Amaryllidaceae Alkaloids Research Articles

An overview on the chemical and biological aspects of lycorine alkaloid

Amaryllidaceae plants are currently appreciated as a plentiful source of unique bioactive alkaloids. Among them, lycorine is one of the major pyrrolophenanthridine alkaloids commonly isolated from different species of this family. Over the past years, lycorine has attracted great research interest owing to its superlative biological potential and pharmacological actions, including antitumor, antiangiogenic, antiviral, antibacterial, antimalarial, anti-parasite, antioxidant, hepatoprotective, analgesic, anti-inflammatory activities, and inhibition of ascorbic acid synthesis, among many others. Therefore, this review was undertaken to highlight the chemical, chromatographic, spectral, and biological aspects of this promising Amaryllidaceae alkaloid, together with a future perspective for its potential application in the pharmaceutical field.

Asymmetric Entry into 10b-aza-Analogues of Amaryllidaceae Alkaloids Reveals a Pronounced Electronic Effect on Antiviral Activity.

Development of a chiral pool-based synthesis of 10b-aza-analogues of biologically active Amaryllidaceae alkaloids is described, involving a concise reductive amination and condensation sequence, leading to ring-B/C-modified, fully functionalized ring-C derivatives. Differentiated anticancer and antiviral activities of these analogues are presented. Despite complete conformational and functional group overlap, the 10b-aza-analogues have diminished anticancer activity and no antiviral activity. These unprecedented electronic effects suggest a possible role for π-type secondary orbital interactions with the biological target.

Antioxidant, anti-diabetic, acetylcholinesterase inhibitory potential and estimation of alkaloids (lycorine and galanthamine) from Crinum species: An important source of anticancer and anti-Alzheimer drug

Crinum L. (Amaryllidaceae J.St. Hil.) is a bulbous monocot well known for its ornamental value and medicinal properties. Aqueous and methanolic leaf extracts of twelve Crinum genotypes were evaluated for their phytochemicals, antioxidants, in vitro anti-diabetic and acetyl cholinesterase (AChE) inhibitory activities. Maximum total phenolic content (TPC) (86.18 ± 0.61 mg TAE g−1 extract) was exhibited by C. asiaticum form 2 whereas maximum total alkaloid content (TAC) (10.81 ± 0.22 mg CoE g−1 extract), total flavonoid content (TFC) (145.06 ± 3.95 mg CE g−1 extract) and TTC (436.55 ± 3.70 mg CE g−1 extract) content were recorded for C. x powelii. The antioxidant activities were determined by 2, 2′-azinobis 3-ethylbenzthiazoline]-6-sulfonic acid (ABTS), 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP) and phosphomolybdenum assays. Methanol extract of C. asiaticum form 2 had the highest FRAP (462.81 ± 1.98 mg Fe II g−1 extract), phosphomolybdenum (116.03 ± 3.80 mg AAE g−1 extract) and DPPH radical scavenging activities (111.54 ± 2.03 mg TE g−1 extract). ABTS radical scavenging activity was greatest in aqueous extract of C. latifolium (39.65 ± 0.91 mg TE g−1 extract). RP-HPLC analysis revealed the highest phenolics in C. asiaticum form 1. Amaryllidaceae alkaloids, galanthamine (GAL) and lycorine (LY) were recorded the highest in C. latifolium (721.3 ± 4.96 μg g−1 dry weight and C. solapurense (3717.0 ± 9.40 μg g−1 DW), respectively. C. jagus revealed the highest inhibition of α-amylase (60.30%) and α-glucosidase (94.04%). AChE inhibition was maximum (76.52%) in the methanol extract of C. latifolium. This study constitutes the first comparative account of antioxidants, phenolic profiling, anti-diabetic potential and simultaneous quantification of anti-Alzheimer and anticancer drugs, viz. GAL and LY, respectively from Crinum genotypes.

