Class Of Alkaloids Research Articles

Synthesis of the ABC Ring of Calyciphylline A-Type Alkaloids by a Stereocontrolled Aldol Cyclization: Formal Synthesis of (±)-Himalensine A.

A synthetic approach to a functionalized ABC-tricyclic framework of calyciphilline A-type alkaloids, a building block toward this class of alkaloids, is reported. The key synthetic steps involve a radical cyclization to form the hydroindole system and piperidine ring closure through a stereocontrolled aldol cyclization. The resulting alcohol allows the methyl group to be installed in the bowl-shaped azatricyclic structure; this crucial reaction takes place with configuration retention. The synthesis of azatricyclic compound I constitutes a formal synthesis of himalensine A.

Inside Back Cover

The cover picture displays a class of novel isosteroidal alkaloids isolated from Fritillaria verticillata Willd. Among them, compounds 1—3 were unprecedented cis‐fused D/E (13α,17α) cevanine alkaloids; compound 6 was one rarely cis‐fused E/F (22α) cevanine alkaloid. Their structures were determined by the solid data acquired from diverse methods. In addition, some proton and carbon signals α to nitrogen in 6 and 7 are unobservable due to the 14N nuclear quadrupolar relaxation, based on the NMR experiments in different solvents, calculated NMR method and X‐ray technology, their structures were determined. The NMR characteristics of cevanine alkaloids to distinguish orientation of long‐pair on nitrogen atom with β‐hydroxyl at C‐20 were also concluded. More details are discussed in the article by Pei et al. on page 1945–1956.image

Chemical characterisation by UPLC-Q-ToF-MS/MS and antibacterial potential of Coffea arabica L. leaves: A coffee by-product.

Coffea arabica L. leaves are considered a by-product of the coffee industry however they are sources of several bioactive compounds. This study aimed to evaluate the chemical composition and the in vitro antibacterial activity of the lyophilised ethanol extract of arabica coffee leaves (EE-CaL). The chemical characterisation of EE-CaL was performed using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-ToF-MS/MS). The in vitro antibacterial effect of EE-CaL was evaluated using the broth microdilution method and the adapted drop plate agar method to determine the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC), respectively. The chemical analysis of EE-CaL revealed the presence of compounds from the alkaloid class, such as trigonelline and caffeine, in addition to the phenolic compounds such as quinic acid, 5-caffeoylquinic acid, caffeic acid-O-hexoside, mangiferin, (epi)catechin, (epi)catechin monoglucoside and procyanidin trimer. Regarding the antibacterial potential, EE-CaL was active against Gram-positive and Gram-negative bacteria, being more effective against Escherichia coli (ATCC 25922) (MIC = 2500 μg/mL and bactericidal effect). The results of this research suggest that coffee leaves, a by-product, possess compounds with antibacterial properties. Thus, further studies with coffee leaf extracts must be carried out to relate the compounds present in the extract with the antibacterial activity and find the mechanisms of action of this extract against bacteria.

Plant secondary metabolites and primate food choices: A meta-analysis and future directions.

The role of plant secondary metabolites (PSMs) in shaping the feeding decisions, habitat suitability, and reproductive success of herbivorous mammals has been a major theme in ecology for decades. Although primatologists were among the first to test these ideas, studies of PSMs in the feeding ecology of non-human primates have lagged in recent years, leading to a recent call for primatologists to reconnect with phytochemists to advance our understanding of the primate nutrition. To further this case, we present a formal meta-analysis of diet choice in response to PSMs based on field studies on wild primates. Our analysis of 155 measurements of primate feeding response to PSMs is drawn from 53 studies across 43 primate species which focussed primarily on the effect of three classes of PSMs tannins, phenolics, and alkaloids. We found a smallbut significant effect of PSMs on the diet choice of wild primates, which was largely driven by the finding that colobine primates showed a moderate aversion to condensed tannins. Conversely, there was no evidence that PSMs had a significant deterrent effect on food choices of non-colobine primates when all were combined into a single group. Furthermore, within the colobine primates, no other PSMs influenced feeding choices and we found no evidence that foregut anatomy significantly affected food choice with respect to PSMs. We suggest that methodological improvements related to experimental approaches and the adoption of new techniques including metabolomics are needed to advance our understanding of primate diet choice.

