cunninghamella blakesleeana can supply an approach to transform canthin-6-one type alkaloids into β-carboline type alkaloids.

Progress in study on effect of harmine on bone and cartilage metabolism

Harmine, a β-carboline alkaloid, is widely distributed in the plants, animals as well as in human tissues and body fluids. Harmine has various types of pharmacological activities including antimicrobial, antiplasmodial, antioxidative, antitumor, antimutagenic, antidiabetic, vasorelaxant and central excitation properties. Moreover, it can exert regenerative and protective effects on bone and cartilage tissues by regulating the proliferation, differentiation and metabolism of osteoclasts, osteoblasts and chondrocytes. These features make harmine a novel candidate for the prevention and treatment of bone and cartilage diseases, such as osteoporosis, bone fracture and osteoarthritis.

Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans

Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus β-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans.

Harmine induces cell cycle arrest and mitochondrial pathway-mediated cellular apoptosis in SW620 cells via inhibition of the Akt and ERK signaling pathways.

Harmine, a β-carboline alkaloid isolated from the seeds of Peganum harmala, possesses both antitumor and anti‑nociceptive effects and inhibits human DNA topoisomerase. However, no detailed data are available concerning the mechanisms of harmine in human colorectal carcinoma SW620 cells. In the present study, we demonstrated that harmine inhibited the proliferation of SW620 cells in a dose-dependent manner using MTT and clone formation assays, and the IC50 value of harmine on the growth inhibition of SW620 cells for 48h was 5.13µg/ml. PI staining showed that harmine altered the cell cycle distribution by decreasing the proportion of cells in the G0-G1phase and increasing the proportion in the Sand G2-Mphase. The expression level of cyclinD1 was decreased, while the expression of cyclinA, E2andB1, CDK1/cdc2, Myt-1 and p-cdc2(Tyr15) were increased, which was in accordance with the S and G2/Mphase arrest. Hoechst33258 staining revealed nuclear fragmentation, chromosomal condensation and cell shrinkage in the SW620 cells treated with harmine. Flow cytometry revealed that the percentage of apoptotic sub-G1 cells increased from 7.19 to 26.58%, while in the control group, sub-G1 cells only increased from 1.53 to 1.60%. Furthermore, early and late apoptotic cells were increased from 11.96 to 26.38% when incubated with the indicated concentration of harmine for 48h, while in the control group, <8% of cells underwent apoptosis. JC-1 staining revealed that harmine decreased mitochondrial transmembrane potential (ΔΨm). The apoptosis of SW620 cells was also detected by western blot analysis, showing caspase-3and-9, and PARP activation; the downregulation of Bcl-2, Mcl-1, Bcl-xL; and the upregulation of Bax. The expression of p-ERK, p-Akt (Ser473) and p-Akt (Thr308) was inhibited, and phosphorylation of downstream targets of Akt, such as p-FoxO3a and p-GSK‑3β were also attenuated. In conclusion, harmine induces cell cycle arrest and mitochondrial pathway-mediated cellular apoptosis in SW620 cells via inhibition of the Akt and ERK signaling pathways.

Ayahuasca: Pharmacology, neuroscience and therapeutic potential.

Ayahuasca is the Quechua name for a tea obtained from the vine Banisteriopsis caapi, and used for ritual purposes by the indigenous populations of the Amazon. The use of a variation of the tea that combines B. caapi with the leaves of the shrub Psychotria viridis has experienced unprecedented expansion worldwide for its psychotropic properties. This preparation contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT) from P. viridis, plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties from B. caapi. Acute administration induces a transient modified state of consciousness characterized by introspection, visions, enhanced emotions and recollection of personal memories. A growing body of evidence suggests that ayahuasca may be useful to treat substance use disorders, anxiety and depression. Here we review the pharmacology and neuroscience of ayahuasca, and the potential psychological mechanisms underlying its therapeutic potential. We discuss recent findings indicating that ayahuasca intake increases certain mindfulness facets related to acceptance and to the ability to take a detached view of one's own thoughts and emotions. Based on the available evidence, we conclude that ayahuasca shows promise as a therapeutic tool by enhancing self-acceptance and allowing safe exposure to emotional events. We postulate that ayahuasca could be of use in the treatment of impulse-related, personality and substance use disorders and also in the handling of trauma. More research is needed to assess the full potential of ayahuasca in the treatment of these disorders.

