Total synthesis of 1,4a-di-epi-ent-pancratistatin, exemplifying a stereodivergent approach to pancratistatin isomers.

The total synthesis of 1,4a-di-epi-ent-pancratistatin, a novel stereoisomer of the anti-tumor Amaryllidaceae alkaloid pancratistatin, was achieved in 14 steps starting from D-mannitol. The construction of the pancratistatin skeleton involved conjugate addition of organocuprate to a nitrosoolefin, which was generated in situ from inosose oxime. This was followed by stereoselective reduction of the oxime to an amine and site-selective formylation. Biological evaluations revealed that the newly synthesized compounds exhibit cytotoxicity toward cancer cells and significant ferroptosis inhibitory activity. These compounds constitute a promising small-molecule library for the development of potent bioactive agents.

Antitumoral activity of different Amaryllidaceae alkaloids: In vitro and in silico assays.

ETHNOPHARMACOLOGY RELEVANCE: The plants of Amaryllidaceae family, such as Amaryllis belladonna L., have been used as herbal remedies for thousands of years to address various disorders, including diseases that might today be identified as cancer. AIM OF THE STUDY: The objective of this work was to evaluate the potential of three Amaryllidaceae alkaloids against four cancer cell lines. MATERIAL AND METHODS: The alkaloids lycorine, 1-O-acetylcaranine, and montanine were evaluated in vitro against colon adenocarcinoma cell line (HCT-116) and breast carcinoma cell lines (MCF-7, MDAMB231, and Hs578T). Computational experiments (target prediction and molecular docking) were conducted to gain a deeper comprehension of possible interactions between these alkaloids and potential targets associated with these tumor cells. RESULTS: Montanine presented the best results against HCT-116, MDAMB231, and Hs578T cell lines, while lycorine was the most active against MCF-7. In alignment with the target prediction outcomes and existing literature, four potential targets were chosen for the molecular docking analysis: CDK8, EGFR, ER-alpha, and dCK. The docking scores revealed two potential targets for the alkaloids with scores similar to co-crystallized inhibitors and substrates: CDK8 and dCK. A visual analysis of the optimal docked configurations indicates that the alkaloids may interact with some key residues in contrast to the other docked compounds. This observation implies their potential to bind effectively to both targets. CONCLUSIONS: In vitro and in silico results corroborate with data literature suggesting the Amaryllidaceae alkaloids as interesting molecules with antitumoral properties, especially montanine, which showed the best in vitro results against colorectal and breast carcinoma. More studies are necessary to confirm the targets and pharmaceutical potential of montanine against these cancer cell lines.

A mini-review of the anti-SARS-CoV-2 potency of Amaryllidaceae alkaloids.