Amaryllidaceae alkaloids from Crinum latifolium with cytotoxic, antimicrobial, antioxidant, and anti-inflammatory activities

Four novel and potently bioactive Amaryllidaceae alkaloids, 4,8-dimethoxy-cripowellin C (1), 4,8-dimethoxy-cripowellin D (2), 9-methoxy-cripowellin B (3), and 4-methoxy-8-hydroxy-cripowellin B (4), together with one known alkaloid, cripowellin C (5) were isolated from the 95% EtOH extract of the bulbs of Crinum latifolium. Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR as well as spectroscopy high resolution mass spectrometry. All isolates were in vitro evaluated for their cytotoxic activity against seven lung cancer cell lines, in addition to antimicrobial activity for eight bacteria, scavenging potential using ABTS·+ and DPPH test, and anti-inflammatory activity for Cox-1 and Cox-2 which had not previously been tested for crinane-type alkaloids with the cleavage between C-1 and C-13. Consequently, alkaloids 1–5 exhibited potent cytotoxicity against all of seven tested tumor cell lines with (IC50 < 30 nM). Alkaloids 3 and 4 displayed the significant antimicrobial activity with IC50 values <0.50 mM and antioxidant activity in the ABTS·+ and DPPH test. Additionally, Alkaloids 1–5 exhibited comparable inhibition of Cox-1 (>64%) and Cox-2 (>90%) with positive control.

Exploiting the Catalytic Diversity of Short-Chain Dehydrogenases/Reductases: Versatile Enzymes from Plants with Extended Imine Substrate Scope.

Numerous short-chain dehydrogenases/reductases (SDRs) have found biocatalytic applications in C=O and C=C (enone) reduction. For NADPH-dependent C=N reduction, imine reductases (IREDs) have primarily been investigated for extension of the substrate range. Here, we show that SDRs are also suitable for a broad range of imine reductions. The SDR noroxomaritidine reductase (NR) is involved in Amaryllidaceae alkaloid biosynthesis, serving as an enone reductase. We have characterized NR by using a set of typical imine substrates and established that the enzyme is active with all four tested imine compounds (up to 99 % conversion, up to 92 % ee). Remarkably, NR reduced two keto compounds as well, thus highlighting this enzyme family's versatility. Using NR as a template, we have identified an as yet unexplored SDR from the Amaryllidacea Zephyranthes treatiae with imine-reducing activity (≤95 % ee). Our results encourage the future characterization of SDR family members as a means of discovering new imine-reducing enzymes.

Catalytic Asymmetric Total Syntheses of Naturally Occurring Amarylidaceae Alkaloids, (-)-Crinine, (-)- epi-Crinine, (-)-Oxocrinine, (+)- epi-Elwesine, (+)-Vittatine, and (+)- epi-Vittatine.

An expeditious approach to catalytic enantioselective total syntheses of crinine-type Amaryllidaceae alkaloids has been accomplished via a Pd-catalyzed enantioselective decarboxylative allylation of allylenol carbonates as a key step (up to 96% ee). Using this strategy, collective total syntheses of Amaryllidaceae alkaloids such as (-)- epi-elwesine (1b), (-)-crinine (1c), (-)- epi-crinine (1e), (-)-oxocrinine (1f), and (-)-buphanisine (1d) have been accomplished. Gratifyingly, naturally occurring Amaryllidaceae alkaloids such as (+)-vittatine (1g), (+)- epi-vittatine (1h), and (+)- epi-elwesine (1i) [enantiomers of (-)-1c, (-)-1e, and (-)-1b, respectively] have also been achieved by switching the antipode of ligand used in the catalytic enantioselective step.

Diversity-Oriented Approach Toward the Syntheses of Amaryllidaceae Alkaloids via a Common Chiral Synthon.

Functionalized hydroindole (1), a common chiral synthon, for versatile transformations to synthesize a broad range of Amaryllidaceae alkaloids (AAs) including (-)-crinine, (-)-crinane, (-)-amabiline, (+)-mesembrine, (-)-maritidine, (-)-oxomaritidine, and (+)-mesembrane is reported. Scaffold 1 is found as a prime structural motif in a wide variety of the AAs and is a novel synthon toward designing a divergent route for the synthesis of these natural products. This is established in a few steps, starting from a chiral aza-bicyclo-heptene sulfone scaffold (2) via conjugate addition and concomitant stereoselective ring opening with allylmagnesium bromide, a key step that generates a crucial quaternary stereocenter, fixing the stereochemistry of the rest of the molecule at an early stage. One carbon truncation followed by intramolecular reductive amination led to the desired core 1 in a multigram scale.