Alkaloid Dimers Isolated from Thalictrum baicalense Have Antitumor Activities

Comprehensive SummaryA pair of heterodimeric isoquinoline alkaloid enantiomers, (±) thaliberberine A, five new thalifaberine‐type aporphine‐benzylisoquinoline (ABI) alkaloids, thalicultratines M—Q, and thirteen known analogues were isolated from the roots of Thalictrum baicalense Turcz. ex Ledeb. The structures were determined by extensive spectroscopic methods and ECD calculations. Thaliberberine A featuring a novel carbon skeleton coupled by two different classes of isoquinoline alkaloids, protoberberine and phthalidoisoquinoline, represents the first natural product with the berberine skeleton substituted at C‐6. Plausible biosynthetic routes of 1 are proposed. All isolated alkaloids were screened for their antiproliferative effects in vitro against HCT116, Caco‐2, and HepG‐2 cancer cell lines. The most active ABI alkaloid, thalifaronine (7) induced G0/G1 cell cycle arrest and apoptosis. Compound 7 effectively inhibited the colony formation and tumor growth of HCT116 cells in xenografts. The thalifaberine‐type ABI dimers represent a group of compounds with antitumor activity. The spectroscopic characteristics of thalifaberine‐type ABI dimers were also analyzed.

Traditional Uses, Phytochemistry and Pharmacological Activities of Annonacae

In 1789, the Annonaceae family was catalogued by de Jussieu. It encompasses tropical and subtropical plants which are widespread in distribution across various continents such as Asia, South and Central America, Australia and Africa. The genus of Annona is one of 120 genera of the Annonaceae family and contains more than 119 species of trees and shrubs. Most species are found in tropical America, where over 105 species have been identified. Due to its edible fruits and medicinal properties, Annona is the most studied genus of Annonaceae family. To date, only a limited number of these species have economic value, including A. squamosa L. (sugar apple), A. cherimola Mill. (Cherimoya), A. muricata L. (guanabana or soursop), A. atemoya Mabb. (atemoya), a hybrid between A. cherimola and A. squamosa, A. reticulata L. (custard apple), A. glabra L. (pond-apple) and A. macroprophyllata Donn. Sm. (ilama). Phytochemically, several classes of secondary metabolites, including acetogenins, essential oils, alkaloids, terpenoids and flavonoids. The pharmacological activities of Annona species leaves and seeds include antibacterial, anticancer, antidiabetic and anti-inflammatory properties.

Biosynthesis of Piperazine-Derived Diazabicyclic Alkaloids Involves a Nonribosomal Peptide Synthetase and Subsequent Tailoring by a Multifunctional Cytochrome P450 Enzyme

Piperazine-derived diazabicycles are privileged structures found in natural products and synthetic chemical entities, including therapeutic agents. Herein, we deciphered the biosynthesis of two unique classes of diazabicyclic alkaloids, fischerazines A-C. Notably, we characterized a multifunctional P450 monooxygenase NfiC that installs ortho-dihydroxyl groups on the dibenzyl-piperazines, in turn triggering a range of NfiC-catalyzed and spontaneous cyclization events.

Spirooxindol-1,3-oxazine Alkaloids: Highly Potent and Selective Antitumor Agents Evolved from Iterative Structure Optimization.

Spirooxindole‐1,3‐oxazines are a small and structurally unique class of spirooxindole alkaloids. To date, only four of these compounds have been isolated from natural sources, and their biological properties remained unknown thus far. Dioxyreserpine is a synthetic spirooxindole‐1,3‐oxazine, that can readily be prepared from the Rauvolfia alkaloid (–)‐reserpine by catalytic photooxygenation. While dioxyreserpine itself was now identified as a moderately effective antitumoral agent, structurally modified analogs of it emerged as a new class of highly potent and selective growth inhibitors of various human cancers, including pancreatic cancers. Systematic structural optimization ultimately led to an inhibitor displaying low‐micromolar IC50‐values against six cancer cell lines as well as selective apoptosis induction in vitro.

Chrysosporazines Revisited: Regioisomeric Phenylpropanoid Piperazine P-Glycoprotein Inhibitors from Australian Marine Fish-Derived Fungi.

