Research progress on the antitumor effects of harmine.

Harmine is a naturally occurring ß-carboline alkaloid originally isolated from Peganum harmala. As a major active component, harmine exhibits a broad spectrum of pharmacological properties, particularly remarkable antitumor effects. Recent mechanistic studies have shown that harmine can inhibit cancer cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle regulation, angiogenesis, and the induction of tumor cell apoptosis. Furthermore, harmine reduces drug resistance when used in combination with chemotherapeutic drugs. Despite its remarkable antitumor activity, the application of harmine is limited by its poor solubility and toxic side effects, particularly neurotoxicity. Novel harmine derivatives have demonstrated strong clinical application prospects, but further validation based on drug activity, acute toxicity, and other aspects is necessary. Here, we present a review of recent research on the action mechanism of harmine in cancer treatment and the development of its derivatives, providing new insights into its potential clinical applications and strategies for mitigating its toxicity while enhancing its efficacy.

Bioinspired total synthesis and biological activity of Pegaharine A.

BACKGROUND: Phytopathogens cause various diseases by parasitizing crops, reducing crop yield and resulting in substantial economic losses in agricultural production. A novel type isolated from the perennial herbaceous Peganum harmala L. seeds, ß-carboline alkaloids pegaharine A (PA), has become a hot topic in developing plant-originated green pesticides owing to their significant physiological activities. RESULTS: A scalable bioinspired total synthesis of PA is accomplished in the present work. The systematical biological assay study showed that PA exhibited moderate inhibitory activity against nine tested plant pathogenic fungi and showed significant inhibitory activity in vitro against the three tested plant pathogenic bacteria. Most noteworthy is the inhibitory rates of PA on Xanthomonas oryzae pv. oryzae (Xoo), X. oryzae pv. oryzicola (Xoc) and X. axonopodis pv. citri (Xac) of 93.6%, 92.1% and 86.1%, respectively, which are better than the control drug, bismerthiazol (63.4%, 61.2% and 53.7% at 100 µg mL-1 concentration). Furthermore, the EC50 value of PA against Xoo, Xoc and Xac was 52.2, 60.0 and 65.1 µg mL-1 , respectively, superior to 72.9, 64.2 and 70.1 µg mL-1 of the control drug. Moreover, the anti-Xoo mechanistic studies revealed that PA exerted its antibacterial effects by increasing the permeability of the bacterial membrane, reducing the extracellular polysaccharide content and inducing morphological changes in bacterial cells. CONCLUSION: A novel ß-carboline alkaloid, PA, was prepared by biomimetic total synthesis. Its significant antibacterial activity was closely related to the permeation of bacterial cell membranes, which was confirmed by anti-Xoo mechanistic studies. More importantly, the structure could be regarded as a model for developing novel bactericides. © 2023 Society of Chemical Industry.

Two new ß-carboline alkaloids from the roots of Anemone altaica.

Two new ß-carboline alkaloids, anemonilins A and B (1-2), and two known ß-carboline alkaloids, flazine (3) and 4-(9H-ß-carbolin-l-yl)-4-oxo-butyric acid (4), were isolated from the roots of Anemone altaica. The structures of the isolated compounds were elucidated with spectroscopic and spectrometric methods (1D and 2DNMR, HRESIMS). Compounds 2 and 4 significantly attenuated the growth inhibition induced by lipopolysaccharide (LPS) in normal rat kidney tubule epithelioid (NRK52e) cells (p < 0.05 or p < 0.01). Furthermore, compound 2 significantly reduced the apoptosis (p < 0.05) and the caspase-3/9 expression of NRK52e cells induced by LPS.

Two new compounds from edible mushroom Sarcomyxa edulis.