BACKGROUND: Nature has perennially served as an infinite reservoir of diverse chemicals with numerous applications benefiting humankind. In recent years, due to the emerging COVID-19 pandemic, there has been a surge in studies on repurposing natural products as anti-SARS-CoV-2 agents, including plant-derived substances. Among all types of natural products, alkaloids remain one of the most important groups with various known medicinal values. The current investigation focuses on Amaryllidaceae alkaloids (AAs) since AAs have drawn significant scientific attention as anti-SARS-CoV-2 agents over the past few years. PURPOSE AND STUDY DESIGN: This study serves as a mini-review, summarizing recent advances in studying the anti-SARS-CoV-2 potency of AAs, covering two aspects: structure-activity relationship and mechanism of action (MOA). METHODS: The study covers the period from 2019 to 2023. The information in this review were retrieved from common databases including Web of Science, ScienceDirect, PubMed and Google scholar. Reported anti-SARS-CoV-2 potency, cytotoxicity and possible biological targets of AAs were summarized and classified into different skeletal subclasses. Then, the structure-activity relationship (SAR) was explored, pinpointing the key pharmacophore-related structural moieties. To study the mechanism of action of anti-SARS-CoV-2 AAs, possible biological targets were discussed. RESULTS: In total, fourteen research articles about anti-SARS-CoV-2 was selected. From the SAR point of view, four skeletal subclasses of AAs (lycorine-, galanthamine-, crinine- and homolycorine-types) appear to be promising for further investigation as anti-SARS-CoV-2 agents despite experimental inconsistencies in determining in vitro half maximal inhibitory effective concentration (EC50). Narciclasine, haemanthamine- and montanine-type skeletons were cytotoxic and devoid of anti-SARS-CoV-2 activity. The lycorine-type scaffold was the most structurally diverse in this study and preliminary structure-activity relationships revealed the crucial role of ring C and substituents on rings A, C and D in its anti-SARS-CoV-2 activity. It also appears that two enantiomeric skeletons (haemanthamine- and crinine-types) displayed opposite activity/toxicity profiles regarding anti-SARS-CoV-2 activity. Pharmacophore-related moieties of the haemanthamine/crinine-type skeletons were the substituents on rings B, C and the dioxymethylene moiety. All galanthamine-type alkaloids in this study were devoid of cytotoxicity and it appears that varying substituents on rings C and D could enhance the anti-SARS-CoV-2 potency. Regarding MOAs, initial experimental results suggested Mpro and RdRp as possible viral targets. Dual functionality between anti-inflammatory activity on host cells and anti-SARS-CoV-2 activity on the SARS-CoV-2 virus of isoquinoline alkaloids, including AAs, were suggested as the possible MOAs to alleviate severe complications in COVID-19 patients. This dual functionality was proposed to be related to the p38 MAPK signaling pathway. CONCLUSION: Overall, Amaryllidaceae alkaloids appear to be promising for further investigation as anti-SARS-CoV-2 agents. The skeletal subclasses holding the premise for further investigation are lycorine-, crinine-, galanthamine- and homolycorine-types.

Biosensor and machine learning-aided engineering of an amaryllidaceae enzyme.

A major challenge to achieving industry-scale biomanufacturing of therapeutic alkaloids is the slow process of biocatalyst engineering. Amaryllidaceae alkaloids, such as the Alzheimer's medication galantamine, are complex plant secondary metabolites with recognized therapeutic value. Due to their difficult synthesis they are regularly sourced by extraction and purification from the low-yielding daffodil Narcissus pseudonarcissus. Here, we propose an efficient biosensor-machine learning technology stack for biocatalyst development, which we apply to engineer an Amaryllidaceae enzyme in Escherichia coli. Directed evolution is used to develop a highly sensitive (EC50 = 20 µM) and specific biosensor for the key Amaryllidaceae alkaloid branchpoint 4'-O-methylnorbelladine. A structure-based residual neural network (MutComputeX) is subsequently developed and used to generate activity-enriched variants of a plant methyltransferase, which are rapidly screened with the biosensor. Functional enzyme variants are identified that yield a 60% improvement in product titer, 2-fold higher catalytic activity, and 3-fold lower off-product regioisomer formation. A solved crystal structure elucidates the mechanism behind key beneficial mutations.

Dynamics of alkaloid accumulation in Narcissus cv. Hawera: a source of Sceletium-type alkaloids.