Review on a Traditional Herbal Medicine, Eurycoma longifolia Jack (Tongkat Ali): Its Traditional Uses, Chemistry, Evidence-Based Pharmacology and Toxicology.

Eurycoma longifolia Jack (known as tongkat ali), a popular traditional herbal medicine, is a flowering plant of the family Simaroubaceae, native to Indonesia, Malaysia, Vietnam and also Cambodia, Myanmar, Laos and Thailand. E. longifolia, is one of the well-known folk medicines for aphrodisiac effects as well as intermittent fever (malaria) in Asia. Decoctions of E. longifolia leaves are used for washing itches, while its fruits are used in curing dysentery. Its bark is mostly used as a vermifuge, while the taproots are used to treat high blood pressure, and the root bark is used for the treatment of diarrhea and fever. Mostly, the roots extract of E. longifolia are used as folk medicine for sexual dysfunction, aging, malaria, cancer, diabetes, anxiety, aches, constipation, exercise recovery, fever, increased energy, increased strength, leukemia, osteoporosis, stress, syphilis and glandular swelling. The roots are also used as an aphrodisiac, antibiotic, appetite stimulant and health supplement. The plant is reported to be rich in various classes of bioactive compounds such as quassinoids, canthin-6-one alkaloids, β-carboline alkaloids, triterpene tirucallane type, squalene derivatives and biphenyl neolignan, eurycolactone, laurycolactone, and eurycomalactone, and bioactive steroids. Among these phytoconstituents, quassinoids account for a major portion of the E. longifolia root phytochemicals. An acute toxicity study has found that the oral Lethal Dose 50 (LD50) of the alcoholic extract of E. longifolia in mice is between 1500–2000 mg/kg, while the oral LD50 of the aqueous extract form is more than 3000 mg/kg. Liver and renal function tests showed no adverse changes at normal daily dose and chronic use of E. longifolia. Based on established literature on health benefits of E. longifolia, it is important to focus attention on its more active constituents and the constituents’ identification, determination, further development and most importantly, the standardization. Besides the available data, more evidence is required regarding its therapeutic efficacy and safety, so it can be considered a rich herbal source of new drug candidates. It is very important to conserve this valuable medicinal plant for the health benefit of future generations.

Pharmacokinetic study of harmane and its 10 metabolites in rat after intravenous and oral administration by UPLC-ESI-MS/MS

Context The β-carboline alkaloid harmane is widely distributed in common foods, beverages and hallucinogenic plants. Harmane exerts potential in therapies for Alzheimer’s and depression diseases. However, little information on its dynamic metabolic profiles and pharmacokinetics in vivo is currently available.Objective This study investigates the dynamic metabolic profiles and pharmacokinetic properties of harmane and its metabolites in rats in vivo.Materials and methods A highly selective, sensitive and rapid ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and well-validated for simultaneous quantitative determination of harmane and its uncertain endogenous metabolite harmine, as well as for semiquantitative determination of 10 harmane metabolites in rats after intravenous injection and oral administration of harmane at 1.0 and 30.0 mg/kg, respectively.Results The calibration curves of harmane and harmine showed excellent linearity within the concentration range of 1–2000 ng/mL with acceptable accuracy, precision, selectivity, recovery, matrix effect and stability. Ten metabolites, including harmane but not harmine, were detected and identified after intravenous and oral administration of harmane. The absolute bioavailability of harmane following an oral dose was 19.41 ± 3.97%. According to the AUC0–t values of all the metabolites, the metabolic levels of phase II metabolites were higher than those of phase I metabolites, and the sulphation pathways were the dominant metabolic routes for harmane in both routes of administration.Discussion and conclusion The pharmacokinetic properties of harmane and its 10 metabolites in rats were determined. Sulphate conjugation was the predominant metabolic process of harmane in rats.