A library of fungi previously recovered from the gastrointestinal tract (GIT) of several fresh, commercially sourced Australian mullet fish was re-profiled for production of a rare class of phenylpropanoid piperazine alkaloids (chrysosporazines) using an integrated platform of; (i) miniaturized 24-well plate cultivation profiling (MATRIX), (ii) UPLC-DAD and UPLC-QTOF-MS/MS (GNPS) chemical profiling, and; (iii) precursor directed biosynthesis to manipulate in situ biosynthetic performance and outputs; to detect two new fungal producers of chrysosporazines. Chemical analysis of an optimized PDA solid phase cultivation of Aspergillus sp. CMB-F661 yielded the new regioisomeric chrysosporazine T (1) and U (2), while precursor directed cultivation amplified production and yielded the very minor new natural products azachrysosporazine T1 (3) and U1 (4), and the new unnatural analogues neochrysosporazine R (5) and S (6). Likewise, chemical analysis of an optimized M1 solid phase cultivation of Spiromastix sp. CMB-F455 lead to the GNPS detection of multiple chrysosporazines and brasiliamides, and the isolation and structure elucidation of chrysosporazine D (7) and brasiliamide A (8). Access to new chrysosporazine regioisomers facilitated structure activity relationship investigations to better define the chrysosporazine P-glycoprotein (P-gp) inhibitory pharmacophore, which is exceptionally potent at reversing doxorubrin resistance in P-gp over expressing colon carcinoma cells (SW600 Ad300).

Natural Composition and Biosynthetic Pathways of Alkaloids in Medicinal Dendrobium Species.

Dendrobium is the second biggest genus in the Orchidaceae family, some of which have both ornamental and therapeutic values. Alkaloids are a group of active chemicals found in Dendrobium plants. Dendrobine has emerged specific pharmacological and therapeutic properties. Although Dendrobium alkaloids have been isolated and identified since the 1930s, the composition of alkaloids and their biosynthesis pathways, including metabolic intermediates, alkaloid transporters, concrete genes involved in downstream pathways, and associated gene clusters, have remained unresolved scientific issues. This paper comprehensively reviews currently identified and tentative alkaloids from the aspect of biogenic pathways or metabolic genes uncovered based on the genome annotations. The biosynthesis pathways of each class of alkaloids are highlighted. Moreover, advances of the high-throughput sequencing technologies in the discovery of Dendrobium alkaloid pathways have been addressed. Applications of synthetic biology in large-scale production of alkaloids are also described. This would serve as the basis for further investigation into Dendrobium alkaloids.

Isolation, Bioactivities, and Synthesis of Lamellarin Alkaloids: A Review

Abstract: Lamellarin alkaloid is a large class of marine alkaloids with diverse bioactivities. These heterocycles have been isolated from diverse marine organisms, mainly ascidians and sponges. They possess a fused 14-phenyl-6H-[1]benzopyrano[40,30:4,5] pyrrolo[2,1- a]isoquinoline or non-fused 3,4-diarylpyrrole-2-carboxylate ring systems. Until now, more than 50 lamellarins have been isolated from marine organisms. Various lamellarins exhibit valuable bioactivities, such as cytotoxicity, topoisomerase I inhibition, protein kinases inhibition, multidrug resistance reversal, and anti-HIV-1 activity. Due to their valuable biological activity, the synthesis of lamerallins has received great attention of chemists and a vast number of synthetic methods have been developed. This article gives overview of studies on lamellarins isolation, their bioactivities, and synthetic approaches for their total synthesis.

Berberine alkaloids inhibit the proliferation and metastasis of breast carcinoma cells involving Wnt/β-catenin signaling and EMT