The Sceletium-type alkaloids, known for their anxiolytic and antidepressant activities, have been recently found to be biosynthesized in Narcissus cv. Hawera, which is largely used as an ornamental plant. An alkaloid fraction enriched with Sceletium-type alkaloids from the plant has shown promising antidepressant and anxiolytic activities. In the present study, qualitative and quantitative analyses of the alkaloids in the plant organs were performed during one vegetation season by GC-MS. The alkaloid pattern and total alkaloid content was found to depend strongly on the stage of development and plant organ. The alkaloid content of bulbs was found to be highest during the dormancy period and lowest in sprouting bulbs. The leaves showed the highest alkaloid content during the intensive vegetative growth and lowest during flowering. In total, 13 alkaloids were detected in the methanol extracts of Narcissus cv. Hawera, six Sceletium-type and seven typical Amaryllidaceae alkaloids. Major alkaloids in the alkaloid pattern were lycorine, 6-epi-mesembrenol, mesembrenone, sanguinine, and galanthamine. The leaves of flowering plants were found to have the highest amount of 6-epi-mesembrenol. Mesembrenone was found to be dominant alkaloid in the leaves of sprouting bulbs and in the flowers. Considering the biomass of the plant, the dormant bulbs are the best source of alkaloid fractions enriched with 6-epi-mesembrenol. The flowers and the young leaves can be used for preparation of alkaloid fractions enriched with mesembrenone. The results indicates that Narcissus cv. Hawera is an emerging source of valuable bioactive compounds and its utilization can be extended as a medicinal plant.

Molecular Docking and GC/MS-Based Approach for Identification of Anxiolytic Alkaloids from Griffinia (Amaryllidaceae) Species in a Zebrafish Model.

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.

Unveiling Amaryllidaceae alkaloids: from biosynthesis to antiviral potential - a review.

Covering: 2017 to 2023 (now)Amaryllidaceae alkaloids (AAs) are a unique class of specialized metabolites containing heterocyclic nitrogen bridging that play a distinct role in higher plants. Irrespective of their diverse structures, most AAs are biosynthesized via intramolecular oxidative coupling. The complex organization of biosynthetic pathways is constantly enlightened by new insights owing to the advancement of natural product chemistry, synthetic organic chemistry, biochemistry, systems and synthetic biology tools and applications. These promote novel compound identification, trace-level metabolite quantification, synthesis, and characterization of enzymes engaged in AA catalysis, enabling the recognition of biosynthetic pathways. A complete understanding of the pathway benefits biotechnological applications in the long run. This review emphasizes the structural diversity of the AA specialized metabolites involved in biogenesis although the process is not entirely defined yet. Moreover, this work underscores the pivotal role of synthetic and enantioselective studies in justifying biosynthetic conclusions. Their prospective candidacy as lead constituents for antiviral drug discovery has also been established. However, a complete understanding of the pathway requires further interdisciplinary efforts in which antiviral studies address the structure-activity relationship. This review presents current knowledge on the topic.

Interplay between Amaryllidaceae alkaloids, the bacteriome and phytopathogens in Lycoris radiata.

Alkaloids are a large group of plant secondary metabolites with various structures and activities. It is important to understand their functions in the interplay between plants and the beneficial and pathogenic microbiota. Amaryllidaceae alkaloids (AAs) are unique secondary metabolites in Amaryllidaceae plants. Here, we studied the interplay between AAs and the bacteriome in Lycoris radiata, a traditional Chinese medicinal plant containing high amounts of AAs. The relationship between AAs and bacterial composition in different tissues of L. radiata was studied. In vitro experiments revealed that AAs have varying levels of antimicrobial activity against endophytic bacteria and pathogenic fungi, indicating the importance of AA synthesis in maintaining a balance between plants and beneficial/pathogenic microbiota. Using bacterial synthetic communities with different compositions, we observed a positive feedback loop between bacteria insensitive to AAs and their ability to increase accumulation of AAs in L. radiata, especially in leaves. This may allow insensitive bacteria to outcompete sensitive ones for plant resources. Moreover, the accumulation of AAs enhanced by insensitive bacteria could benefit plants when challenged with fungal pathogens. This study highlights the functions of alkaloids in plant-microbe interactions, opening new avenues for designing plant microbiomes that could contribute to sustainable agriculture.

Amaryllidaceae alkaloids from the bulbs of Crinum latifolium L. and their cholinesterase inhibitory activities.