The Role of β-Carboline Alkaloids in the Pathogenesis of Essential Tremor.

Essential tremor (ET) is one of the most prevalent neurological disorders in the world. Environmental factors have been implicated in the pathogenesis of ET. In particular, epidemiological studies have suggested that neurotoxic agents, especially β-carboline alkaloids (βCAs), might be generated through Maillard-type reaction. βCAs are molecules which are members of a large group of heterocyclic amines (HCAs, the so-called products of cooking meat). βCAs are highly tremorogenic in animals, producing a marked generalized action tremor soon after systemic administration in a wide range of laboratory animals such as mice, rats and monkeys. Administration of βCAs remains currently the main experimental model of ET. We review the pathogenesis of ET, with a focus on the biochemistry of βCAs, their occurrence and biological activity, their endogenous biosynthesis, their formation in food, their toxicokinetics and their neurotoxicity. We highlight open questions regarding the effects of βCAs in humans.

Novel mechanism of harmaline on inducing G2/M cell cycle arrest and apoptosis by up-regulating Fas/FasL in SGC-7901 cells.

Harmaline (HAR), a natural occurrence β-carboline alkaloid, was isolated from the seeds of Peganum harmala and exhibited potent antitumor effect. In this study, the anti-gastric tumor effects of HAR were firstly investigated in vitro and in vivo. The results strongly showed that HAR could inhibit tumor cell proliferation and induce G2/M cell cycle arrest accompanied by an increase in apoptotic cell death in SGC-7901 cancer cells. HAR could up-regulate the expressions of cell cycle-related proteins of p-Cdc2, p21, p-p53, Cyclin B and down-regulate the expression of p-Cdc25C. In addition, HAR could up-regulate the expressions of Fas/FasL, activated Caspase-8 and Caspase-3. Moreover, blocking Fas/FasL signaling could markedly inhibit the apoptosis caused by HAR, suggesting that Fas/FasL mediated pathways were involved in HAR-induced apoptosis. Interestingly, HAR could also exert on antitumor activity with a dose of 15 mg/kg/day in vivo, which was also related with cell cycle arrest. These new findings provided a framework for further exploration of HAR which possess the potential antitumor activity by inducing cell cycle arrest and apoptosis.

Exploring the therapeutic potential of Ayahuasca: acute intake increases mindfulness-related capacities.

Ayahuasca is a psychotropic plant tea used for ritual purposes by the indigenous populations of the Amazon. In the last two decades, its use has expanded worldwide. The tea contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT), plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties. Acute administration induces an introspective dream-like experience characterized by visions and autobiographic and emotional memories. Studies of long-term users have suggested its therapeutic potential, reporting that its use has helped individuals abandon the consumption of addictive drugs. Furthermore, recent open-label studies in patients with treatment-resistant depression found that a single ayahuasca dose induced a rapid antidepressant effect that was maintained weeks after administration. Here, we conducted an exploratory study of the psychological mechanisms that could underlie the beneficial effects of ayahuasca. We assessed a group of 25 individuals before and 24h after an ayahuasca session using two instruments designed to measure mindfulness capacities: The Five Facets Mindfulness Questionnaire (FFMQ) and the Experiences Questionnaire (EQ). Ayahuasca intake led to significant increases in two facets of the FFMQ indicating a reduction in judgmental processing of experiences and in inner reactivity. It also led to a significant increase in decentering ability as measured by the EQ. These changes are classic goals of conventional mindfulness training, and the scores obtained are in the range of those observed after extensive mindfulness practice. The present findings support the claim that ayahuasca has therapeutic potential and suggest that this potential is due to an increase in mindfulness capacities.

