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Griffinia gardneriana Ravenna, Griffinia liboniana Morren and Griffinia nocturna Ravenna (Amarillydaceae) are bulbous plants found in tropical regions of Brazil. Our work aimed to determine the alkaloid profiles of Griffinia spp. and evaluate their anxiolytic potential through in vivo and in silico assays. The plants grown in greenhouses were dried and their ground bulbs were subjected to liquid-liquid partitions, resulting in alkaloid fractions that were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Anxiolytic activity was evaluated in zebrafish (Danio rerio) through intraperitoneal injection at doses of 40, 100 and 200 mg/kg in light-dark box test. GC-MS analyses revealed 23 alkaloids belonging to different skeleton types: lycorine, homolychorine, galanthamine, crinine, haemanthamine, montanine and narcisclasine. The chemical profiles were relatively similar, presenting 8 alkaloids common to the three species. The major component for G. gardneriana and G. liboniana was lycorine, while G. nocturna consisted mainly of anhydrolycorine. All three alkaloid fractions demonstrated anxiolytic effect. Furthermore, pre-treatment with diazepam and pizotifen drugs was able to reverse the anxiolytic action, indicating involving the GABAergic and serotonergic receptors. Molecular docking showed that the compounds vittatine, lycorine and 11,12-dehydro-2-methoxyassoanine had high affinity with both receptors, suggesting them to be responsible for the anxiolytic effect., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Lycorine is an Amaryllidaceae alkaloid that presents anti-Trichomonas vaginalis activity. T. vaginalis causes trichomoniasis, the most common non-viral sexually transmitted infection. The modulation of T. vaginalis purinergic signaling through the ectonucleotidases, nucleoside triphosphate diphosphohydrolase (NTPDase), and ecto-5'-nucleotidase represents new targets for combating the parasite. With this knowledge, the aim of this study was to investigate whether NTPDase and ecto-5'-nucleotidase inhibition by lycorine could lead to extracellular ATP accumulation. Moreover, the lycorine effect on the reactive oxygen species (ROS) production by neutrophils and parasites was evaluated as well as the alkaloid toxicity. The metabolism of purines was assessed by HPLC. ROS production was measured by flow cytometry. Cytotoxicity against epithelial vaginal cells and fibroblasts was tested, as well as the hemolytic effect of lycorine and its in vivo toxicity in Galleria mellonella larvae. Our findings showed that lycorine caused ATP accumulation due to NTPDase inhibition. The alkaloid did not affect the ROS production by T. vaginalis; however, it increased ROS levels in neutrophils incubated with lycorine-treated trophozoites. Lycorine was cytotoxic against vaginal epithelial cells and fibroblasts; conversely, it was not hemolytic neither exhibited toxicity against the in vivo model of G. mellonella larvae. Overall, besides having anti-T. vaginalis activity, lycorine modulates ectonucleotidases and stimulates neutrophils to secrete ROS. This mechanism of action exerted by the alkaloid could enhance the susceptibility of T. vaginalis to host immune cell, contributing to protozoan clearance.

A novel series of aromatic esters (1a-1m) related to the Amaryllidaceae alkaloid (AA) haemanthamine were designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the synthesized compounds revealed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory profile. Significant human AChE (hAChE) inhibition was demonstrated by 11-O-(3-nitrobenzoyl)haemanthamine (1j) with IC 50 value of 4.0 ± 0.3 µM. The strongest human BuChE (hBuChE) inhibition generated 1-O-(2-methoxybenzoyl)haemanthamine (1g) with IC 50 value 3.3 ± 0.4 µM. Moreover, 11-O-(2-chlorbenzoyl)haemanthamine (1m) was able to inhibit both enzymes in dose-dependent manner. The mode of hAChE and hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 1j-, 1m-hAChE and 1g-, 1m-hBuChE complexes. The blood-brain barrier (BBB) permeability was investigated applying the parallel artificial membrane permeation assay (PAMPA) to predict the CNS availability of the compounds., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A new narciclasine glycoside, narciclasine-4- O - β -D-xylopyranoside ( 1 ) was characterised along with four known alkaloids pancratistatin ( 2 ), 1- O -(3-hydroxybutyryl) pancratistatin ( 3 ), vittatine ( 4 ), 9- O -demethylgalanthine ( 5 ) from Zephyranthes minuta . Their structures were established on the basis of spectroscopic data analysis. The in vitro cytotoxic study of extract, fractions and isolated compounds against two human cancer cell lines (KB and SiHa) indicated the potential activity of extract and n -butanol fraction due to presence of active alkaloids pancratistatin, 1- O -(3-hydroxybutyryl) pancratistatin, lycorine and haemanthamine.