Aphicidal activities of Amaryllidaceae alkaloids from bulbs of Lycoris radiata against Aphis citricola

Aphids are one of the most destructive and economically important pests of plants on earth, causing severe financial losses worldwide. The extensive and unscientific use of insecticides has resulted in a universal zooming insecticide resistance among aphids across regions and substantial detrimental influences on the environment. This study investigates the insecticidal activity of alkaloids from L. radiata against A. citricola. The crude extract of Lycoris radiate showed a remarkable aphicidal activity against A. citricola. Ten known amaryllidaceous alkaloids were obtained according to the bioassay-guided isolation. The structures of these known alkaloids were identified as amabiline (1), deoxydihydrotazettine (2), deoxytazettine (3), 3-epimacronine (4), galanthamine (5), 11-hydroxygalanthamine (6), N-allylnorgalanthamine (7), 11β-hydroxygalanthamine (8), lycorine (9) and colchicine (10). The results of aphicidal bioassay against A. citricola showed that compounds 1-9 exhibited considerable aphicidal activity with LD50 values of 67.44, 76.33, 78.30, 96.70, 17.47, 32.60, 4.92, 20.33, 70.41 ng/aphid. N-Allylnorgalanthamine (7) possessed the highest aphicial activity, which was comparable with the commercial pesticide methomyl (2.91 ng/aphid). The results of in vivo AChE assay revealed that N-allylnorgalanthamine showed an obvious inhibitory effect on AChE in A. citricola in a time- and dose-dependent manner. The in vitro inhibition of AChE activity by N-allylnorgalanthamine was remarkable with an IC50 value of 2.1 × 10−8 M, which was 104 times stronger than the positive control methomyl with an IC50 value of 4.2 × 10–4 M. Meanwhile, N-allylnorgalanthamine can lead to an increase of the activities of SOD and CAT. The present work comprises the first report on insecticidal action of Amaryllidaceae alkaloids. N-Allylnorgalanthamine displayed a significant inhibition on AChE in Aphis citricola both in vivo and vitro. The insecticidal L. radiata extracts can be possibly used for controlling pests and isolated compounds, designing for new pesticides, can be the promising temples.

Green techniques in comparison to conventional ones in the extraction of Amaryllidaceae alkaloids: Best solvents selection and parameters optimization

An undisputed trend in sample preparation at present is to meet the requirements of green chemistry especially in the field of natural products. Green technology continuously pursues new solvents to replace common organic solvents that possess inherent toxicity. Over the past two decades, non-ionic surfactants have gained enormous attention from the scientific community. The micelle-mediated extraction and cloud-point preconcentration (CPE) methods offer a convenient alternative to the conventional extraction systems. Recently, natural deep eutectic solvents (NDESs) have emerged as green and sustainable solvents for efficient extraction of bioactive compounds or drugs. They are generally composed of neutral, acidic or basic compounds that form liquids of high viscosity when mixed in certain molar ratio. The presented work aimed to comprehensively compare and evaluate the potential and effectiveness of NDES as well as non-ionic surfactants (Genapol X-080, Triton X-100 and Triton X-114) for extraction of Amaryllidaceae alkaloids from Crinum powellii bulbs as representative example of plant material, in comparison to the conventional solvents (methanol, ethanol and water).A new validated high-performance thin-layer chromatographic (HPTLC) method has been developed for the simultaneous quantitation of three alkaloids markers, lycorine, crinine and crinamine, in the bulbs of C. powellii. Extraction efficiency of the targeted alkaloids from the bulb matrix with organic and ecofriendly (green) solvents were studied. Results revealed that NDES and surfactants were significantly more efficient in alkaloid extraction than previous methods requiring the consumption of organic solvents and water. Genapol X-80 demonstrated 138%, 149% and 145%, while choline chloride: fructose (5:2): H2O (35%) NDES mixture demonstrated 243%, 225% and 238% of the total alkaloidal extraction capacity of ethanol, methanol and water, respectively at 50 °C for extraction time 1 h using ultrasonication for all experiments. Furthermore, Box–Behnken response surface design combined with the overall desirability value were successfully employed to optimize and study the individual and interactive effect of process variables such as extraction temperature, time and surfactant %, for Genapol X-80, and sonication extraction temperature, time and water concentration, for choline chloride: fructose: H2O NDES mixture, on the alkaloidal yield from C. powellii. It was evident that parameters interacting together can act in synergism if adjusted properly according to the optimized conditions to obtain maximum alkaloids extractability. It is for the first time that the efficiency of micelle-mediated extraction has been compared to that of natural deep eutectic solvents for the extraction of alkaloids and the results thoroughly discussed.

Molecular Cloning and Characterization of a meta/para-O-Methyltransferase from Lycoris aurea.