ChemInform Abstract: Dragmacidol A and Dragmacidolide A from the Australian Marine Sponge Dragmacidon australe.

Two new secondary metabolites, the xylerythrin derivative dragmacidol A (1) and the steroid dragmacidolide A (2), were isolated from a specimen of the marine sponge Dragmacidon australe, collected off the coast of the Whitsunday Islands in Queensland, Australia. Their structures were fully characterized via analysis of 1D/2D NMR and MS data. The proton-poor structure of 1 was also supported through successful 13C DFT-NMR calculations. The isolation of these two metabolites from this sponge genus is quite unusual, given that previous reports of Dragmacidon secondary metabolites have been dominated by indole and β-carboline alkaloids.

Discovery of natural products potentially active against myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM 1) is a genetically inherited muscle disorder that is characterised by progressive muscle wasting and weakening, cataracts, and cardiac conduction defects. At present there is no cure or effective treatment for this disabling disease. In this context, a collection of 70 pure compounds and 2100 extracts from different plants and fungal strains were screened with a novel DM 1-based biochemical assay for their ability to inhibit the formation of the pathogenic complex formed between (CUG)n-RNA and the splicing-factor muscleblind-like 1 (MBNL1). As a result, eight extracts from different plant species were found to be active (≥50% inhibition at 100 µg/mL). Active constituents were tracked using HPLC-based activity profiling, an approach which combines bioactivity data, structural information from online HPLC-UV-MS and offline microprobe NMR analyses, and database searches. Methylenetanshinquinone and 1,2-dihydrotanshinquinone were found to be the most active compounds in Salvia miltiorrhiza. The β-carboline alkaloid harmine was responsible for the activity of Peganum harmala, and the iridoid-glycoside auroside was identified as the active constituent in Lamium album. The HPLC profiles suggested the presence of tannins in the remaining five active extracts. Retesting of these extracts after tannin removal by filtration over polyamide confirmed the nonspecific interaction of the original extracts with the protein-based screen. In addition, the protoberberine alkaloid berberine was identified as a potent hit from the library of pure compounds. Overall, this study identified several small molecules of natural origin which are promising hit compounds in (CUG)n-MBNL1 complex inhibition. In a secondary cellular assay some of the identified small molecules partially reversed the splicing defects associated with DM 1. Detailed secondary in vitro and in vivo investigations on these compounds are ongoing.

Harmaline-induced amnesia: Possible role of the amygdala dopaminergic system

In this study, we examined the effect of bilateral intra-basolateral amygdala (intra-BLA) microinjections of dopamine receptor agents on amnesia induced by a β-carboline alkaloid, harmaline in mice. We used a step-down method to assess memory and then, hole-board method to assess exploratory behaviors. The results showed that pre-training intra-BLA injections of dopamine D1 receptor antagonist and agonist (SCH23390 (0.5μg/mouse) and SKF38393 (0.5μg/mouse), respectively) impaired memory acquisition. In contrast, pre-training intra-BLA injections of dopamine D2 receptor antagonist and agonist (sulpiride and quinpirole, respectively) have no significant effect on memory acquisition. Pre-training intra-peritoneal (i.p.) injection of harmaline (1mg/kg) decreased memory acquisition. However, co-administration of SCH 23390 (0.01μg/mouse) with different doses of harmaline did not alter amnesia. Conversely, pre-training intra-BLA injection of SKF38393 (0.1μg/mouse), sulpiride (0.25μg/mouse) or quinpirole (0.1μg/mouse) reversed harmaline (1mg/kg, i.p.)-induced amnesia. Furthermore, all above doses of drugs had no effect on locomotor activity. In conclusion, the dopamine D1 and D2 receptors of the BLA may be involved in the impairment of memory acquisition induced by harmaline.

