Related Indole Alkaloids Research Articles

New Indole Alkaloids from the Fungus Talaromyces assiutensis JTY2.

Three new indole alkaloids, named talatensindoids A-C (1-3), together with two known biogenetically related indole alkaloids tryptamine (4) and L-tryptophan (5) were isolated from the Talaromyces assiutensis JTY2 based on the guidance of OSMAC approach. The structures of these indole alkaloids were determined by comprehensive spectroscopic analyses. The absolute configuration of 3 was confirmed by X-ray crystallographic analysis. Compound 1 represent the rare example of a chlorine-substituted indole alkaloid from natural products. The inhibitory activity of compounds 1-5 against two phytopathogenic fungi and three phytopathogenic bacteria was evaluated. Compound 1 exhibited broad spectrum antibacterial activities.

Akuammiline alkaloid derivatives: divergent synthesis and effect on the proliferation of rheumatoid arthritis fibroblast-like synoviocytes.

During the past decades, rheumatoid arthritis had become a serious problem, torturing millions of patients because of unclear pathogenesis and no ideal therapies. Natural products remain an important source of medicines to treat various major diseases such as rheumatoid arthritis (RA) given their excellent biocompatibility and structural diversity. Herein, we have developed a versatile synthetic method for constructing various skeletons of akuammiline alkaloid analogs based on our previous research on the total synthesis of the related indole alkaloids. We have also evaluated the effect of these analogs on the proliferation of RA fibroblast-like synoviocytes (FLSs) in vitro and analyzed the corresponding structure-activity relationship (SAR). Among these analogs, compounds 9 and 17c have demonstrated a promising inhibitory effect on the proliferation of RA-FLSs, with IC50 values of 3.22 ± 0.29 μM and 3.21 ± 0.31μM, respectively. Our findings provide a solid foundation for future pharmacological studies on akuammiline alkaloid derivatives and inspiration for the development of anti-RA small molecule drugs derived from natural products.

Pegriseofamines A−E: Five cyclopiazonic acid related indole alkaloids from the fungus Penicillium griseofulvum

Five new cyclopiazonic acid related indole alkaloids, pegriseofamines A−E (1–5), were isolated from the fungus Penicillium griseofulvum. Their structures and absolute configurations were determined by NMR, HRESIMS, quantum-chemical calculation, and X-ray diffraction experiments. Among them, pegriseofamine A (1) possesses an undescribed 6/5/6/7 tetracyclic ring system generated by the fusion of an azepine and an indole unit via a cyclohexane, and the postulated biosynthetic origin of 1 was discussed. Compound 4 could relieve liver injury and prevent hepatocyte apoptosis in ConA-induced autoimmune liver disease.

Cover Feature: Total Syntheses of (+)‐Villocarine A, (−)‐Apogeissoschizine, and (+)‐Geissoschizine (Chem. Eur. J. 18/2023)

Geissoschizine is a very important biosynthetic intermediate of monoterpenoid alkaloids in higher plants. In this study, the enantioselective and stereodivergent total syntheses of geissoschizine and two related indole alkaloids (villocarine A and apogeissoschizine) were achieved. The three synthesized natural products are represented as Nishikigoi (varicolored carp), which are also called “swimming jewels” in Japan, and the cascade reaction is represented by their graceful swimming along a river. More information can be found in the Research Article by H. Ishikawa and co-workers (DOI: 10.1002/chem.202300179).

Divergent biosynthesis of indole alkaloids FR900452 and spiro-maremycins.

FR900452 and spirocyclic maremycins, including F and G components, are structurally related indole alkaloids, previously identified from different Streptomyces species. These alkaloids feature an indole diketopiperazine motif linked with a cyclopentenone moiety, but the linkage differs in FR900452 and the spirocyclic maremycins. Here, FR900452 and its two new analogues were identified from the fermentation broth of Streptomyces sp. B9173, the producer of maremycins. Gene inactivation and heterologous expression of the mar gene cluster confirmed that production of FR900452 shares the same biosynthetic machinery that produces maremycins. FR900452 was identified as the precursor of maremycin A/B by feeding studies. MarP, a SnoaL-like protein, was demonstrated to differentiate the biosynthesis of FR900452 from that of spiro-form maremycin G.

An Efficient Synthesis of (±)-Dehaloperophoramidine.