Berberine alkaloids belong to the class of isoquinoline alkaloids that have been shown to possess anticancer potential, berberine exhibits inhibitory effects on breast cancer development. However, the exact mechanisms of action for anti-breast carcinoma of the alkaloids, including epiberberine, berberrubine and dihydroberberine are still unclear. MTT assay, colony formation, wound healing and transwell invasion assays detected these alkaloids suppressed proliferation, migration and invasion of breast cancer cells. Hoechst and Annexin V-FITC/PI staining were used to analyze the apoptosis of breast cancer cells. Western blotting investigated the changes noted in the expression levels of the key proteins involved in the Wnt/β-catenin signaling pathway and epithelial to mesenchymal transition (EMT). The results showed that inhibited the proliferation of breast cancer cells. Berberine alkaloids inhibited the cell cycle at G2/M phase in MCF-7 cells, but in MDA-MB-231 cells berberine alkaloids arrested the cell cycle in G0/G1 and G2/M phases. By decreasing β-catenin expression, increasing GSK-3β expression and decreasing N-cadherin expression, increasing E-cadherin expression, which proved that epiberberine, berberrubine and dihydroberberine inhibited of metastasis of breast cancer cells through Wnt signaling pathway and reversed EMT except berberine. Furthermore, berberine alkaloids exert their anti-breast cancer effects through the synergistic action of intrinsic and extrinsic pathways of apoptosis. These findings highlight the different effects of different berberine alkaloids on breast cancer cells and confirm that berberine alkaloids may be potentially used in the treatment of breast cancer.

Alkaloid Biosynthetic Enzyme Generates Diastereomeric Pair via Two Distinct Mechanisms.

Ergopeptines constitute one of the representative classes of ergoline alkaloids and carry a tripeptide extension on the lysergic acid core. In the current study, we discovered and structurally characterized newly isolated ergopeptine-like compounds named lentopeptins from a filamentous fungus Aspergillus lentulus, a close relative of A. fumigatus. Interestingly, in lentopeptins, the common lysergic acid moiety of ergopeptines is replaced by a cinnamic acid moiety at the N-terminus of the peptide segment. Moreover, lentopeptins lack the C-terminal proline residue necessary for the spontaneous cyclization of the peptide extension. Herein, we report the atypical lentopeptin biosynthetic pathway identified through targeted deletion of the len cluster biosynthetic genes predicted from the genome sequence. Further in vitro characterizations of the thiolation-terminal condensation-like (T-CT) didomain of the nonribosomal peptide synthetase LenA and its site-specific mutants revealed the mechanism of peptide release via diketopiperazine formation, an activity previously unreported for CT domains. Most intriguingly, in vitro assays of the cytochrome P450 LenC illuminated the unique mechanisms to generate two diastereomeric products. Lentopeptin A forms via a stereospecific hydroxylation, followed by a spontaneous bicyclic lactam core formation, while lentopeptin B is produced through an initial dehydrogenation, followed by a bicyclic lactam core formation and stereospecific hydration. Our results showcase how nature exploits common biosynthetic enzymes to forge new complex natural products effectively (213/250).

Molecular physiology of pumiliotoxin sequestration in a poison frog.

Poison frogs bioaccumulate alkaloids for chemical defense from their arthropod diet. Although many alkaloids are accumulated without modification, some poison frog species can metabolize pumiliotoxin (PTX 251D) into the more potent allopumiliotoxin (aPTX 267A). Despite extensive research characterizing the chemical arsenal of poison frogs, the physiological mechanisms involved in the sequestration and metabolism of individual alkaloids remain unclear. We first performed a feeding experiment with the Dyeing poison frog (Dendrobates tinctorius) to ask if this species can metabolize PTX 251D into aPTX 267A and what gene expression changes are associated with PTX 251D exposure in the intestines, liver, and skin. We found that D. tinctorius can metabolize PTX 251D into aPTX 267A, and that PTX 251D exposure changed the expression level of genes involved in immune system function and small molecule metabolism and transport. To better understand the functional significance of these changes in gene expression, we then conducted a series of high-throughput screens to determine the molecular targets of PTX 251D and identify potential proteins responsible for metabolism of PTX 251D into aPTX 267A. Although screens of PTX 251D binding human voltage-gated ion channels and G-protein coupled receptors were inconclusive, we identified human CYP2D6 as a rapid metabolizer of PTX 251D in a cytochrome P450 screen. Furthermore, a CYP2D6-like gene had increased expression in the intestines of animals fed PTX, suggesting this protein may be involved in PTX metabolism. These results show that individual alkaloids can modify gene expression across tissues, including genes involved in alkaloid metabolism. More broadly, this work suggests that specific alkaloid classes in wild diets may induce physiological changes for targeted accumulation and metabolism.