Chemical investigation of the edible mushroom Sarcomyxa edulis led to the isolation of one new highly degraded sterol (1), and one new ß-carboline alkaloid (2), along with nine known compounds (3-11) for the first time from this mushroom. The structures of new compounds were elucidated using HR-ESI-MS data and NMR spectroscopy. In addition, anti-inflammatory activity of new compounds was evaluated against lipopolysaccharide-induced NO production in RAW 264.7 macrophages. Compound 2 exhibited a good anti-inflammatory activity with IC50 value of 9.88 ± 0.48 µM, and compound 1 exhibited a weak inhibitory effect with IC50 value of 71.36 ± 5.11 µM.

New sesquiterpene dilactone and ß-carboline alkaloid and the α-glucosidase inhibitory activity of selected phytochemicals from Neolitsea cassia (L.) Kosterm.

One new sesquiterpene dilactone, coccinine (1) and one new ß-carboline alkaloid, daibucarboline F (2) together with 10 known compounds; linderane (3), linderalactone (4), pseudoneolinderane (5), linderanlide C (6), linderanine A (7), epicatechin (8), (-)-taxifolin (9), astilbin (10), L-quercitrin (11) and afzelin (12) were isolated from the stems and leaves of Neolitsea cassia (L.) Kosterm (Lauraceae). The structures of (1 and 2) were established by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in literature. The relative stereochemistry of compound (1) was assigned by X-ray diffraction analysis with Cu-Kα irradiation. Compounds (3-8) and (10) were evaluated for their α-glucosidase enzymatic inhibitory activity. Compounds (4-6), (8) and (10) exhibited inhibition towards α-glucosidase enzymatic activity with IC50 values ranging from 12.10 to 96.77 µM. This is the first report on the isolation of phytochemicals from N. cassia and their bioactivities.

Trigonostemon species in south China: Insights on its chemical constituents towards pharmacological applications.

ETHNOPHARMACOLOGY RELEVANCE: The Euphorbiaceae family, which contains about 300 genera and more than 5000 species, is widely distributed in different regions. Trigonostemon genus comprises a wide group of tropical and temperate plants belonging to the Euphorbiaceae family. This genus includes at least 50 species throughout tropical Asia, extending from India and Sri Lanka to New Guinea. They have been employed by local populations for the treatment of asthma, poisonous snake bites, and food poisoning. AIM OF THE REVIEW: The main aim of the review is to critically analyze the reported traditional uses, bioactive chemical constituents and pharmacological activities of Trigonostemon species. MATERIALS AND METHODS: Scientific databases, including Google Scholar, PubMed, CNKI, SpringerLink, Web of Science, Wiley Online Library and SciFinder, were searched using keywords such as "Trigonostemon", "South China", "chemical constituents", or "traditional use". Thus, available articles from 2000 to 2020 were collected and analyzed. RESULTS AND DISCUSSION: This paper provides systematic data that Trigonostemon species possess a diverse phytochemical composition, (including diterpenes, alkaloids, coumarins, lignins, sesquiterpenes, triterpenoids, flavonoids, and polyphenols) found in different plant organs. Research on Trigonostemon plants has revealed critical therapeutic properties, such as antiviral, anti-tumor, antimicrobial, anti-inflammatory, and insecticidal activities. CONCLUSIONS: It is envisaged that the current review will add value to more scientific research on Trigonostemon species and enhance/promote the increased interest in the sustainable use of Trigonostemon species as well as lead to the validation of unverified ethnobotanical claims. Future studies on Trigonostemon species would focus on establishing the links between the traditional uses, active compounds and reported pharmacological activities.

