Type Alkaloids Research Articles

Clinanthus microstephium, an Amaryllidaceae Species with Cholinesterase Inhibitor Alkaloids: Structure-Activity Analysis of Haemanthamine Skeleton Derivatives.

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.

Sanguinarine induces apoptosis of human lens epithelial cells by increasing reactive oxygen species via the MAPK signaling pathway.

Posterior capsular opacification (PCO) remains a major complication of cataract surgery and is the most common reason for loss of vision. PCO is primarily associated with uncontrolled proliferation of residual human lens epithelial cells (HLEs). Sanguinarine is a type of benzophenanthridine alkaloid extracted from the herbaceous plant Sanguinaria canadensis, which is widely used for its anti-microbial, anti-inflammatory, anti-oxidative and anti-proliferative properties. However, studies examining the effect of sanguinarine on HLEs and the underlying mechanism are scarce. The present study aimed to investigate the effects of sanguinarine on HLEs. An MTT assay was used to determine the effect of sanguinarine on cell viability. Flow cytometry was used to evaluate cell apoptosis, and the mitochondrial membrane potential and reactive oxygen species (ROS) levels. A caspase 3/7 activity assay was also used to evaluate cell apoptosis, while western blotting was performed to determine protein levels. The results demonstrated that sanguinarine exerted an anti-proliferative effect by inducing ROS, and caused cell apoptosis via mitochondrial and caspase-dependent pathways. Treatment with sanguinarine led to the loss of mitochondrial membrane potential. Sanguinarine also significantly increased the phosphorylation levels of c-Jun N-terminal kinase and p38, which indicated the involvement of the mitogen-activated protein kinase signaling pathway. These results suggested that sanguinarine may have a noteworthy pro-apoptotic effect on HLEs, and may be used as a potential drug for PCO or even cataract prevention.

Punicagranine, a new pyrrolizine alkaloid with anti-inflammatory activity from the peels of Punica granatum

A novel pyrrolizine alkaloid, 5-(furan-3-carbonyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylic acid, was isolated from the peels of Punica granatum. Its structure was elucidated on the basis of 1D- and 2D-NMR and HR-ESI-MS spectra and then confirmed by X-ray diffraction. It represents a new type of natural pyrrolizine alkaloid, named, punicagranine (1). 1 showed inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells. To our knowledge, the pyrrolizine alkaloid skeleton was reported in natural products for the first time.

Metabolite Profiling of Anti-Addictive Alkaloids from Four Mexican Tabernaemontana Species and the Entheogenic African Shrub Tabernanthe iboga (Apocynaceae).

Ibogaine and other ibogan type alkaloids present anti-addictive effects against several drugs of abuse and occur in different species of the Apocynaceae family. In this work, we used gas chromatography-mass spectrometry (GC/MS) and principal component analysis (PCA) in order to compare the alkaloid profiles of the root and stem barks of four Mexican Tabernaemontana species with the root bark of the entheogenic African shrub Tabernanthe iboga. PCA demonstrated that separation between species could be attributed to quantitative differences of the major alkaloids, coronaridine, ibogamine, voacangine, and ibogaine. While T. iboga mainly presented high concentrations of ibogaine, Tabernaemontana samples either showed a predominance of voacangine and ibogaine, or coronaridine and ibogamine, respectively. The results illustrate the phytochemical proximity between both genera and confirm previous suggestions that Mexican Tabernaemontana species are viable sources of anti-addictive compounds.

12α-hydroxy-N-demethyl-sauroxine, a lycodane type alkaloid from Phlegmariurus saururus

12α-hydroxy-N-demethyl-sauroxine (1), another new Lycopodium alkaloid from the Lycodane group, was isolated from Phlegmariurus saururus (Lam.) B. Øllg. (Lycopodiaceae). Elucidation of the chemical structure and relative stereochemistry were stated by spectroscopic data and chemical correlation. In addition, the inhibitory activity on acetylcholinesterase for 1 was determined as well as for N-methyllycodine (2), a derivative with the same nucleus, previously identified in P. saururus (IC50 = 33.8 ± 0.8 μM and 547.5 ± 0.5 μM, respectively) and N-demethylsauroxine (3) whose inhibition in the actual conditions was better than the previously informed.