Eleven previously undescribed Amaryllidaceae alkaloids, crinalatifolines A-K (1-11), and two first naturally occurring alkaloids, dihydroambelline (12) and N-demethyldihydrogalanthamine (13), were isolated from the bulbs of Crinum latifolium L. Additionally, thirty-seven known alkaloids and one alkaloid artifact were also isolated from this plant species. Their structures and absolute configurations were elucidated using extensive spectroscopic techniques, including IR, NMR, MS, and ECD. Evaluations of the cholinesterase inhibitory activities of most of these compounds were conducted. Among the tested compounds, ungeremine exhibited the highest potency against acetylcholinesterase and butyrylcholinesterase, with the IC50 values of 0.10 and 1.21 µM, respectively. These values were 9.4- and 2.4-fold more potent than the reference drug galanthamine.

Advances on the Amaryllidacea Alkaloids Collected in South Africa, Andean South America and the Mediterranean Basin.

The alkaloids are one of the most represented family of natural occurring biological active compounds. Amaryllidaceae are also very well known for their beautiful flower and are thus used as ornamental plants in historic and public gardens. The Amaryllidacea alkaloids constitute an important group that is subdivided into different subfamilies with different carbon skeletons. They are well known from ancient times for their long application in folk medicine, and in particular, Narcissus poeticus L. was known to Hippocrates of Cos (ca. B.C. 460-370), who treated uterine tumors with a formulate prepared from narcissus oil. To date, more than 600 alkaloids of 15 chemical groups exhibiting various biological activities have been isolated from the Amaryllidaceae plants. This plant genus is diffused in regions of Southern Africa, Andean South America and the Mediterranean basin. Thus, this review describes the chemical and biological activity of the alkaloids collected in these regions in the last two decades as weel those of isocarbostyls isolated from Amaryllidaceae in the same regions and same period.

Anti-SARS-CoV-2 Activity and Cytotoxicity of Amaryllidaceae Alkaloids from Hymenocallis littoralis.

The Amaryllidaceae species are well-known as a rich source of bioactive compounds in nature. Although Hymenocallis littoralis has been studied for decades, its polar components were rarely explored. The current phytochemical investigation of Amaryllidaceae alkaloids from H. littoralis led to the identification of three previously undescribed compounds: O-demethyl-norlycoramine (1), (-)-2-epi-pseudolycorine (2) and (+)-2-epi-pseudolycorine (3), together with eight known compounds: 6α-hydroxyhippeastidine (4), 6ß-hydroxyhippeastidine (5), lycorine (6), 2-epi-lycorine (7), zephyranthine (8), ungeremine (9), pancratistatin (10) and 9-O-demethyl-7-O-methyllycorenine (11). Among the eight previously reported compounds, five were isolated from H. littoralis for the first time (compounds 4, 5, 7, 8, and 9). Compounds 1, 4, 5, 7, 8, and 11 exhibited weak anti-SARS-CoV-2 activity (EC50 = 40-77 µM) at non-cytotoxic concentrations. Assessment of cytotoxicity on the Vero-E6 cell line revealed lycorine and pancratistatin as cytotoxic substances with CC50 values of 1.2 µM and 0.13 µM, respectively. The preliminary structure-activity relationship for the lycorine-type alkaloids in this study was further investigated, and as a result ring C appears to play a crucial role in their anti-SARS-CoV-2 activity.

Gas chromatography-mass spectrometry of some homolycorine-type Amaryllidaceae alkaloids.