Design, synthesis and biological evaluation of harmine derivatives as potent GSK-3ß/DYRK1A dual inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss and behavioral disturbances, ultimately leading to death. Glycogen synthase kinase 3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation regulated kinase1A (DYRK1A) have gained a lot of attention for its role in tau pathology. To search for potential dual GSK-3ß/DYRK1A inhibitors, we focused on harmine, a natural ß-carboline alkaloid, which has been extensively studied for its various biological effects on the prevention of AD. In this study, a new series of harmine derivatives were designed, synthesized and evaluated as dual GSK-3ß/DYRK1A inhibitors for their multiple biological activities. The in vitro results indicated that most of them displayed promising activity against GSK-3ß and DYRK1A. Among them, compound ZDWX-25 showed potent inhibitory effects on GSK-3ß and DYRK1A with IC50 values of 71 and 103 nM, respectively. Molecular modelling and kinetic studies verified that ZDWX-25 could interact with the ATP binding pocket of GSK-3ß and DYRK1A. Western blot analysis revealed that ZDWX-25 inhibited hyperphosphorylation of tau protein in okadaic acid (OKA)-induced SH-SY5Y cells. In addition, ZDWX-25 showed good blood-brain barrier penetrability in vitro. More importantly, ZDWX-25 could ameliorate the impaired learning and memory in APP/PS1/Tau transgenic mice. These results indicated that the harmine-based compounds could be served as promising dual-targeted candidates for AD.

Flavopereirine Inhibits Hepatocellular Carcinoma Cell Growth by Inducing Cell-cycle Arrest, Apoptosis, and Autophagy-related Protein Expression.

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Resistance to chemotherapy and side-effects remain a challenge for treating advanced and recurrent HCC. Therefore, there is an emerging need to develop new drugs to treat HCC. MATERIALS AND METHODS: We evaluated the anti-growth activity of flavopereirine in HepG2 and Huh7 HCC cell lines. Cell viability, cell-cycle profile, apoptosis, and autophagy-related protein expressions were analysed after flavopereirine treatment. RESULTS: Flavopereirine treatment induced G0/G1 cell-cycle arrest, with an increase of sub-G1 cells detected at the higher concentration and longer exposure to flavopereirine in HCC cells. Intrinsic and extrinsic pathways were involved in flavopereirine-induced apoptosis, as demonstrated by an increase of cleaved caspase 8 and 9 by western blotting. An alteration of autophagy-related protein expression was also found after flavopereirine treatment. CONCLUSION: Taken together, the current results indicate that flavopereirine exhibits good anticancer activity in HCC cells.

New alkaloids and isocoumarins from the marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501.

Two new ß-carboline alkaloids, aspergillspins A-B (1-2), three new quinolone alkaloids, aspergillspins C-E (3-5), and two new isocoumarins, aspergillspins F-G (6-7), together with four known alkaloids were isolated from the marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501. Their structures were identified by spectroscopic analysis, and the absolute configurations of several chiral carbons in 2 and 3 were further established by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Their cytotoxic and antibacterial activities were also evaluated.

(±)-Quassidine K, a pair of cytotoxic bis-ß-carboline alkaloid enantiomers from Picrasma quassioides.

(±)-Quassidine K (1), a pair of new bis-ß-carboline alkaloid enantiomers, were isolated from Picrasma quassioides. Their structures were determined on the basis of detailed spectroscopic data analysis. The absolute configurations of (+)-S-quassidine K (1a) and (-)-R-quassidine K (1b) were determined by comparing with the reported experimental ECD spectra after chiral separation. The cytotoxicity assay showed activity against HeLa cells with IC50 values of 15.8 and 20.1 µM, respectively.

Identification of biosynthetic genes for the ß-carboline alkaloid kitasetaline and production of the fluorinated derivatives by heterologous expression.

ß-Carboline alkaloids exhibit a broad spectrum of pharmacological and biological activities and are widely distributed in nature. Genetic information on the biosynthetic mechanism of ß-carboline alkaloids has not been accumulated in bacteria, because there are only a few reports on the microbial ß-carboline compounds. We previously isolated kitasetaline, a mercapturic acid derivative of a ß-carboline compound, from the genetically modified Kitasatospora setae strain and found a plausible biosynthetic gene cluster for kitasetaline. Here, we identified and characterized three kitasetaline (ksl) biosynthetic genes for the formation of the ß-carboline core structure and a gene encoding mycothiol-S-conjugate amidase for the modification of the N-acetylcysteine moiety by using heterologous expression. The proposed model of kitasetaline biosynthesis shows unique enzymatic systems for ß-carboline alkaloids. In addition, feeding fluorotryptophan to the heterologous Streptomyces hosts expressing the ksl genes led to the generation of unnatural ß-carboline alkaloids exerting novel/potentiated bioactivities.