Phytochemicals From Vicia faba Beans as Ligands of the Aryl Hydrocarbon Receptor to Regulate Autoimmune Diseases.

Legumes are associated with gut health benefits, and increasing evidence indicates that their consumption reduces the risk of chronic diseases that include autoimmunity. Beans are rich sources of compounds with health-promoting effects, and recent metabolomic approaches have enabled the comprehensive characterization of the chemical composition of Vicia faba L. This article reviewed whether the phytocompounds in broad beans might modulate the aryl hydrocarbon receptor (AhR), which plays an essential role in autoantigen tolerance as a potential dietary strategy for autoimmune disease management. Therefore, thirty molecules present in Vicia faba of the chemical classes of flavonoids, chalcones, stilbenes, jasmonates, alkaloids, and amino acids, and either a human- or microbiome-derived product of biotransformation, retrieved from the literature or predicted in silico were evaluated by docking for affinity against the ligand-binding domain of AhR. Most analyzed compounds showed high affinity even after their metabolism which indicate that some AhR modulators remain active despite several steps in their biotransformation. Hence, our results suggest that in similitude with the gut metabolism of the tryptophan, phytocompounds mainly polyphenols also lead to metabolites that induce the AhR pathway. Furthermore, wyerone acid, wyerone epoxide, jasmonic acid, stizolamine, vicine, and convicine and their metabolite derivatives are reported for the first time as potential AhR ligands. Overall, chronic consumption of phytochemicals in Vicia faba L. and their gut biotransformation may protect against autoimmune disease pathogenesis by AhR modulation.

Evaluation of biologically active constituents of ethanol extracts of <em>H. verticillata</em> leave, <em>L. aestuans </em>leave and seeds of <em>L. aestuans</em>

There has been a great interest in the study of products of natural origin as an alternative and an adjunct to the chemically synthesized drugs for various therapeutic roles owing to the vast array of their medicinal activities and structural differences that abound in plants secondary metabolites. The preliminary analysis of the phytonutrients presents in the ethanol extracts of Hydrocotyle verticillata and Laportea aestuans showed the presence of saponins, various classes of alkaloids, Cardiac glycosides, Steroids, Phenolic chemicals, Tannins, Flavonoids, but Coumarins, Proteins and Quinines were lacking in both extracts. Noteworthy is that, tannins and alkaloids were predominant compared to other phytochemicals in the ethanol extract of Hydrocotyle verticillata leave. In the same vain, tannins and alkaloids were the more abundant phytochemicals in the Laportea aestuans leave extract. Analysis of the extract using combined chromatographic and spectrometric (GCMS) approach of Hydrocotyle verticillata leaves identified 3 major chemicals in descending order as 3. beta. 17.beta.-dihydroxyestr-4-ene [10.89%]; Hexadecanoic acid, ethyl ester [7.49%]; and 1-Methylbicyclo [3.2.1] octane [7.28%]. On the other hand, the 3 highest occurring chemical compounds identified in the ethanol extract of L. aestuans leaves are Diazoprogesterone [9.45%]; hexadecanoic acid, ethyl ester [8.29%]; and linoleic acid ethyl ester [7.31%]. It has been established that these chemical constituents were found to exert useful biological effects ranging from cellular, anticarcinogenic, anti-cholinergic effects, antioxidant, virus antagonists, anti-inflammatory as well as having profound effects on bacterial infections. Due to the numerous listed biological effects, the extracts could be used as an adjunct in a diverse number of diseases.

A Compilation of Synthetic Strategies to Access the Most Utilized Indoloquinoline Motifs.

Indoloquinoline alkaloids constitute an important class of aromatic heterocycles consisting of quinoline and indole fused together in various orientations. These compounds, both natural and synthetic, often display various bioactivities which have established them to be one of the interesting medicinal targets. This class of compounds have stimulated much interest among synthetic and medicinal chemists as evidenced by growth in the number of synthetic methods to prepare and study this class of alkaloids. This review compiles the synthetic strategies and methods currently known in the literature for the construction of four important indoloquinoline skeletons.

