Bisindole Alkaloids Research Articles

A pair of novel bisindole alkaloid enantiomers from marine fungus Fusarium sp. XBB-9

A preliminary research on the marine fungus Fusarium sp. XBB-9 resulted in a pair of novel bisindole alkaloid enantiomers, (+)- and (–)-fusaspoid A (1a/1b) and 12 diverse compounds. One strain many compound (OSMAC) method was used to enhance as many biosynthetic pathways as possible. The structures of the compounds were elucidated by spectroscopic analysis, and the absolute configuration of 1a was determined by X-ray single-crystal diffraction analysis. Compounds 1a and 1b were tested for cytotoxic activity against HCT-15, RKO cell lines, but were inactive. Compounds 1a and 1b were the first example of bisindole alkaloids isolated from fungus Fusarium sp. XBB-9.

Alkaloids and phenylpropanoid from Rhizomes of Arundo donax L

A new bis-indole alkaloid, named arundaline (1), a new phenylpropanoid, named arundalcohol (2), and four known alkaloids, N-acetyltryptamine (3), trans-N-(p-coumaroyl)serotonin (4), trans-N-feruloylserotonin (5), and tuberosine B (6), were isolated from 70% aqueous ethanol extracts of the rhizomes of Arundo donax L. Their structures were elucidated by spectroscopic analysis and comparison of the data with literature values. Compounds 3–6 were isolated from the genus Arundo for the first time.

CrERF5, an AP2/ERF Transcription Factor, Positively Regulates the Biosynthesis of Bisindole Alkaloids and Their Precursors in Catharanthus roseus.

Catharanthus roseus contains a variety of monoterpenoid indole alkaloids (MIAs), among which bisindole alkaloids vinblastine and vincristine are well-known to have antitumor effects and widely used in clinical treatment. However, their contents in C. roseus is extremely low and difficult to meet market demands. Therefore, it is of great significance to study the transcriptional regulation mechanism of MIAs biosynthesis for high yielding of bisindole alkaloids in C. roseus. Studies have shown that MIAs biosynthesis in C. roseus has complex temporal and spacial specificity and is under tight transcriptional regulation, especially bisindole alkaloids. In this study, an AP2/ERF transcription factor CrERF5 was selected by RNA-seq of C. roseus organs, and its full-length sequence was cloned and characterized. CrERF5 responds to both ethylene and JA signals and is localized in the nucleus. CrERF5 could activate the transcriptional activity of the TDC promoter. Transient overexpressing CrERF5 in C. roseus petals caused a significant increase of the expression levels of key genes in both the upstream and downstream pathways of MIAs biosynthesis while silencing CrERF5 resulted in a decrease of them. Accordingly, the contents of bisindole alkaloids anhydrovinblastine and vinblastine, monoindole alkaloids ajmalicine, vindoline, and catharanthine were strongly enhanced in CrERF5-overexpressing petals while their contents decreased in CrERF5-silenced plants. These results suggested that CrERF5 is a novel positive ethylene-JA-inducible AP2/ERF transcription factor upregulating the MIAs biosynthetic pathway leading to the bisindole alkaloids accumulation.

Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for Enantioselective Total Synthesis of Mavacuran Alkaloids.

Reported is the enantioselective total syntheses of mavacuran alkaloids, (+)-taberdivarine H, (+)-16-hydroxymethyl-pleiocarpamine, and (+)-16-epi-pleiocarpamine, and their postulated biosynthetic precursor 16-formyl-pleiocarpamine. This family of monoterpene indole alkaloids is a target of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline. Inspired by the biosynthetic hypothesis, an oxidative coupling approach from the geissoschizine framework to form the N1-C16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I2 as it masks the nucleophilicity of the aliphatic nitrogen center and locks in the required cis conformation.

Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for Enantioselective Total Synthesis of Mavacuran Alkaloids

AbstractReported is the enantioselective total syntheses of mavacuran alkaloids, (+)‐taberdivarine H, (+)‐16‐hydroxymethyl‐pleiocarpamine, and (+)‐16‐epi‐pleiocarpamine, and their postulated biosynthetic precursor 16‐formyl‐pleiocarpamine. This family of monoterpene indole alkaloids is a target of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline. Inspired by the biosynthetic hypothesis, an oxidative coupling approach from the geissoschizine framework to form the N1−C16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I2 as it masks the nucleophilicity of the aliphatic nitrogen center and locks in the required cis conformation.

Marine bisindole alkaloid 2,2-bis(6-bromo-3-indolyl)ethylamine to control and prevent fungal growth on building material: a potential antifungal agent.

The potential antifungal activity of the marine alkaloid 2,2-bis(6-bromo-3-indolyl)ethylamine (URB 1204) was firstly assessed by minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) against different fungi. Then, URB 1204 was applied to a building material experimentally contaminated with selected fungi, in single and mixed species, for determining its potential application in preventing fungal growth. In addition, the over-time protection efficacy of URB 1204 was verified, subjecting the treated building surfaces to natural fungal contamination for 6weeks. URB 1204 showed different antifungal activity, with the lowest MIC value (16μg/mL) observed against Aspergillus flavus IDRA01, Cladosporium cladosporioides ATCC 16022 and Mucor circinelloides EHS03, and the highest MIC (128μg/mL) against the dermatophytes strains. The growth Alternaria alternata BC01, Penicillium citrinum LS1, and C. cladosporioides ATCC 16022 on building material treated with URB 1204 water solution (64μg/mL) was remarkably reduced with an effect time-dependent and related to the examined fungi. In terms of over-time efficacy, the samples treated with URB 1204 showed a delay of fungal growth comparable with that of a commercial antifungal product. These findings evidenced not only the ability of 2,2-bis(6-bromo-3-indolyl)ethylamine to limit the growth of different fungal species on building material but also to provide long-term protection against mold growth and proliferation, opening new perspectives for URB 1204 as preventive agent.

Marine Natural Product Bis-indole Alkaloid Caulerpin: Chemistry and Biology.

Marine bis-indole alkaloids comprise a large and increasingly growing class of secondary metabolites, and continue to deliver a great variety of structural templates for diverse biological targets. The alkaloids derived from marine resources play a crucial role in medicinal chemistry and as chemical agents. In particular, bis-indole alkaloid caulerpin which has been isolated from marine green algae Caulerpa and a red algae Chondria armata at various places around the world, was tested for several therapeutic potentials such as anti-diabetic, antinociceptive, anti-inflammatory, anti-tumor, anti- larvicidal, anti-herpes, anti-tubercular, anti-microbial and immunostimulating activities as well as a means of other chemical agents. Herein, we summarized the discovery and isolation of caulerpin, and its potential medicinal and chemical applications in chronological order with various aspects. Additionally, synthesis of caulerpin and its functional analogues have also been reviewed.

Leucophyllinines A and B, bisindole alkaloids from Leuconotis eugeniifolia.

Two new bisindole alkaloids, leucophyllinines A (1) and B (2) consisting of eburnane and quebrachamine-type skeletons were isolated from the bark of Leuconotis eugeniifolia, and their structures were elucidated on the basis of spectroscopic data. Leucophyllinines A and B showed antiplasmodial activities against Plasmodium falciparum 3D7.

Conolodinines A-D, Aspidosperma- Aspidosperma Bisindole Alkaloids with Antiproliferative Activity from Tabernaemontana corymbosa.