RATIONALE: Gas chromatography-mass spectrometry (GC-MS) is the most frequently applied technique for analyzing Amaryllidaceae alkaloids in plant extracts. Having these compounds, known for their potent bioactivities, is a distinctive chemotaxonomic feature of the Amaryllidoideae subfamily (Amaryllidaceae). The Amaryllidaceae alkaloids of homolycorine type with a C3-C4 double bond generally show molecular and diagnostic ions at the high-mass region with low intensity in the EIMS mode, leading to problematic identification in complex plant extracts. METHODS: Eleven standard homolycorine-type alkaloids (isolated and identified by 1D and 2D nuclear magnetic resonance) were subjected to separation with GC and studied with electron impact mass spectrometry (EIMS) including single quadrupole (GC-EIMS), tandem (GC-EIMS/MS), and high-resolution (GC-HR-EIMS) detectors, as well as with chemical ionization mass spectrometry (GC-CIMS). Alkaloid fractions from two Hippeastrum species and Clivia miniata were subjected to GC-EIMS and GC-CIMS for alkaloid identification. RESULTS: GC-EIMS in combination with GC-CIMS provided significant structural information of homolycorine-type alkaloids with C3-C4 double bond, facilitating their unambiguous identification. Based on the obtained typical fragmentation, other 11 homolycorine-type compounds were identified in extracts from two Hippeastrum species by parallel GC-EIMS, GC-CIMS, and liquid chromatography-electrospray ionization time-of-flight mass spectrometry and in extracts from C. miniata by GC-EIMS. CONCLUSIONS: GC-MS can be successfully applied for the identification of new and known homolycorine-type alkaloids, among others within the Amaryllidoideae subfamily, as well as for chemotaxonomical and chemoecological studies.

Narciclasine suppresses oral cancer metastasis by modulating cathepsin B and extracellular signal-related kinase pathways.

Oral cancer is a malignancy with unfavorable prognosis due to its high rates of recurrence and lymph node metastasis. Narciclasine is extracted from Narcissus species (Amaryllidaceae), which have antitumor and anti-inflammatory properties. However, the antitumor properties of narciclasine toward oral cancer remain unclear. The present study explored the antimetastatic effects of narciclasine in oral cancer as well as the underlying molecular mechanisms. We treated three oral cancer cell lines with noncytotoxic concentrations of narciclasine and discovered a dose-dependent antimetastatic effect. Mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), were regulated by narciclasine. We further discovered the ERK pathway to directly affect narciclasine-induced metastasis inhibition by combining treatment with narciclasine and ERK inhibitor. Furthermore, downregulation of cathepsin B (CTSB) in the SAS and SCC-47 cell lines revealed the critical role of CTSB in the antimetastatic effect of narciclasine. Our findings indicate that narciclasine inhibits oral cancer metastasis by regulating the ERK pathway and CTSB. This study provides evidence of the mechanism of narciclasine-induced inhibition oral cancer metastasis and suggests potential targets for use in oral cancer treatment.

Structurally diverse alkaloids with nine frameworks from Zephyranthes candida and their acetylcholinesterase inhibitory and anti-inflammatory activities.

Twenty-six structurally diverse Amaryllidaceae alkaloids, including ten undescribed compounds named zephyranines A-I and 6-O-ethylnerinine, two undescribed natural products zephyranthine-6-one and 3-O-deacetyl-sternbergine, were isolated from whole plants of Zephyranthes candida. Their structures were determined by HRESIMS, 1D and 2D NMR, CD data analysis, NMR and ECD calculations, and single-crystal X-ray diffraction analysis. All structures were classified into nine framework types: 10b,11-seco-crinine, graciline, crinine, homolycorine, trisphaeridine, lycorine, galasine, tazettine, and belladine. Zephyranine A represents the first naturally occurring 10b,11-seco-crinine type alkaloid, and zephyranine B is the sixth graciline type alkaloid. 6-O-ethylnerinine is an artifact from the extraction and isolation. All isolates were evaluated for their acetylcholinesterase (AChE) inhibitory and anti-inflammatory activities. Zephyranines A, G, and H exhibited moderate AChE inhibitory activities, with IC50 values of 8.2, 39.0, and 10.8 µM, respectively. Zephyranine B, haemanthamine, haemanthidine, 11-hydroxyvittatine, and 8-demethoxy-10-O-methylhostasine exhibited potent anti-inflammatory activity on the LPS-induced NO production in RAW264.7 mouse macrophages with IC50 values of 21.3, 4.6, 12.2, 5.6, and 17.4 µM, respectively. Structure-activity-relationship analysis and docking studies indicated that interactions with the key Trp286 and Tyr337 residues are required for potent AChE inhibitors.