Morphological and phytochemical characterization of susceptible and resistant sengon (Falcataria moluccana) tree to gall rust disease

Abstract. Rahmawati D, Khumaida N, Siregar UJ. 2019. Morphological and phytochemical characterization of susceptible and resistant sengon (Falcataria moluccana) tree to gall rust disease. Biodiversitas 20: 907-913. Gall rust disease has severely attacked sengon tree (Falcataria moluccana Miq. Barneby & J.W. Grimes)) and it rapidly spread in tree plantations causing the decrease of wood productivity. Although sengon is widely cultivated in several areas in Indonesia, there are limited studies on secondary metabolite composition of its wood. This research was aimed to study differences on morphology, wood anatomy and secondary metabolites content of resistant and susceptible sengon tree trunk to gall rust disease. Both resistant and susceptible tree samples to gall rust were selected from the same plantation plots to minimize environmental effects. Structure of wood samples was observed using Scanning Electron Microscope (SEM) JSM-5310LV. Seven types of secondary metabolites, i.e., alkaloids, flavonoids, saponins, phenolic hydroquinones, tannins, triterpenoids, and steroids were qualitatively analyzed from powdered wood samples. Based on field observations, the gall rust fungi changed the color, texture, pores of the tree surface and decreased wood density. In microscopic observations, sengon trunk, which is resistant to gall rust disease, showed organized and regularly structured wood anatomy and did not show hyphae of the infecting fungi inside the wood. The fungi damaged susceptible sengon trunk as indicated by the dispersed and irregular structure of wood tissue, while the presence of fungal hyphae among wood cells was detected. Phytochemical analyses indicated that trunk of sengon containing flavonoids, saponins, phenolic hydroquinones, tannins, triterpenoids, and steroids, except alkaloids. Sengon trunk, which is resistant to gall rust disease, had stronger reactions of flavonoids, saponins, triterpenoids, and steroids compared to that susceptible one.

The effect of alkaloid composition of larkspur (Delphinium) species on the intoxication of Angus heifers1.

Cattle losses from larkspur (Delphinium spp.) toxicity are a long-term challenge on the rangelands of western North America. In addition to animal factors that affect livestock poisonings, plant alkaloid composition (chemotype) affects the intoxication of cattle because some chemotypes are significantly more toxic. Differences in larkspur chemotype toxicity are due to the ratios of N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type alkaloids to non-MSAL-type alkaloids and the concentrations of those alkaloids in the plant material. The objective of this study was to compare the responses of 6 Angus heifers to 6 chemotypes of larkspur using a Latin square study design. These Angus heifers from the USDA-ARS, Meat Animal Research Center in Clay Center, NE, were chosen for this research because they are the most larkspur-susceptible cattle observed to date. The 6 heifers were given an oral dose of dried ground larkspur and tested for muscle weakness with an exercise test (i.e., walk time). The 6 chemotypes of larkspur had non-MSAL to MSAL-type alkaloid ratios ranging from 1.4:1 to 6:1 and were administered at an oral dose of 7.5 mg/kg MSAL-type alkaloids BW. There was a treatment effect due to larkspur chemotype (P < 0.0001), and period effects were not significant (P = 0.6). There were also significant correlations between the length of time walking on a dirt track at 5 to 6 km/h, and total alkaloid dose (r = -0.92, P = 0.0045) and alkaloid ratio (r = -0.81, P = 0.0258). Serum alkaloid concentrations at 24 h after dosing were representative of the relative abundance of the alkaloid in the plant material. Results from this work suggest that total alkaloid concentrations in combination with alkaloid ratios can be used together to accurately predict the plant risk component of larkspur poisoning to grazing cattle. Animal factors such as cattle age, breed, and sex must also be considered to comprehensively manage larkspur risk.

A Review on Camptothecin Analogs with Promising Cytotoxic Profile.

Camptothecin (CPT), obtained from Camptotheca acuminata (Nyssaceae), is a quinoline type of alkaloid. Apart from various traditional uses, it is mainly used as a potential cytotoxic agent acting against a variety of cancer cell lines. Though searches have been continued for last six decades, still it is a demanding task to design potent and cytotoxic CPTs. Different CPT analogs are synthesized to enhance the cytotoxic potential as well as to increase the pharmacokinetic properties of these analogs. Some of these analogs were proven to be clinically effective in different cancer cell lines. In this article, different CPT analogs have been highlighted extensively to get a detail insight about the structure-property relationships as well as different quantitative structure-activity relationships (QSARs) modeling of these analogs are also discussed. This study may be beneficial for designing newer CPT analogs in future.

Anticancer and Reversing Multidrug Resistance Activities of Natural Isoquinoline Alkaloids and their Structure-activity Relationship.