Examination of the EtOH extract of the leaves of the Malayan Tabernaemontana corymbosa resulted in the isolation of four new (1-4) and two known bisindole alkaloids (5, 6) of the Aspidosperma- Aspidosperma type. The structures of these alkaloids were determined based on analysis of the spectroscopic data (NMR and HRESIMS). X-ray diffraction analyses of the related bisindole alkaloids conophylline (5) and conophyllinine (6) established the absolute configurations. Treatment of the bisindole alkaloid conophylline (5) with benzeneselenic anhydride gave, in addition to the known bisindole polyervinine (7) previously isolated from another Malayan Tabernaemontana, another bisindole product, 8, an isolable tautomer of 7. X-ray diffraction analyses yielded the absolute configurations of both bisindoles and in addition showed that polyervinine (7) exists primarily as the neutral dione structure. The bisindoles (1-8) and the related conophylline-type bisindoles (9-13) showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, A549, HT-29, and HCT 116 cells, with IC50 values for the active compounds in the 0.01-5 μM range.

Effect of the algal alkaloid caulerpin on neuropeptide Y (NPY) expression in the central nervous system (CNS) of Diplodus sargus

Recent studies have suggested that Mediterranean indigenous fish species are affected by bioactive metabolites coming from marine invasive species via food web interactions. In particular, both physiological and behavioural changes in the white sea bream Diplodus sargus were related to caulerpin (CAU), a bisindolic alkaloid particularly abundant in the invasive alga Caulerpa cylindracea, on which the fish actively feed. Dietary administration of CAU decreased aggressiveness in D. sargus, suggesting an anxiolytic-like effect of CAU possibly mediated by endogenous anxiolytic agents. This hypothesis is supported here by the finding of a significant increase of NPY transcriptional expression in the brain of fish fed with CAU enriched food, shedding more light on the neural mechanisms behind the altered behaviour of D. sargus.

Influence of seasonal and ontogenic parameters on the pattern of key terpenoid indole alkaloids biosynthesized in the leaves of Catharanthus roseus

Catharanthus roseus is known for its anticancer bisindole alkaloids, vinblastine and vincristine that are derived from the condensation of monomeric terpenoid indole alkaloids (TIAs), catharanthine and vindoline. The in planta content of TIAs varies with seasons and ontogeny making it difficult for growers to define the optimal parameters for harvesting for specific TIAs. Here, specific leaf TIAs were profiled in the plant at frequent intervals throughout the year covering various seasons under North-Indian conditions. Higher bisindole alkaloid content was observed during summer (June; average day temperature ≥ 40 °C), whereas vindoline content was higher in winter and spring (mid-December to mid-April). Further, the plant was analyzed for variation in ontogenic localization of TIAs in the leaves. The monomeric TIAs were present maximally in the top-level leaf-pairs, whereas the bisindole alkaloids were present maximally in the middle-level leaf-pairs. Analysis of relative abundance of individual TIAs in the total alkaloid pool indicated a clear partitioning between vindoline on one hand and bisindole alkaloids on the other. qRT-PCR-based expression analysis of 10 pathway genes (tdc, str, sgd, t16h, omt, t3o, t3r, nmt, d4h, dat) involved in the biosynthesis of key TIAs, like vindoline, indicated that the transcript abundance of all the genes, except sgd, was significantly higher in winter as compared to summer. Also, upon moving down from the top to the lower level leaf-pairs, the transcript abundance of all the genes decreased significantly. This study defines the seasonal and ontogenic parameters for harvesting of C. roseus leaves for optimal recovery of specific TIAs.

Exploration of Indole Alkaloids from Marine Fungus Pseudallescheria boydii F44-1 Using an Amino Acid-Directed Strategy.

The composition of the culture medium has great influence on the metabolite production of the marine fungus Pseudallescheria boydii F44-1. By adding amino acids to GPY culture medium, two new bisindole alkaloids, pseudboindoles A and B (1 and 2), together with 11 known indole alkaloids were isolated from the culture broth. Their structures were elucidated by comprehensive analysis of the NMR, MS, IR, and UV spectra. The 3,3′-cyclohexylidenebis(1H-indole) (3) showed cytotoxic activity against various cancer cell lines.

Marine Alkaloid 2,2-Bis(6-bromo-3-indolyl) Ethylamine and Its Synthetic Derivatives Inhibit Microbial Biofilms Formation and Disaggregate Developed Biofilms.