Identification and Characterization of Bioactive Components in Datura stramonium Leaves: an insight into Drugs Discovery

Medicines from plants help in treating ailments, but to utilize them effectively in the management of diseases requires the identification of potent phytochemicals relative to conventional drugs. These phytochemicals are compared with synthetics drugs in line with their treatment regimen. An investigation was designed to identify, and characterized the different phytochemicals in Datura stramonium (Jimson weed) leaves and compared them with conventional or standard drugs. The identified phytochemicals were blasted on the drugs bank website to find their correlation and relativity. GC/MS technique was used to analyze the phytochemicals. The results showed 80 different phytochemicals belonging to several categories of phytochemicals - alkaloids, flavonoids, terpenoids, saponins, amine, and steroids. The flavonoid class had - 1.24% of 5H-Dibenzo[c, f][1, 2] diazepine, 3, 8 dichloro-6,11-dihydro, at 3.702 RT, Alkaloid class has – 2.98% 2,6-Dibromobenzoquinone was detected at 4.403 RT, steroid – 2.98% Acetanilide, 2-chloro-4'-nitro- at 4.403 RT was obtained and Terpene – 2.05% of Methyl-beta.-[N-methylanilino]acrylate was detected at 4.719 RT, respectively. Most of the identified phytochemicals matched with synthetic drugs and confirmed the purpose of their applicability in traditional medicine. Considering the presence of numerous components and their correlation with conventional drugs, one can infer that this plant species has a good therapeutic application and can be utilized for health benefits.

Phytochemistry, Ethnobotany and Pharmacological Uses of Tinospora cordifolia with Special Reference to SARS-COV-2

Medicinal plants or medicinal herbs possess therapeutic properties or exert beneficial pharmacological effects on human. From time immemorial, people have been using various medicinal plants without even knowing their phytochemistry and pharmacological properties as a medicine for treating numerous ailments. As technology developed and upgraded, people used to screen out various phytoconstituents as well as evaluate their basic pharmacological properties. Tinospora cordifolia is a medicinal herb which is commonly known as Giloy belong to family menispermaceae. It can also be found in places like Africa, China, South-East Asia, Indo-Malaya region and Australia. Traditionally, people use this herb as prominent food materials due to their higher nutraceutical value and various healing properties. For phytochemical investigation, extraction of whole plant is preferable whereas most of the phytochemical are found to be present in leaves. Various potent phytochemicals are found in this herb such as tinosponone, tinocordiside, tinosporaside, cordifoliside, β-sitosterol, mekisterone A, etc. which are belong to class of alkaloids, sesquiterpenoids, glycosides, steroids, volatile oil, etc. Owing to the presence of these potent compounds, it exhibits wide range of large number of pharmacological activities such as antiviral, antibacterial, antifungal, antioxidant, antidiabetic, anticancer activities, etc. In past two years, SARS-CoV-2 infections has taken life of millions of people across the globe and there were no any vaccine or proper antiviral medicine available to defend this deadly pandemic, hence people were mostly relying on herbal plant therapy. Giloy is one such magical herb which exhibit healing properties in SARS-CoV-2 infected patients. Moreover, in-silico studies have been carried out to determine the binding affinity as well as inhibiting potential of various phytoconstituents of giloy. In this review work, we compiled all the updated information about T. cordifolia as well as emphasizing more on SARS-CoV-2 inhibiting potential.

Novel Alkaloids from Marine Actinobacteria: Discovery and Characterization.

The marine environment is an excellent resource for natural products with therapeutic potential. Its microbial inhabitants, often associated with other marine organisms, are specialized in the synthesis of bioactive secondary metabolites. Similar to their terrestrial counterparts, marine Actinobacteria are a prevalent source of these natural products. Here, we discuss 77 newly discovered alkaloids produced by such marine Actinobacteria between 2017 and mid-2021, as well as the strategies employed in their elucidation. While 12 different classes of alkaloids were unraveled, indoles, diketopiperazines, glutarimides, indolizidines, and pyrroles were most dominant. Discoveries were mainly based on experimental approaches where microbial extracts were analyzed in relation to novel compounds. Although such experimental procedures have proven useful in the past, the methodologies need adaptations to limit the chance of compound rediscovery. On the other hand, genome mining provides a different angle for natural product discovery. While the technology is still relatively young compared to experimental screening, significant improvement has been made in recent years. Together with synthetic biology tools, both genome mining and extract screening provide excellent opportunities for continued drug discovery from marine Actinobacteria.