The severe anticancer situation as well as the emergence of multidrug-resistant (MDR) cancer cells has created an urgent need for the development of novel anticancer drugs with different mechanisms of action. A large number of natural alkaloids, such as paclitaxel, vinblastine and camptothecin have already been successfully developed into chemotherapy agents. Following the success of these natural products, in this review, twenty-six types of isoquinoline alkaloids (a total of 379 alkaloids), including benzyltetrahydroisoquinoline, aporphine, oxoaporphine, isooxoaporphine, dimeric aporphine, bisbenzylisoquinoline, tetrahydroprotoberberine, protoberberine, protopine, dihydrobenzophenanthridine, benzophenanthridine, benzophenanthridine dimer, ipecac, simple isoquinoline, pavine, montanine, erythrina, chelidonine, tropoloisoquinoline, azafluoranthene, phthalideisoquinoline, naphthylisoquinoline, lycorine, crinane, narciclasine, and phenanthridone, were summarized based on their cytotoxic and MDR reversing activities against various cancer cells. Additionally, the structure-activity relationships of different types of isoquinoline alkaloid were also discussed. Interestingly, some aporphine, oxoaporphine, isooxoaporphine, bisbenzylisoquinoline, and protoberberine alkaloids display more potent anticancer activities or anti-MDR effects than positive control against the tested cancer cells and are regarded as attractive targets for discovery new anticancer drugs or lead compounds.

Alkaloids of the Lauraceae.

This chapter presents an overview of the chemistry and pharmacology of the alkaloids found in species of the Lauraceae family. The occurrence of alkaloids from Lauraceae species as well as their chemical structures is summarized in informative and easy-to-understand tables. Within the Lauraceae family, the genera Ocotea (195), Litsea (180), Cryptocarya (133), and Neolitsea (110) have led to the greater number of publications regarding alkaloids content. Valuable and comprehensive information about the structure of these alkaloids is provided. The alkaloids of the aporphine type, found in 22 of the 23 genera, represent the predominant group in this family. Many of the isolated alkaloids exhibit unique structures. From plants of this family, 22 different types of skeletons have been isolated, among them only the purine alkaloids are classified as pseudoalkaloids, and the types phenethylamines, phenethylcinnamides, and phthalidoisoquinoline are classified as protoalkaloids. The chapter is presented as a contribution for the scientific community, mainly to enable the search for alkaloids in species belonging to the Lauraceae family.

Progress of Picrotoxane Type Alkaloids in Dendrobium

Progress of Picrotoxane Type Alkaloids in Dendrobium

Enantiomeric β-carboline dimers from Picrasma quassioides and their anti-hepatoma potential

Four pairs of enantiomeric β-carboline alkaloids, (+/−)-kumudine A-D, along with their biosynthesis-related compound kumudine E, were obtained from the stems of Picrasma quassioides. Their structures, including the absolute configurations, were determined via extensive spectroscopic data combined with electronic circular dichroism (ECD) spectroscopic analyses and quantum mechanical ECD calculations. (+/−)-Kumudine A possessed a scaffold of β-carboline-phenylpropanoid adduct, which were the first examples of this type of β-carboline alkaloid from nature. The cytotoxicity assay against hepatocellular carcinoma Hep3B and HepG2 cells was evaluated by SRB assay, which showed that (−)-Kumudine B had stronger effect than its enantiomer (+)-Kumudine B in Hep3B cells. Moreover, further flow cytometry analysis also supported the enantioselectivity between (+)-Kumudine B and (−)-Kumudine B, suggesting that the compounds caused death of hepatoma cells through apoptosis induction.

Discovery and characterisation of lycorine-type alkaloids in Lycoris spp. (Amaryllidaceae) using UHPLC-QTOF-MS.

Lycorine, one of the most common alkaloids in Lycoris spp., is believed to possess pharmacological activity. To discover and identify lycorine-type alkaloids in the crude extracts of bulbs from six Lycoris spp. by ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) detection. A qualitative analytical method with a data mining strategy was utilised. Based on the fragmentation patterns of standards investigated in positive tandem mass spectrometry (MS/MS) mode, the fragmentation rules of lycorine-type alkaloids were summarised. These types of alkaloids were additionally classified as different subtypes based on structural features and MS/MS fragmentation patterns, and the diagnostic ions for characterisation of different subtypes of alkaloids were designated. Thirty-seven lycorine type alkaloids, including 16 previously undescribed compounds, were efficiently screened out and tentatively identified from the crude extracts of six Lycoris spp. Lycoris sprengri may be a preferable species for studying or extracting lycorine-type alkaloids because of elevated relative concentrations and highest diversity of alkaloids. The UHPLC-QTOF-MS and MS/MS data-mining strategy proved useful for the detection and tentative identification of lycorine-type alkaloids in bulbs of Lycoris spp. and could be extended to other Amaryllidaceae genera. The consequent profiling of the lycorine-type alkaloids will be useful in the quality control of raw materials of Lycoris species and the exploration of superior species.