The antimicrobial activity of the marine bisindole alkaloid 2,2-bis(6-bromo-3-indolyl) ethylamine (1) and related synthetic analogues (compounds 2–8) against target microorganisms was investigated by Minimum Inhibitory Concentration (MIC) determination. Compound 1 showed the greatest antimicrobial activity with the lowest MIC (8 mg/L) against Escherichia coli, Staphylococcus aureus, and Klebsiella pneumoniae, while the derivatives exhibited higher MICs values (from 16 to 128 mg/L). Compounds 1, 3, 4, and 8, the most active ones, were then tested against E. coli, S. aureus, K. pneumoniae, and Candida albicans during biofilms formation as well as on 24 h developed biofilms. The natural alkaloid 1 inhibited the biofilm formation of all the tested microorganisms up to 82.2% and disaggregated biofilms of E. coli, S. aureus, K. pneumoniae, and C. albicans after 30 min of contact, as assessed by viable plate count and crystal violet (CV) staining (optical density at 570 nm). Synthetic derivatives 3, 4, and 8 displayed anti-biofilm activity toward individual bacterial populations. This study highlights the potential of marine bisindole alkaloid 1 as anti-biofilm agent and shows, through a preliminary structure activity relationship (SAR), the importance of halogens and ethylamine side chain for the antimicrobial and antibiofilm activities of this bisindole series.

Melosuavine I, an apoptosis-inducing bisindole alkaloid from Melodinus suaveolens

A new bisindole alkaloid, melosuavine I (1) possessing an aspidosperma-aspidosperma dimeric skeleton, was isolated from the leaves of Melodinus suaveolens. The structure with absolute configuration of 1 was elucidated by a combination of MS, NMR and computational methods. MTT assays indicated that 1 exhibited significant cytotoxicity on human breast cancer BT549 cells with an IC50 value of 0.89 μM. Further study showed that 1 inhibited BT549 cell proliferation by inducing apoptosis through activation of caspase 3 and p53, and down-regulation of Bcl-2.

Synthesis of Pseudellone Analogs and Characterization as Novel T-type Calcium Channel Blockers.

T-type calcium channel (CaV3.x) blockers are receiving increasing attention as potential therapeutics for the treatment of pathophysiological disorders and diseases, including absence epilepsy, Parkinson’s disease (PD), hypertension, cardiovascular diseases, cancers, and pain. However, few clinically approved CaV3.x blockers are available, and selective pharmacological tools are needed to further unravel the roles of individual CaV3.x subtypes. In this work, through an efficient synthetic route to the marine fungal product pseudellone C, we obtained bisindole alkaloid analogs of pseudellone C with a modified tryptophan moiety and identified two CaV3.2 (2, IC50 = 18.24 µM; 3, IC50 = 6.59 µM) and CaV3.3 (2, IC50 = 7.71 µM; 3, IC50 = 3.81 µM) selective blockers using a FLIPR cell-based assay measuring CaV3.x window currents. Further characterization by whole-cell patch-clamp revealed a preferential block of CaV3.1 activated current (2, IC50 = 5.60 µM; 3, IC50 = 9.91 µM), suggesting their state-dependent block is subtype specific.

Aspidosperma pyrifolium, a medicinal plant from the Brazilian caatinga, displays a high antiplasmodial activity and low cytotoxicity