Perophoramidine and communesin F are structurally related indole alkaloids with an intriguing polycyclic core containing vicinal all-carbon quaternary stereocenters. Dehaloperophoramidine is a dehalogenated synthetic analogue of perophoramidine. Synthetic studies toward the total synthesis of dehaloperophoramidine have led to the discovery of two novel domino processes, the first encompassing four steps and resulting in the formation of an ortho-amide. A thorough study of the reactivity of the ortho-amide functionality revealed the second domino reaction and ultimately yielded the target molecule. The vicinal all-carbon quaternary stereocenters having trans relative stereochemistry are constructed early in the reaction sequence by employing Overman's samarium mediated reductive dialkylation procedure. Described are the synthetic studies that led to the final eight-step synthesis of dehaloperophoramidine.

A sequential cycloaddition strategy for the synthesis of Alsmaphorazine B traces a path through a family of Alstonia alkaloids

Driven by a new biogenetic hypothesis, the first total synthesis of alsmaphorazine B and several related indole alkaloids has been achieved. Numerous early approaches proved unsuccessful owing to unproductive side reactivity; nevertheless, they provided important clues that guided the evolution of our strategy. Critical to our success was a major improvement in our Zincke aldehyde cycloaddition strategy, which permitted the efficient gram-scale synthesis of akuammicine. The sequential chemoselective oxidations of akuammicine leading up to the key oxidative rearrangement also yielded several biogenetically related indole alkaloids en route to alsmaphorazine B.

Indole Alkaloids of the Stigonematales (Cyanophyta): Chemical Diversity, Biosynthesis and Biological Activity.

The cyanobacteria are well recognized as producers of a wide array of bioactive metabolites including toxins, and potential drug candidates. However, a limited number of taxa are generally considered with respect to both of these aspects. That said, the order Stigonematales, although largely overlooked in this regard, has become increasingly recognized as a source of bioactive metabolites relevant to both human and environmental health. In particular, the hapalindoles and related indole alkaloids (i.e., ambiguines, fischerindoles, welwitindolinones) from the order, represent a diverse, and phylogenetically characteristic, class of secondary metabolites with biological activity suggestive of potential as both environmental toxins, and promising drug discovery leads. The present review gives an overview of the chemical diversity of biologically active metabolites from the Stigonematales—and particularly the so-called hapalindole-type alkaloids—including their biosynthetic origins, and their pharmacologically and toxicologically relevant bioactivities. Taken together, the current evidence suggests that these alkaloids, and the associated cyanobacterial taxa from the order, warrant future consideration as both potentially harmful (i.e., “toxic”) algae, and as promising leads for drug discovery.

Construction of Hexahydropyrido[3,2‐c]carbazole and Hexahydropyrrolo[3,2‐c]carbazole Skeletons for the Synthesis of Related Indole Alkaloids

Synthesis of tetracyclic hexahydropyrido[3,2‐c]carbazoles (9a and 9b) and hexahydropyrrolo[3,2‐c]carbazoles (13a and 13b) structures was achieved via a new synthetic approach for the synthesis of related indole alkaloids such as deethylaspidospermidine and deethylibophyllidine. Hexahydropyrrolo[3,2‐c]carbazole structure was constructed for the first time starting from ethyl 4‐oxo‐cyclohexanecarboxylate in seven steps. Some tetrahydrocarbazole derivatives (4, 5, 6, 7, 11, and 12) were also synthesized.

Indole alkaloids from Fischerella inhibit vertebrate development in the zebrafish (Danio rerio) embryo model.

Cyanobacteria are recognized producers of toxic or otherwise bioactive metabolite associated, in particular, with so-called “harmful algal blooms” (HABs) and eutrophication of freshwater systems. In the present study, two apparently teratogenic indole alkaloids from a freshwater strain of the widespread cyanobacterial genus, Fischerella (Stigonemataceae), were isolated by bioassay-guided fractionation, specifically using the zebrafish (Danio rerio) embryo, as a model of vertebrate development. The two alkaloids include the previously known 12-epi-hapalindole H isonitrile (1), and a new nitrile-containing variant, 12-epi-ambiguine B nitrile (2). Although both compounds were toxic to developing embryos, the former compound was shown to be relatively more potent, and to correlate best with the observed embryo toxicity. Related indole alkaloids from Fischerella, and other genera in the Stigonemataceae, have been widely reported as antimicrobial compounds, specifically in association with apparent allelopathy. However, this is the first report of their vertebrate toxicity, and the observed teratogenicity of these alkaloids supports a possible contribution to the toxicity of this widespread cyanobacterial family, particularly in relation to freshwater HABs and eutrophication.