Gene Discovery in Gelsemium Highlights Conserved Gene Clusters in Monoterpene Indole Alkaloid Biosynthesis.

Genome mining is a routine technique in microbes for discovering biosynthetic pathways. In plants, however, genomic information is not commonly used to identify novel biosynthesis genes. Here, we present the genome of the medicinal plant and oxindole monoterpene indole alkaloid (MIA) producer Gelsemium sempervirens (Gelsemiaceae). A gene cluster from Catharanthus roseus, which is utilized at least six enzymatic steps downstream from the last common intermediate shared between the two plant alkaloid types, is found in G. sempervirens, although the corresponding enzymes act on entirely different substrates. This study provides insights into the common genomic context of MIA pathways and is an important milestone in the further elucidation of the Gelsemium oxindole alkaloid pathway.

The impact of Keap1/Nrf2, P38MAPK/NF-κB and Bax/Bcl2/caspase-3 signaling pathways in the protective effects of berberine against methotrexate-induced nephrotoxicity

Berberine (BBR) is a natural compound of plant origin belonging to isoquinoline type of alkaloid. Methotrexate (MTX) is an anti-metabolite used widely for a variety of tumors and autoimmune conditions. Clinical uses of MTX were severely limited by its concomitant renal intoxication. The current study was designed to investigate the efficacy of BBR against MTX-induced nephrotoxicity and for exploring the underlying molecular mechanisms through examining the Keap1/Nrf2, NF-κB/P38MAPK and Bax/Bcl2/caspase-3 pathways. Adults male rats were assigned to 4 groups: control, BBR, MTX and MTX + BBR. As compared to MTX-treated group, BBR effectively reduced the serum levels of creatinine, urea, uric acid and kidney/body weight ratio with a remarkable increase in serum level of albumin and the final body weight. Moreover, down-regulation of Keap1, P38MAPK and NF-κB genes along with marked up-regulation of Nrf2 gene were observed. In addition, BBR negatively regulated both Bax and caspase-3 proteins expression along with increased expression of the Bcl2 protein. Also, BBR restored GSH content and SOD activity while it decreased both TBARS and NO2− contents. Biochemical findings confirmed and markedly supported by alleviation of histopathological changes in kidney tissues. Furthermore, MTX cytotoxic activity was markedly enhanced by BBR in vitro using some human cancer cell lines. In conclusion, the current findings indicated that co-administration of BBR with MTX may be a reasonable therapeutic strategy for attenuation of MTX -induced renal damage.

Green and efficient extraction of different types of bioactive alkaloids using deep eutectic solvents

Deep eutectic solvents (DESs) have attracted increasing attention as eco-friendly and efficient alternatives to conventional organic solvents. In this study, five herbal medicines (HMs) including Caulis sinomenii, Coptis chinensis, Stephania tetrandra, Tetradium ruticarpum, and Sophora flavescens were selected for the first time to comprehensively evaluate the potential and effectiveness of DESs on the extraction of Morphinane, Protoberberine, Bisbenzylisoquinoline, Indole and Quinolizidine alkaloids, respectively. A total of 75 types of binary or ternary DESs with different polarity, viscosity, pH, and solubilization abilities were tailored to screen a suitable DESs for extraction of morphinane alkaloids from Caulis sinomenii, and the extraction conditions were optimized using response surface methodology (RSM) and artificial neural network hybridized with genetic algorithm (ANN-GA) for the first time. The results demonstrated that DESs were excellent solvents for extraction of alkaloids with superior efficiency to conventional extraction solvents. Moreover, both ANOVA and sensitivity analysis demonstrated that the most critical parameter for alkaloids extraction was water content in DESs. This study reveals the potential of eco-friendly DESs for applications involving the efficient extraction of bioactive alkaloids from natural sources.