O-methyltransferases (OMTs) have been demonstrated to play key roles in the biosynthesis of plant secondary metabolites, such as alkaloids, isoprenoids, and phenolic compounds. Here, we isolated and characterized an OMT gene from Lycoris aurea (namely LaOMT1), based on our previous transcriptome sequencing data. Sequence alignment and phylogenetic analysis showed that LaOMT1 belongs to the class I OMT, and shares high identity to other known plant OMTs. Also, LaOMT1 is highly identical in its amino acid sequence to NpN4OMT, a norbelladine 4′-OMT from Narcissus sp. aff. pseudonarcissus involved in the biosynthesis of Amaryllidaceae alkaloids. Biochemical analysis indicated that the recombinant LaOMT1 displayed both para and meta O-methylation activities with caffeic acid and 3,4-dihydroxybenzaldehyde, and showed a strong preference for the meta position. Besides, LaOMT1 also catalyzes the O-methylation of norbelladine to form 4′-O-methylnorbelladine, which has been demonstrated to be a universal precursor of all the primary Amaryllidaceae alkaloid skeletons. The results from quantitative real-time PCR assay indicated that LaOMT1 was ubiquitously expressed in different tissues of L. aurea, and its highest expression level was observed in the ovary. Meanwhile, the largest concentration of lycorine and galanthamine were found in the ovary, whereas the highest level of narciclasine was observed in the bulb. In addition, sodium chloride (NaCl), cold, polyethylene glycol (PEG), sodium nitroprusside (SNP), and methyl jasmonate (MeJA) treatments could significantly increase LaOMT1 transcripts, while abscisic acid (ABA) treatment dramatically decreased the expression level of LaOMT1. Subcellular localization showed that LaOMT1 is mainly localized in cytoplasm and endosome. Our results in this study indicate that LaOMT1 may play a multifunctional role, and lay the foundation for Amaryllidaceae alkaloid biosynthesis in L. aurea.

Enantioselective Synthesis of All-Carbon Quaternary Centers Structurally Related to Amaryllidaceae Alkaloids.

Enantioselective synthesis of all-carbon quaternary centers remains a considerable challenge for synthetic organic chemists. Here, we report a two-step protocol to synthesize such centers including tandem cyclization/Suzuki cross-coupling followed by halocarbocyclization. During this process, two rings, three new C-C bonds and a stereochemically defined all-carbon quaternary center are formed. The absolute configuration of this center is controlled by the stereochemistry of the adjacent stereocenter, which derives from an appropriate enantioenriched starting material. Using this method, we synthesized polycyclic compounds structurally similar to Amaryllidaceae alkaloids in high enantiomeric excesses. Because these products resemble naturally occurring compounds, our protocol can be used to synthesize various potentially bioactive compounds.

Functional characterization of phenylalanine ammonia-lyase- and cinnamate 4-hydroxylase-encoding genes from Lycoris radiata, a galanthamine-producing plant

Galanthamine (GAL), the well-known Amaryllidaceae alkaloid, is a clinically used drug for the treatment of Alzheimer's disease. L-Phenylalanine (Phe) and trans-cinnamic acid (CA) were enzymatically transformed into the catechol portion of GAL. Herein, a Phe ammonia-lyase-encoding gene LrPAL3 and a cinnamate 4-hydroxylase-encoding gene LrC4H were cloned from Lycoris radiata, a GAL-producing plant. LrPAL3 was overexpressed in Escherichia coli and purified to homogeneity. LrPAL3 catalyzes the forward deamination conversion of L-Phe into trans-CA. The 3-chloro- and 4-fluoro-L-Phe were deaminated to generate the corresponding 3-chloro- and 4-fluoro-trans-CA by LrPAL3. LrPAL3-catalyzed reverse hydroamination was confirmed by the conversion of trans-CA into L-Phe with exceptional regio- and stereo-selectivity. LrC4H was overexpressed in E. coli with tCamCPR, a cytochrome P450 reductase-encoding gene. LrC4H catalyzes the regioselective para-hydroxylation on trans-CA to form p-coumaric acid. The transcriptional levels of both LrPAL3 and LrC4H were positively associated with the GAL contents within the leaves and flowers of L. radiata, which suggested that their expression and function are co-regulated and involved in the biosynthesis of GAL. The present investigations on the biosynthetic genes of GAL will promote the development of synthetic biology platforms for this kind of important drug via metabolic engineering.