The process of angiogenesis is involved in several pathological conditions, such as tumor growth or age-related macular degeneration. Although the available anti-angiogenic drugs have improved the therapy of these diseases, major drawbacks, such as unwanted side effects and resistances, still exist. Consequently, the search for new anti-angiogenic substances is still ongoing. Narciclasine, a plant alkaloid from different members of the Amaryllidaceae family, has extensively been characterized as anti-tumor compound. Beyond the field of cancer, the compound has recently been shown to possess anti-inflammatory properties. Surprisingly, potential actions of narciclasine on endothelial cells in the context of angiogenesis have been neglected so far. Thus, we aimed to analyze the effects of narciclasine on angiogenic processes in vitro and in vivo and to elucidate the underlying mechanism. Narciclasine (100-300 nM) effectively inhibited the proliferation, undirected and directed migration, network formation and angiogenic sprouting of human primary endothelial cells. Moreover, narciclasine (1 mg/kg/day) strongly reduced the VEGF-triggered angiogenesis in vivo (Matrigel plug assay in mice). Narciclasine mediated its anti-angiogenic effects in part by a RhoA-independent activation of the Rho kinase ROCK. Most importantly, however, the compound reduced the de novo protein synthesis in endothelial cells by approx. 50% without exhibiting considerable cytotoxic effects. As a consequence, narciclasine diminished the presence of proteins with a short half-life, such as the VEGF receptor 2, which is the basis for its anti-angiogenic effects. Taken together, our study highlights narciclasine as an interesting anti-angiogenic compound that is worth to be further evaluated in preclinical studies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In this study, an extract from the bulbs of Cyrtanthus contractus showed strong anti-inflammatory activity in vitro. The extract was partially separated into 14 fractions and analyzed by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry metabolomics, and the correlation coefficients were calculated between biological activities and metabolite levels. As a result, the top-scoring metabolite narciclasine (1) is proposed as the active principle of C. contractus. This was confirmed by comparing the biological effect of crude extract with that of an authentic standard.

Plants of the Amaryllidaceae family are well-known (not only) for their ornamental value but also for the alkaloids that they produce. In this report, the first phytochemical study of Clinanthus genus was carried out. The chemical composition of alkaloid fractions from Clinanthus microstephium was analyzed by GC/MS and NMR. Seven known compounds belonging to three structural types of Amaryllidaceae alkaloids were identified. An epimeric mixture of a haemanthamine-type compound (6-hydroxymaritidine) was tested as an inhibitor against acetyl- and butyrylcholinesterase enzymes (AChE and BChE, respectively), two enzymes relevant in the treatment of Alzheimer's disease, with good results. Structure-activity relationships through molecular docking studies with this alkaloid and other structurally related compounds were discussed., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Twelve derivatives 1a - 1m of the β-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3β (GSK-3β) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11- O -(2-methylbenzoyl)-haemanthamine ( 1j ) and 11- O -(4-nitrobenzoyl)-haemanthamine ( 1m ), revealed the most intriguing profile, both being acetylcholinesterase ( h AChE) inhibitors on a micromolar scale, with GSK-3β inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds' plausible binding modes in the active sites of h AChE and h BuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.