Antiviral alkaloid principles of the plant family Amaryllidaceae.

BACKGROUND: Viral-borne diseases are amongst the oldest diseases known to mankind. They are responsible for some of the most ravaging effects wrought on human health and well-being. The use of plants against these ailments is entrenched in both traditional and secular medicine around the globe. Their natural abundance and chemical diversity have also boosted their appeal in drug discovery. AIM: The plant family Amaryllidaceae is distinguished for its alkaloid principles, some of which are of considerable interest in the clinical arena. This account is the outcome of a literature review undertaken to establish the applicability of these substances as antiviral agents. METHODS: The survey utilized the search engines Google Scholar, PubMed, SciFinder, Scopus and Web of Science engaging the word 'antiviral' in conjunction with 'Amaryllidaceae' and 'Amaryllidaceae alkaloid'. The search returned over five hundred hits, of which around eighty were of relevance to the theme of the text. RESULTS: Over eighty isoquinoline alkaloids have been screened against nearly fifty pathogens from fourteen viral families, the majority of which were RNA viruses. Potent activities were reported in some instances, such as that of trans-dihydronarciclasine against Yellow fever virus (IC50 0.003 µg/ml), with minimal effects being manifested on host cells. There were also promising results obtained from in vivo studies, in most cases without lethal effects on test subjects. Structure-activity relationship studies afforded useful insight to the antiviral pharmacophore, with the phenanthridone alkaloid nucleus shown to be the most enabling. Although the mechanistic basis to these activities pertained mostly to inhibition of DNA, RNA and protein synthesis, evidence was also forthcoming about the inhibitory action of some of the alkaloids against viral neuraminidase, protease and reverse transcriptase. In silico methods of analysis have offered further perspectives of how some of the alkaloids interact at the active sites of their targets. CONCLUSION: The Amaryllidaceae offers a viable platform for plant-based antiviral drug discovery. Its cause is strengthened not only by its wide proliferation and exploitation of its members in alternative forms of medicine, but also by its rich chemical diversity which has already spawned useful antiviral drug leads.

Chemical Principles of Boophone, Nerine, Crossyne, Clivia, Cryptostephanus, Haemanthus and Scadoxus of the South African Amaryllidaceae and Their Biological Properties.

The Amaryllidaceae features prominently amongst bulbous flowering plant families. Accommodating about a third of its species, South Africa affords a sound basis for Amaryllidaceae plant research. Boophone, Nerine, Crossyne, Clivia, Cryptostephanus, Haemanthus and Scadoxus have been well-represented in such endeavors. The account herein summarizes the studies undertaken between 2013 - 2020 on these genera in regards to their chemical and biological characteristics. A total of 136 compounds comprising 63 alkaloids and 73 non-alkaloid entities were described during this period from eighteen members of the title genera. The alkaloids were reflective of the structural diversity found in eight isoquinoline alkaloid groups of the Amaryllidaceae. Of these, the crinane (29 compounds), lycorane and homolycorine (11 compounds each) groups were the most-represented. The non-alkaloid substances were embracive of the same number of unrelated groups including, acids, phenolics, flavonoids and triterpenoids. A wide variety of assays were engaged to ascertain the biological activities of the isolated compounds, notably in regards to cancer and motorneuron-related diseases. There were also attempts made to determine the antimicrobial, anti-inflammatory and antioxidant effects of some of the substances. New information has also emerged on the herbicidal, insecticidal and plant growth regulatory effects of selected alkaloid principles. Coupled to the biological screening measures were in instances probes made to establish the molecular basis to some of the activities, particularly in relation to cancer and Parkinson's disease.

Chemical Synthesis and Biological Activities of Amaryllidaceae Alkaloid Norbelladine Derivatives and Precursors.