Identification of ß-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.

A compound library, which consists of 75 natural ß-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-ß-carboline-3-carboxylic acid (37), 1-acetophenone-1,2,3,4-tetrahydro-ß-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 ß-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 ß-carboline-type alkaloids and canthinone-type alkaloids may exert an anti-inflammatory effect through different mechanism.

A new β-carboline alkaloid from stems of Picrasma quassioidies / 中草药

Objective To study the alkaloids from the stems of Picrasma quassioidies. Methods The isolation and purification were carried out by column chromatography on CG161M, silica gel, ODS, and Sephadex LH-20. The structures were elucidated on the basis of physicochemical properties and spectroscopic analysis. Results A total of 16 alkaloids were isolated and identified from 85% ethanol aqueous extract of the stems of P. quassioidies. It included 12 β-carboline alkaloids including 1-(1-hydroxy)-ethyl-6-hydroxy-β-carboline (1), 6-hydroxy-β-carboline-1-carboxylic acid (2), β-carboline-1-carboxylic acid (3), β-carboline-1-propanoic acid (4), 3-hydroxy-β-carboline (5), 1-acetyl-β-carboline (6), 1-ethoxycarbonyl-β-carboline (7), 1-(9H-β-carbolin-1-yl)-ethanol (8), picrasidine X (9), 1-hydroxymethyl-β-carboline (10), 9H-pyrido [3,4-b] indole (11), 6-hydroxy-2-methyl-9H-β-carbolin-2-ium (12); and four cantin-6-one alkaloids, including 4,5-dimethoxycanthin-6-one (13), 3-methylcanthin-5,6-dione (14), 5-hydroxy-4-methoxylcanthin-6-one (15), and picrasidine O (16). Conclusion Compound 1 is a new β-carboline alkaloid named picrasidine Z, and compound 12 is a new natural product.

Alkaloids from an aqueous extract of Uncaria rhynchophylla / 药学学报

Five alkaloids were isolated from a decoction of Uncaria rhynchophylla by a combination of various chromatographic techniques, including macroporous adsorbent resin, MCI resin, silica gel, Sephadex LH-20, and reversed phase HPLC. Their structures were characterized by comprehensive analyses of spectroscopic data as monoterpene indole alkaloids (+)-(7R)-3-oxo-7-hydroxy-3,7-seco-dihydrorhynchohylline (1), (+)-(7S)-3-oxo-7-hydroxy-3,7-seco-dihydrorhyncho-hylline (2), (+)-(7R)-3-oxo-7-hydroxy-3,7-seco-rhynchohylline (3) and (+)-(7S)-3-oxo-7-hydroxy-3,7-seco-rhynchohylline (4), and a β-carboline alkaloid 1,2,3,4-tetrahydro-1-oxo-β-carboline (5). Among them, 1 and 2 are new compounds, 3 and 4 are new natural products that were semi-synthesized from isorhynchohylline with incorrect specific rotations, and 5 is isolated for the first time from the genus Uncaria.

Characterization of a new microbial Pictet-Spenglerase NscbB affording the ß-carboline skeletons from Nocardiopsis synnemataformans DSM 44143.