Caspase-inducing effects of lycorane and crinane alkaloids of the Amaryllidaceae

Cancer is a leading cause of death worldwide. This, in spite of the tremendous gains made in cancer chemotherapies over the past several decades. The identification and development of new targets with greater structural diversities and better potencies are at the forefront of drug discovery endeavors across disciplines. Plants have afforded a significant number of successful anticancer drugs, several of which manifest their activities by inducing apoptosis (or programmed cell death) in cancer cells. The Amaryllidaceae alkaloids have similarly distinguished themselves as potent antiproliferative agents, some at the nanomolar level, with selective apoptosis inducing effects demonstrated in a wide variety of cancer cells. The proteolytic enzymes caspases are the key effectors of the apoptotic pathways, the main function of which is, in turn, the activation of caspases. Once activated caspases set in motion an intricately choreographed cascade of events leading to eventual cell death and phagocytosis. The lycorane and crinane group of alkaloids were amongst the first of the Amaryllidaceae for which apoptosis and attendant caspase inducing effects were discovered. These have been central in ongoing efforts to unravel the mechanistic basis to the cytotoxicity of these alkaloids. This review focuses on the various caspases which have been shown to be integral in apoptosis signaling pathways mediated by lycorane and crinane alkaloids.

N-oxide alkaloids from Crinum amabile (Amaryllidaceae).

Natural products play an important role in the development of new drugs. In this context, the Amaryllidaceae alkaloids have attracted considerable attention in view of their unique structural features and various biological activities. In this study, twenty-three alkaloids were identified from Crinum amabile by GC-MS and two new structures (augustine N-oxide and buphanisine N-oxide) were structurally elucidated by NMR. Anti-parasitic and cholinesterase (AChE and BuChE) inhibitory activities of six alkaloids isolated from this species, including the two new compounds, are described herein. None of the alkaloids isolated from C. amabile gave better results than the reference drugs, so it was possible to conclude that the N-oxide group does not increase their therapeutic potential.

Total Synthesis of (±)-Crinane from 6,6-Dibromobicyclo[3.1.0]hexane Using a 5- exo- trig Radical Cyclization Reaction to Assemble the C3a-Arylated Perhydroindole Substructure.

Crinane embodies the tetracyclic framework associated with some of the most common Amaryllidaceae alkaloids. It has now been prepared in 10 steps from 6,6-dibromobicyclo[3.1.0]hexane (2). The initial step involves the thermally induced electrocyclic ring opening of cyclopropane 3 and capture of the resulting π-allyl cation with benzylamine to give an allylic amine that is readily elaborated to the 3°-amine 10. This last compound was engaged in a 5- exo- trig free radical cyclization reaction to give the C3a-arylated perhydroindole 11. Compound 11 was then converted, over two steps, into (±)-crinane, the hydrochloride salt of which has been subjected to single-crystal X-ray analysis.

Anti-TMV Effects of Amaryllidaceae Alkaloids Isolated from the Bulbs of\xa0Lycoris radiata and Lycoricidine Derivatives

Fifteen known amaryllidaceae alkaloids were isolated from the bulbs of Lycoris radiata. Some of the compounds and lycoricidine derivatives had been screened for the activities against tobacco mosaic virus (TMV) by the conventional half-leaf method. Lycoricidine derivatives were also carried out the assay of effect on systemic infection of TMV by western-blot and RT-PCR analysis. The tested compounds showed moderate inactivation effect, whereas the lycoricidine derivatives showed good protective effect. The protective inhibitory activity of compounds L1 (N-methyl-2,3,4-trimethoxylycoricidine) (60.8%) and L3 (N-methyl-2-methoxy-3,4-acetonidelycoricidine) (62.0%) was almost similar to the positive control, Ningnanmycin (66.4%). RT-PCR and Western-blot analysis displayed that compounds L1, L3, L5 (N-allyl-2,3,4-triallyloxylycoricidine) exhibited antiviral activity, which was evidenced by reducing TMV-CP gene replication and TMV-CP protein expression. Additionally, defensive enzyme activities confirmed that compound L1 could increase the activity of PAL, POD, SOD to improve disease resistance of tobacco.Graphical

Amaryllidaceae alkaloids as agents with protective effects against oxidative neural cell injury