Lycodine type alkaloids from Lycopodiastrum casuarinoides with cytotoxic and cholinesterase inhibitory activities

A chemical investigation on the 70% EtOH extract of the aerial parts of Lycopodiastrum casuarinoides led to the isolation of six novel lycodine type alkaloids, lycocasuarines A-F (1–6). The structures of the isolated compounds were established based on 1D and 2D (1H1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated alkaloids were tested in vitro for cytotoxic potentials against seven malignant melanoma cell lines as well as acetylcholinesterase (AChE) and butyrocholinesterase (BuChE) inhibitory activities. As a result, alkaloids 1 and 3 exhibited significant cytotoxic activities against all the tested tumor cell lines with IC50 values <10 μM and the inhibitory activities for AchE (0.94 ± 0.15 and 0.24 ± 0.03 μM, respectively) and BuchE (1.82 ± 0.12 and 7.31 ± 0.42 μM, respectively).

A structural study of seven N-acylindolines and their Pd(II)-mediated intramolecular oxidative coupling reactions for the synthesis of pyrrolophenanthridone alkaloids

Direct synthesis of the pyrrolophenanthridone scaffold was explored using an intramolecular Pd(II)-mediated coupling reaction of different N-acylindolines via CH activation. Amaryllidaceae alkaloids of the lycorine type belong to this type. Depending on the substitution pattern of the starting materials, the pathway yielded different product patterns and yields. Introduction of electron-withdrawing substituents into the 6-position of the indoline moiety did not improve coupling. Seven N-acylindoline precursors were structurally characterized by X-ray crystallography and NMR spectroscopy. The crystal structure of the lycorine type alkaloid oxoassoanine is reported for the first time.

Theoretical and experimental study by DFT, molecular docking calculations and cytotoxicity assay of 7,7-dimethylaporphine alkaloids type isolated from Guatteria friesiana (Annonaceae)

A combined experimental and theoretical DFT study of the structural, vibrational and electronic properties of 9-methoxyguatterfriesine (I), (R)-6,6a-dihydro-9-methoxyguatterfriesine (II) and 4,5-dehydro-9-methoxyguatterfriesine (III) is presented using B3LYP exchange-correlation functional with 6-311G (2d, p) basis set. The theoretical geometry optimization data were compared with the X-ray data for (−)-N-acetylanonaine, showing close values. In addition, molecular electrostatic potential surface (MEPS) calculation, HOMO-LUMO energy gap, natural bond orbitals (NBOs) and first and second order hyperpolarizabilities were also performed with the same calculation level. Transitions for UV spectrum for the three structures were assigned and the calculated bands showed good agreement with the measured experimental data. The comparative IR studies showed intermolecular hydrogen bonds that stabilize dimeric forms proposed for the three molecules and also revealed several characteristic vibrations for the structures. Molecular docking studies with DNA Topoisomerase II-DNA complex showed binding free energies of −7.6, −7.5 and −8.7 kcal/mol, for I, II and III respectively, which indicate III as a better potential inhibitor for this enzyme. In vitro cytotoxicity assay revealed an expressive antitumor activity of III against HepG2 cell line.

Matrine has pro-apoptotic effects on liver cancer by triggering mitochondrial fission and activating Mst1-JNK signalling pathways.

Mitochondrial homeostasis is closely associated with liver cancer progression via multiple mechanisms and is also a potential tumour-suppressive target in clinical practice. However, the role of mitochondrial fission in liver cancer cell viability has not been adequately investigated. Matrine, a type of alkaloid isolated from Sophoraflavescens, has been widely used to treat various types of cancer. However, the molecular effect of matrine on mitochondrial homeostasis is unclear. Therefore, the aim of the current study was to determine the role of mitochondrial fission in cell apoptosis, viability, migration and proliferation of HepG2 cells in vitro. The effect of matrine on mitochondrial fission and its mechanism were also explored. The results of our study showed that HepG2 cells treated with matrine had reduced viability, an increased apoptotic rate, a blunted migratory response, and impaired proliferation capacity. At the molecular level, matrine treatment activated mitochondrial fission, which promoted mitochondrial dysfunction, caused cellular oxidative stress, disrupted cellular energy metabolism and initiated cell apoptotic pathways. However, blockade of mitochondrial fission abolished the deleterious effects of matrine on HepG2 cells. Further, we demonstrated that the Mst1-JNK signalling axis was required for matrine-modulated mitochondrial fission. Matrine-mediated mitochondrial dysfunction was reversed by inhibiting Mst1-JNK pathways. Together, our results demonstrated that mitochondrial fission could be a potential upstream tumour-suppressive signal for liver cancer by modifying mitochondrial function and cell death. By contrast, matrine exerted an anticancer function in liver cancer by activating mitochondrial fission mediated by Mst1-JNK pathways.