Effects of harmine, an acetylcholinesterase inhibitor, on spatial learning and memory of APP/PS1 transgenic mice and scopolamine-induced memory impairment mice

Harmine, a β-carboline alkaloid present in Peganum harmala with a wide spectrum of pharmacological activities, has been shown to exert strong inhibition against acetylcholinesterase in vitro. However, whether it can rescue the impaired cognition has not been elucidated yet. In current study, we examined its effects on scopolamine-induced memory impairment mice and APP/PS1 transgenic mice, one of the models for Alzheimer's disease, using Morris Water Maze test. In addition, whether harmine could penetrate blood brain barrier, interact with and inhibit acetylcholinesterase, and activate downstream signaling network was also investigated. Our results showed that harmine (20mg/kg) administered by oral gavage for 2 weeks could effectively enhance the spatial cognition of C57BL/6 mice impaired by intraperitoneal injection of scopolamine (1mg/kg). Meanwhile, long-term consumption of harmine (20mg/kg) for 10 weeks also slightly benefited the impaired memory of APP/PS1 mice. Furthermore, harmine could pass through blood brain barrier, penetrate into the brain parenchyma shortly after oral administration, and modulate the expression of Egr-1, c-Jun and c-Fos. Molecular docking assay disclosed that harmine molecule could directly dock into the catalytic active site of acetylcholinesterase, which was partially confirmed by its in vivo inhibitory activity on acetylcholinesterase. Taken together, all these results suggested that harmine could ameliorate impaired memory by enhancement of cholinergic neurotransmission via inhibiting the activity of acetylcholinesterase, which may contribute to its clinical use in the therapy of neurological diseases characterized with acetylcholinesterase deficiency.

Harmine Induces Gastric Cancer Cell Apoptosis through the ROSmediated PI3K/AKT Signaling Pathway

Harmine (HM), a β-carboline alkaloid extracted from the seeds of Peganum harmala L., has been reported to have antitumor effects. However, the effects and mechanism of action of HM in human gastric cancer cells remain unclear. This study evaluated the antitumor effects of HM in human gastric cancer in vitro. The in vitro cytotoxicity test indicated that HM inhibits gastric cancer cell viability in a dose- and time-dependent manner. Intracellular ROS production was measured using the fluorescent substrate DCFH-DA. The percentage of apoptotic cells was determined by flow cytometry analysis and DAPI staining. Western blot analysis showed the expression of p-AKT, Bcl-2, Bax and caspase-3 in SGC-7901 cells treated with various agents. We demonstrated that HM induces gastric cancer cell apoptosis through the ROS-mediated PI3K/AKT signaling pathway. Therefore, data from this study not only confirm the potential of HM for the treatment of gastric cancer but also offer a promising anticancer therapeutic strategy for treating gastric cancer. Keywords: Anticancer, apoptosis, gastric cancer, harmine, reactive oxygen species.

7-Methoxy-(9H-β-Carbolin-1-il)-(E)-1-Propenoic Acid, a β-Carboline Alkaloid From Eurycoma longifolia, Exhibits Anti-Inflammatory Effects by Activating the Nrf2/Heme Oxygenase-1 Pathway.