BackgroundSeveral species of Aspidosperma plants are referred to as remedies for the treatment of malaria, especially Aspidosperma nitidum. Aspidosperma pyrifolium, also a medicinal plant, is used as a natural anti-inflammatory. Its fractionated extracts were assayed in vitro for activity against malaria parasites and for cytotoxicity.MethodsAspidosperma pyrifolium activity was evaluated against Plasmodium falciparum using extracts in vitro. Toxicity towards human hepatoma cells, monkey kidney cells or human monocytes freshly isolated from peripheral blood was also assessed. Anti-malarial activity of selected extracts and fractions that presented in vitro activity were tested in mice with a Plasmodium berghei blood-induced infection.ResultsThe crude stem bark extract and the alkaloid-rich and ethyl acetate fractions from stem extract showed in vitro activity. None of the crude extracts or fractions was cytotoxic to normal monkey kidney and to a human hepatoma cell lines, or human peripheral blood mononuclear cells; the MDL50 values of all the crude bark extracts and fractions were similar or better when tested on normal cells, with the exception of organic and alkaloidic-rich fractions from stem extract. Two extracts and two fractions tested in vivo caused a significant reduction of P. berghei parasitaemia in experimentally infected mice.ConclusionConsidering the high therapeutic index of the alkaloidic-rich fraction from stem extract of A. pyrifolium, it makes the species a candidate for further investigation aiming to produce a new anti-malarial, especially considering that the active extract has no toxicity, i.e., no mutagenic effects in the genototoxicity assays, and that it has an in vivo anti-malarial effect. In its UPLC-HRMS analysis this fraction was shown to have two major components compatible with the bisindole alkaloid Leucoridine B, and a novel compound, which is likely to be responsible for the activity against malaria parasites demonstrated in in vitro tests.

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

Summary Organisms have evolved to produce various natural products from a common precursor as a means of maximizing the number of secondary metabolites, thus acquiring selectional advantages. By adopting nature's divergent biosynthetic strategy, we transformed (+)-catharanthine to various iboga and post-iboga alkaloids, including (−)-conodusine A, (+)-conodusines B and C, (−)-voatinggine, (−)-tabertinggine, and (+)-dippinine B. Well-orchestrated oxidations and reorganizations of catharanthine derivatives enabled chemical access to these natural products.

Bisleuconothines B-D, Modified Eburnane-Aspidosperma Bisindole Alkaloids from Leuconotis griffithii.

Three new bisindole alkaloids, bisleuconothines B-D (1-3), were isolated from the bark of Leuconotis griffithii. Their structures were elucidated by 1D and 2D NMR spectroscopy and DFT calculations. Bisleuconothine B (1) is the first monoterpene indole alkaloid dimer featuring bridges between both C-16-C-10' and C-2-O-C-9'. All compounds were deemed noncytotoxic (IC50 > 10 μM) when tested against A549 human lung adenocarcinoma cells.

Theionbrunonines A and B: Dimeric Vobasine Alkaloids Tethered by a Thioether Bridge from Mostuea brunonis.

Theionbrunonines A and B (1 and 2), the first examples of monoterpene bisindole alkaloids linked by a thioether bridge, were isolated from the stems of Mostuea brunonis, guided by a molecular networking-based dereplication strategy. Their structures were elucidated by a combination of spectroscopic data and ECD calculations. A plausible biosynthetic pathway for 1 and 2 was postulated. Theionbrunonines A and B (1 and 2) showed moderate antiplasmodial activities in the micromolar range against the strain FcB1 of Plasmodium falciparum and no cytotoxic activity against the MRC-5 cell line at 20 μM.

Attempted Synthesis of Vinca Alkaloids Condensed with Three-Membered Rings.

Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmons–Smith reaction was followed to build up further three-membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform and bromoform, respectively, in the presence of diethylzinc. Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative. Unexpectedly, in the case of the dimer alkaloids vinblastine and vincristine, the rearranged products containing an oxirane ring in the catharanthine part were isolated from the reactions. The attempted epoxidation of vindoline and catharanthine also led to anomalous rearranged products. In the epoxidation reaction of vindoline, an o-quinonoid derivative was obtained, in the course of the epoxidation of catharanthine, a hydroxyindolenine type product and a spiro derivative formed by ring contraction reaction, were isolated. The coupling reaction of vindoline and the spiro derivative obtained in the epoxidation of catharanthine did not result in a bisindole alkaloid. Instead, two surprising vindoline trimers were discovered and characterized by NMR spectroscopy and mass spectrometry.