Amaryllidaceae alkaloids (AAs) are a structurally diverse family of alkaloids recognized for their many therapeutic properties, such as antiviral, anti-cholinesterase, and anticancer properties. Norbelladine and its derivatives, whose biological properties are poorly studied, are key intermediates required for the biosynthesis of all ~650 reported AAs. To gain insight into their therapeutic potential, we synthesized a series of O-methylated norbelladine-type alkaloids and evaluated their cytotoxic effects on two types of cancer cell lines, their antiviral effects against the dengue virus (DENV) and the human immunodeficiency virus 1 (HIV-1), and their anti-Alzheimer's disease (anti-cholinesterase and -prolyl oligopeptidase) properties. In monocytic leukemia cells, norcraugsodine was highly cytotoxic (CC50 = 27.0 µM), while norbelladine was the most cytotoxic to hepatocarcinoma cells (CC50 = 72.6 µM). HIV-1 infection was impaired only at cytotoxic concentrations of the compounds. The 3,4-dihydroxybenzaldehyde (selectivity index (SI) = 7.2), 3',4'-O-dimethylnorbelladine (SI = 4.8), 4'-O-methylnorbelladine (SI > 4.9), 3'-O-methylnorbelladine (SI > 4.5), and norcraugsodine (SI = 3.2) reduced the number of DENV-infected cells with EC50 values ranging from 24.1 to 44.9 µM. The O-methylation of norcraugsodine abolished its anti-DENV potential. Norbelladine and its O-methylated forms also displayed butyrylcholinesterase-inhibition properties (IC50 values ranging from 26.1 to 91.6 µM). Altogether, the results provided hints of the structure−activity relationship of norbelladine-type alkaloids, which is important knowledge for the development of new inhibitors of DENV and butyrylcholinesterase.

Progress towards the Total Syntheses of Amaryllidaceae Alkaloids γ-Lycorane.

γ-Lycorane, a degradation product of the Aromaticaceae alkaloid lycorine, is one of the most attractive molecules in the Aromaticaceae family. It remains a popular target for synthesis due to its pentacyclic structure, which presents a vehicle for demonstrating the utility of new synthetic strategies. Various synthetic methods have been developed by synthetic chemists since the first synthesis of γ-lycorane by Nasuo in 1966. Thus, this review presents an overview of the literature on the ways utilized within the synthesis of γ-lycorane in racemic and enantiopure forms via electrophilic arylation, Pd-catalyzed C-C coupling, Bischler-Napieralski cyclization, Pictet-Spengler cyclization, photocyclization, radical cyclization, chiral pool synthesis, chiral auxiliary-mediated synthesis, and catalytic asymmetric synthesis, ranging from 1966 to 2022.

The Phytochemistry and Pharmacology of Tulbaghia, Allium, Crinum and Cyrtanthus: 'Talented' Taxa from the Amaryllidaceae.

Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer's disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates. Given the reciprocal relationship of the increasing burden of human diseases and limited availability of medicinal therapies, more rapid drug discovery and development are desirable. To expedite clinically relevant drug development, we present here evidence on bioactive compounds from the genera Allium, Tulgbaghia, Cyrtanthus and Crinum and describe their traditional and pharmacological applications.

Conversion of Natural Narciclasine to Its C-1 and C-6 Derivatives and Their Antitumor Activity Evaluation: Some Unusual Chemistry of Narciclasine.

During the search for a general, efficient route toward the synthesis of C-1 analogues of narciclasine, natural narciclasine was protected and converted to its C-1 enol derivative using a novel semi-synthetic route. Attempted conversion of this material to its triflate in order to conduct cross-coupling at C-1 resulted in a triflate at C-6 that was successfully coupled with several functionalities. Four novel compounds were fully deprotected after seven steps and subjected to evaluation for cytotoxic activity against three cancer cell lines. Only one derivative showed moderate activity compared to that of narciclasine. Spectral and physical data are provided for all new compounds.