Eurycoma longifolia is an herbal medicinal plant popularly used in Southeast Asian countries. In the present study, we show that 7-methoxy-(9H-β-carbolin-1-il)-(E)-1-propenoic acid (7-MCPA), a β-carboline alkaloid isolated from E. longifolia, exerted anti-inflammatory effects by activating the nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. 7-MCPA inhibited lipopolysaccharide (LPS)-induced production of nitric oxide (NO), prostaglandin E2 (PGE2 ), and interleukin-6 (IL-6) in RAW264.7 cells and rescued C57BL/6 mice from LPS-induced lethality in vivo. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and IL-6 was also significantly suppressed by treatment of 7-MCPA in RAW264.7 cells. 7-MCPA induced nuclear translocation of Nrf2 and increased transcription of its target genes, such as HO-1. Treating RAW264.7 cells with 7-MCPA increased the intracellular level of reactive oxygen species (ROS) and the phosphorylation level of p38 mitogen-activated protein kinase (MAPK); however, co-treatment with the antioxidant N-acetyl-cysteine (NAC) blocked 7-MCPA-induced p38 MAPK phosphorylation. Moreover, NAC or SB203580 (p38 MAPK inhibitor) blocked 7-MCPA-induced nuclear translocation of Nrf2, suggesting that 7-MCPA activated Nrf2 via a ROS-dependent p38 pathway. 7-MCPA induced HO-1 protein and mRNA expression and knockdown of Nrf2 with siRNA or SB203580 blocked 7-MCPA-mediated induction of HO-1 expression. Inhibiting Nrf2 or HO-1 abrogated the anti-inflammatory effects of 7-MCPA in LPS-stimulated RAW264.7 cells. We also demonstrated that 7-MCPA suppressed LPS-induced nuclear factor κB (NF-κB) activation. These results provide the first evidence that 7-MCPA exerts its anti-inflammatory effect by modulating the Nrf2 and NF-κB pathways and may be a potential Nrf2 activator to prevent or treat inflammatory diseases.

C ring may be dispensable for β-carboline: Design, synthesis, and bioactivities evaluation of tryptophan analog derivatives based on the biosynthesis of β-carboline alkaloids

According to our previous work and the latest research on the biosynthesis of β-carboline, and using the reverse thinking strategy, tryptophan, the biosynthesis precursor of β-carboline alkaloids, and their derivatives were synthesized, and their biological activities and structure–activity relationships were studied. This bioassay showed that these compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV); especially (S)-2-amino-3-(1H-indol-3-yl)-N-octylpropanamide (4) (63.3±2.1%, 67.1±1.9%, 68.7±1.3%, and 64.5±3.1%, 500μg/mL) exhibited the best antiviral activity both in vitro and in vivo. Compound 4 was chosen for the field trials and the acute oral toxicity test, the results showed that the compound exhibited good anti-TMV activity in the field and low acute oral toxicity. We also found that these compounds showed antifungal activities and insecticidal activities.

Determination of the absolute configuration of picrasidine Y, a naturally occurring β-carboline alkaloid

The absolute configuration of picrasidine Y, a β-carboline alkaloid isolated from Picrasma quassioides (Simaroubaceae), has not been determined. To determine the absolute configuration of picrasidine Y, we synthesized stereoisomers of picrasidine Y through 7-step chemical reactions using tartaric acid as a starting material. Moreover, we extended the scope of application of this synthetic method to canthin-5,6-dione compounds. The absolute configuration of natural picrasidine Y was elucidated based on comparisons of chemically synthesized isoforms with the naturally occurring compound in 1H and 13C NMR spectra, specific optical rotation, HPLC analysis with chiral columns, computational molecular simulation, and analysis with the CD exciton chirality method.

Synthesis and Fungicidal Activity of β-Carboline Alkaloids and Their Derivatives.

A series of β-Carboline derivatives were designed, synthesized, and evaluated for their fungicidal activities in this study. Several derivatives electively exhibited fungicidal activities against some fungi. Especially, compound F5 exhibited higher fungicidal activity against Rhizoctonia solani(53.35%) than commercial antiviral agent validamycin (36.4%); compound F16 exhibited high fungicidal activity against Oospora citriaurantii ex Persoon(43.28%). Some of the alkaloids and their derivatives (compounds F4 and F25) exhibited broad-spectrum fungicidal activity. Specifically, compound F4 exhibited excellent high broad-spectrum fungicidal activity in vitro, and the curative and protection activities against P. litchi in vivo reached 92.59% and 59.26%, respectively. The new derivative, F4, with optimized physicochemical properties, obviously exhibited higher activities both in vitro and in vivo; therefore, F4 may be used as a new lead structure for the development of fungicidal drugs.