The enzymatic Pictet-Spengler (PS) reaction, catalyzed by Pictet-Spenglerase (PSase), is the feature of ß-carboline (ßC) alkaloid biosynthesis. NscbB is a rare microbial PSase discovered from a cryptic ß-carboline alkaloid biosynthetic gene cluster (BGC) in the Nocardiopsis synnemataformans DSM 44143 (kidney transplant patient derived) by homologous alignment with its well-characterized counterpart McbB. The biochemical analysis showed that NscbB could catalyze l-tryptophan (KM = 89.64 ±â€¯8.69 µM) and methylglyoxal (KM = 147.70 ±â€¯16.38 µM), without cofactors, to form the two ßC skeletons 1-acetyl-3-carboxy-ß-carboline and 1-acetyl-ß-carboline in vitro. Additionally, the heterologous expression of nscbB in E. coli BL21 (DE3) revealed the efficient bioproductivity of NscbB to bioproduce two ßC skeletons, 1-acetyl-3-carboxy-ß-carboline (5.5 mg/L) and 1-acetyl-ß-carboline (3.1 mg/L), within 16 h fermentation. These results demonstrate NscbB is a novel and practical microbial PSase, which is useful for future bioactive ßC alkaloid exploitation and development.

Phytochemical study of Harrisia adscendens

ABSTRACT Harrisia adscendens (Gürke) Britton & Rose is a species of the family Cactaceae found in the northeastern semi-arid and popularly known as foxtail. In folk medicine, the roots of this species are used for the treatment of toothache and heartburn. The objective of this study was to perform the isolation and identification of the secondary metabolites obtained from the vegetal drug by chromatographic and spectroscopic techniques and to evaluate the antimicrobial activity of the extract. The qualitative phytochemical analysis of the extract showed suggestive results for the presence of alkaloids. Two compounds were isolated and identified: 2-methyl-9H-β-carboline-2-ion, a β-carboline alkaloid obtained for the first time as a natural product and 2',6'-dihydroxy-4'-methoxyacetophenone-2'-O-β-glucoside. In the antimicrobial tests, it was possible to observe activity against Pseudomonas aeruginosa. The results obtained by spectroscopic techniques allowed to characterize the phytochemical properties of the vegetal drug and may be useful in future studies for production of herbal medicines.

Harmine, a small molecule derived from natural sources, inhibits enterovirus 71 replication by targeting NF-κB pathway.

Enterovirus 71 (EV71) infection of young children can cause neurological manifestations, which is mainly responsible for the fatality. Although a vaccine is recently available for preventing enterovirus 71 infection, its efficacy remains to be seen. Therefore, there is a pressing need for anti-viral agents for the treatment of EV71 infection. By screening a natural compound library for inhibitory activity of EV71 replication, we identified a small molecule, harmine, that inhibited EV71 replication by targeting NF-κB signaling pathway. Harmine is a ß-carboline alkaloid found in the medicinal plant Peganum harmala, which is used as a folk antitumor medicine in China and other parts of the Asia. The estimated EC50 value for harmine to block EV71 infection was 20 µM, while the CC50 was estimated at 500 µM in vitro. Harmine inhibited replication of EV71, as evidenced by its ability to diminish plague formation induced by EV71 and to reduce the level of viral RNA and protein. Mechanistic studies indicated that harmine suppressed EV71 replication through inhibition of NF-κB signaling pathway. Harmine treatment also reduced EV71-induced reactive oxygen species (ROS) formation, which was associated with a decline in EV71-associated NF-κB activation. In addition, the harmine treatment could protect AG129 mice against EV71 replication in vivo. These findings suggest that harmine may present as a candidate antiviral drug for the treatment of EV71 infection.

Exposure Characteristics of the Analogous ß-Carboline Alkaloids Harmaline and Harmine Based on the Efflux Transporter of Multidrug Resistance Protein 2.