An efficient protocol for the isolation of narciclasine from common Amaryllidaceae bulbs, separation from haemanthamine, and the occurrence of a trace alkaloid, 2- epi-narciclasine, are reported. Attempts to convert natural narciclasine to its C-2 epimer by Mitsunobu inversion or oxidation/reduction sequences were compromised by rearrangement and aromatization processes, through which a synthesis of the alkaloid narciprimine was achieved. The methylation of the 7-hydroxy group of natural narciclasine followed by protection of the 3,4-diol function and oxidation/reduction sequence provided the target C-2 epimer. A de novo chemoenzymatic synthesis of 2- epi-narciclasine from m-dibromobenzene is also described. Haemanthamine and narciprimine were readily detected in the crude extracts of Narcissus and Galanthus bulbs containing narciclasine, and the occurrence of 2- epi-narciclasine as a trace natural product in Galanthus sp. is reported for the first time.

Lycorine is an alkaloid isolated from bulbs of Pancratium foetidum Pom Amaryllidaceae of the genus Lycoris. It has very strong pharmacodynamics properties and biological effects, among others, antimalarial, antiviral, antitumor, and anti-inflammatory. Lycorine has been identified and characterized by thin layer chromatography, IR and NMR (1H and 13C NMR, COZY, HMBC, HSQC and NOESY). The antibacterial activity of lycorine has been evaluated. Lycorine has a moderate antibacterial activity on the majority of strains studied, nevertheless it is more effective than Streptomycin and Ampicillin against bacteria: P. aeruginosa, En. cloacae. To confirm these results, it is necessary to use qualitative techniques and methods, etc… We performed a virtual docking ligand-lycorine protein screening study to predict and characterize their mode of interaction with the LpxC receptor. Docking results have shown that lycorine can interact with target amino residues studied by hydrogen and metal-ion bonds. In addition, the ADME-Tox profile study has shown that lycorine is all in agreement, either with Lipinski's critics or with the toxicity standards., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Eleven new alkaloids (1-11), classified as the 12-acetylplicamine (1), N-deformyl-seco-plicamine (2), plicamine (3-6), 4a-epi-plicamine (7), seco-plicamine (8), and lycorine (9-11) framework types, along with 15 known alkaloids (12-26) were isolated from the whole plants of Zephyranthes carinata. The structures of the new alkaloids 1-11 were established by extensive spectroscopic data interpretation. The absolute configurations of 9 and 10 were defined by single-crystal X-ray diffraction analysis. Zephycarinatines A (1), B (2), and G (7) represent the first examples of 12-acetylplicamine, N-deformyl-seco-plicamine, and 4a-epi-plicamine alkaloids, respectively. Alkaloids 6, 11, 17, and 20-23 exhibited AChE inhibitory activities with IC 50 values ranging from 1.21 to 184.05 μM, and a preliminary structure-activity relationship is discussed.

Extracellular matrix (ECM) degrading enzymes, including matrix metalloproteinases (MMPs), are critical for cartilage destruction in the progression of osteoarthritis (OA). Thus, identifying novel drugs, which suppress the synthesis of MMPs may facilitate the treatment of OA. The cytotoxicity of lycorine was determined using a CCK8 assay. The effects of lycorine on IL‑1β‑induced upregulation of MMPs and activation of mitogen‑activated protein kinase pathways were detected by western blot analysis and reverse transcription‑quantitative polymerase chain reaction. Hematoxylin and eosin staining and Safranin O staining were used to evaluate the effect of lycorine in a mouse anterior cruciate ligament transection model. In the present study, it was demonstrated for the first time, to the best of our knowledge, that lycorine (LY) suppressed interleukin‑1β (IL‑1β)‑induced synthesis of MMP‑3 and MMP‑13 in vitro. Molecular analysis revealed that LY abrogated the phosphorylation of c‑Jun N‑terminal kinase (JNK) and the activation of the nuclear factor (NF)‑κB signaling pathway caused by IL‑1β stimulation. In addition, in vivo experiments in a mouse anterior cruciate ligament transection model confirmed the protective role of LY on cartilage. Taken together, the data obtained in the present study demonstrated that LY suppressed the IL‑1β‑induced expression of MMP‑3 and MMP‑13 through inhibition of the JNK and NF‑κB pathways, suggesting that LY may be used as a potential drug for the treatment of OA.