AimsDetermine a relationship between the neuroprotective activity and the antioxidant capacity of the Amaryllidaceae alkaloids in a model of Glu excitotoxicity in rat cortical neurons. Materials and methodsWas evaluated several alkaloidal fractions isolated from Amaryllidaceae species, a family known to contain neuroprotective alkaloids, in a model of Glu excitotoxicity in rat cortical neurons. In addition, several mechanisms of antioxidant activity were used, and a theoretical study of the antioxidants was performed. Key findingsThe results of this study suggest that a possible neuroprotective mode of action of the alkaloidal fractions of Eucharis bonplandii (Kunth) Traub bulbs, Eucharis caucana Meerow bulbs, and Clivia miniata Regel leaves, is through their antioxidant activity and ability to stabilize free radicals generated from an excitotoxic process mediated by Glu. The chemical structure characterization and antioxidant activity of the fractions suggest that the phenol and enol groups in the structures of the alkaloids are critical for the stabilization of ROS and RNS. Additionally, the pair of free electrons on the N is spatially close to a hydroxyl group, which benefits the cleavage of this group and, consequently, the stabilization of the generated O. SignificanceThe versatility of the structures of the studied Amaryllidaceae alkaloids suggests that they have potential as neuroprotective agents against an oxidative stimulus.

Daffodils as Potential Crops of Biologically-active Compounds: Assessment of 40 Ornamental Taxa for their Alkaloid Profile and Cholinesterases Inhibition Activity

Many varieties of Narcissus (Amaryllidaceae) are planted on a large scale for ornamental purposes and at the same time they represent a rich reservoir of potential small chemical molecules that display several medicinal properties. Of the Amaryllidaceae alkaloids, considerable attention has been given to galanthamine, which possesses acetylcholinesterase inhibitory activity. Recent investigation has shown the pharmaceutical potential of other Amaryllidaceae alkaloids, such as lycorine, haemanthamine, and pancratistatine, primarily as anticancer drugs. In the current study, 40 Narcissus taxa were evaluated for their alkaloid profile by GC-MS. The aim of this work was to find the most suitable Narcissus varieties for a reliable source of galanthamine, lycorine, and haemanthamine for commercial production. Based on their mass spectra, 97 typical Amaryllidaceae alkaloids were detected of which 49 were identified. The highest concentrations of pharmaceutically-interesting Amaryllidaceae alkaloids were identified in the ornamental taxa N. cv Sundisc (galanthamine), N. cv. Jenny (lycorine), and N. cv. Sealing (haemanthamine). All alkaloidal extracts were also screened for their acetylcholinesterase and butyrylcholinesterase inhibitory activities.

Amaryllidaceae Alkaloids as Potential Glycogen Synthase Kinase-3β Inhibitors.

Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine protein kinase that was originally identified as an enzyme involved in the control of glycogen metabolism. It plays a key role in diverse physiological processes including metabolism, the cell cycle, and gene expression by regulating a wide variety of well-known substances like glycogen synthase, tau-protein, and β-catenin. Recent studies have identified GSK-3β as a potential therapeutic target in Alzheimer´s disease, bipolar disorder, stroke, more than 15 types of cancer, and diabetes. GSK-3β is one of the most attractive targets for medicinal chemists in the discovery, design, and synthesis of new selective potent inhibitors. In the current study, twenty-eight Amaryllidaceae alkaloids of various structural types were studied for their potency to inhibit GSK-3β. Promising results have been demonstrated by alkaloids of the homolycorine-{9-O-demethylhomolycorine (IC50 = 30.00 ± 0.71 µM), masonine (IC50 = 27.81 ± 0.01 μM)}, and lycorine-types {caranine (IC50 = 30.75 ± 0.04 μM)}.

The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth

Alkaloids isolated from the Amaryllidaceae plants have potential as therapeutics for treating human diseases. Haemanthamine has been studied as a novel anticancer agent due to its ability to overcome cancer cell resistance to apoptosis. Biochemical experiments have suggested that hemanthamine targets the ribosome. However, a structural characterization of its mechanism has been missing. Here we present the 3.1Å resolution X-ray structure of haemanthamine bound to the Saccharomyces cerevisiae 80S ribosome. This structure reveals that haemanthamine targets the A-site cleft on the large ribosomal subunit rearranging rRNA to halt the elongation phase of translation. Furthermore, we provide evidence that haemanthamine and other Amaryllidaceae alkaloids also inhibit specifically ribosome biogenesis, triggering nucleolar stress response and leading to p53 stabilization in cancer cells. Together with a computer-aided interpretation of existing structure-activity relationships of Amaryllidaceae alkaloids congeners, we provide a rationale for designing molecules with enhanced potencies and reduced toxicities.