Harmaline and harmine occur naturally in plants and are distributed endogenously in human and animal tissues. The two ß-carboline alkaloids possess potential for treating Alzheimer's disease, Parkinson's disease, depression and other central nervous system diseases. However, studies have showed that the two compounds have similar structures but with quite different bioavailability. The aim of this study was to elucidate the exposure difference and characterize the in vitro transport, metabolism, and pharmacokinetic properties of harmaline and harmine. The results showed that the harmaline and harmine transport across the Caco-2 and MDCK cell monolayers was varied as the time, concentration, pH and temperature changed. The absorption of harmaline and harmine was significantly decreased when ES (OATPs inhibitor), TEA (OCTs/OCTNs substrate), NaN3 (adenosine triphosphate inhibitor), or sodium vanadate (ATPase Na+/K+-dependent inhibitor) was added. However, when given MK571 and probenecid (the typical MRP2 inhibitor), the PappAB of harmine was increased (1.62- and 1.27-folds), and the efflux ratio was decreased from 1.59 to 0.98 and from 1.59 to 1.19, respectively. In addition, the uptake ratio of harmine at 1 µM was >2.65 in the membrane vesicles expressing human MRP2. Furthermore, harmine could slightly up-regulate the expression of MRP2, which implying harmine might be the substrate of MRP2. Particularly, the CLint -value for harmine was ~1.49-folds greater than that of harmaline in human liver microsomes. It was worth noting that the F-value of harmine was increased 1.96-folds after harmine co-administration with probenecid. To summarize, comprehensive analysis indicated that harmaline and harmine were absorbed by transcellular passive diffusion and a pH- and Na+-dependent mechanism might be mediated by OATPs and OCTs/OCTNs. MRP2 but MDR1 or BCRP might be involved in the transport of harmine. Furthermore, harmine was more unstable and easily metabolized than harmaline. All these findings suggested that harmine not only appears be an MRP2 substrate, but also possesses weak metabolic stability, and eventually leads to a low oral bioavailability. Taken together, the elucidated absorption, transport, metabolism as well as pharmacokinetic characteristics of harmaline and harmine provide useful information for designing delivery systems, pharmacological applications and avoiding drug-drug interactions.

Pharmacological and Toxicological Profile of Harmane-ß-Carboline Alkaloid: Friend or Foe.

BACKGROUND: The plant secondary metabolites have an outstanding therapeutic potential and success over the years. In fact, it is the foundation of numerous clinically used drugs. Similarly, these is a general perception that these products are inherent safety. However, such products might have toxic/unwanted lethal effects therefore, along with biological relevance, toxicological evaluation is equally important for clinical applications. Therefore, harmane- ß-carboline alkaloid was investigated for both therapeutic and toxicological potential. METHODS: The literature related to the therapeutic/toxicological effects of the alkaloid was searched using various scientific data bases including Google, ScienceDirect, PubMed, SpringerLink, ASC. The peer reviewed articles were only selected. RESULTS: The harmane-ß-carboline alkaloid has shown several pharmacological activities such as antianxiety, antidepressant, antiplatelet, antidiabetic, acetylcholinesterase and myeloperoxidase inhibition, antioxidant, antiparasitic, hypotensive, morphine withdrawal syndrome alleviation, and antinociceptive effects. On the other hand, it exhibited tremorogenic effect, for a symptom of Parkinson's disease. Adverse effect of the alkaloid on learning and memory have also been observed. CONCLUSIONS: All together, it is, concluded in this review that harmane elicited marked pharmacological effects but simultaneously, it possessed some serious side effects that could be the primary hurdle in the way of its clinical testing.

Alkaloids from aerial parts of Houttuynia cordata and their anti-inflammatory activity.

New alkaloids, houttuynamide B and C (1, 2) and houttuycorine (14), were isolated from the aerial parts of Houttuynia cordata Thunb. in addition to eighteen known alkaloids. Their structures were elucidated through extensive spectroscopic analysis. All the isolates were tested for their inhibitory activity against NO production in RAW 264.7 cells stimulated by LPS. Of the tested compounds, compound 15 showed the most potent anti-inflammatory activity with an IC50 value of 8.7µM.