A pair of unprecedented spiro-trisindole enantiomers fused through a five-member ring from Laurencia similis

Abstract Similisines A (1a) and B (1b), a pair of unprecedented polybrominated spiro-trisindole enantiomers fused through a five-member ring, along with seven known biologically related indole alkaloids, were isolated from Laurencia similis. The structures and absolute configurations of the enantiomers were elucidated by comprehensive spectroscopic analysis, computer modeling, and comparison of experimental and theoretically calculated ECD. The proposed biogenetic pathway of 1a and 1b and cytotoxic activity of all isolates were also discussed.

Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator

Chemical analysis of a specimen of the sponge Ianthella cf. flabelliformis returned two new sesquiterpene glycinyl lactams, ianthellalactams A (1) and B (2), the known sponge sesquiterpene dictyodendrillin (3) and its ethanolysis artifact ethyl dictyodendrillin (4), and five known sponge indole alkaloids, aplysinopsin (5), 8E-3′-deimino-3′-oxoaplysinopsin (6), 8Z-3′-deimino-3′-oxoaplysinopsin (7), dihydroaplysinopsin (8) and tubastrindole B (9). The equilibrated mixture 6/7 exhibited glycine-gated chloride channel receptor (GlyR) antagonist activity with a bias towards α3 over α1 GlyR, while tubastrindole B (9) exhibited a bias towards α1 over α3 GlyR. At low- to sub-micromolar concentrations, 9 was also a selective potentiator of α1 GlyR, with no effect on α3 GlyR—a pharmacology that could prove useful in the treatment of movement disorders such as spasticity and hyperekplexia. Our investigations into the GlyR modulatory properties of 1–9 were further supported by the synthesis of a number of structurally related indole alkaloids.

Fascinating organic molecules from nature

(Right) C N Sundaresan is currently an Associate Professor in the Department of Chemistry at the Sri Sathya Sai Institute of Higher Learning, Bangalore. His research interests are in synthesis of biologically active compounds, and pharmacuetical co-crystals. European explorers of the New World brought back to Europe exotic specimens of plant and animal origin. One of these was curare, the arrow poison used by the natives of the Orinoco and the Amazon river basins mainly to capture birds and animals for food. Three types of curare were known, namely tubocurare, calabash curare and pot curare. The main plant component of tubocurare was identified as the Menispermaceaeplant Chondrodendrontomentosum, whereas in calabash curare the chief ingredient was the bark of Strychnos toxifera. From tubocurare, the quaternary base, d-tubocurarine was isolated. It is a bis-benzylisoquinoline alkaloid. Calabash curare is a complex mixture of several closely related indole alkaloids.

Phytochemical analysis of the herbal 'legal high' kratom (Mitragyna speciosa)

'Legal highs' are psychoactive synthetic or natural products that can be purchased from the internet or in retail stores without legal restriction. In 2011, the European Monitoring Center for Drugs and Drug Addiction reported a rapid growth in legal high online sales mostly from the US and UK. Products from the leaves of Mitragyna speciosa Korth (Kratom), a psychoactive plant from Southeast Asia, were the most common legal highs provided by internet suppliers. While the growing and selling of the plant are restricted in the source countries, products labeled as 'Kratom' are legally and widely distributed in western countries. In this study, ten commercial samples of Kratom were acquired from different UK-based websites. Phytochemical analyses of the samples were carried out using TLC, NMR, ESI-MS and HPLC techniques. Mitragynine (1), a psychoactive component possessing opiate-like effects was used as a standard marker, and was detected in all samples. Quantitative phytochemical analysis led to the isolation of other related indole alkaloids, demonstrating that the Kratom products were authentic and of plausible pharmacognostical origin. The presence of 7-hydroxy-mitragynine, the major µ-opioid agonist from this species was also confirmed, suggesting that these samples may have opiate-like harm potential.

Implementation of a design of experiments to study the influence of the background electrolyte on separation and detection in non‐aqueous capillary electrophoresis–mass spectrometry

Non-aqueous capillary electrophoresis (NACE) background electrolytes are most often composed of a mixture of methanol and acetonitrile (ACN) with soluble ammonium salts added as electrolyte. In this study on NACE-MS, we used a mixture of glacial acetic acid and ACN giving rise to an acidic background electrolyte (BGE) with a very low dielectric constant. Impressive changes in selectivity and resolution were observed for structurally closely related indole alkaloids including diastereomers upon addition of ammonium formate as electrolyte and upon variation of the solvent ratio. In order to obtain best separation and MS detection conditions and to reveal the influence of the parameters of the BGE on separation and detection and vice versa of the MS parameters on separation, an optimization strategy was employed using a design of experiments in a central composite design with response surface methodology. It was proven that at high electroosmotic flow conditions capillary electrophoretic separations and thus optimization can be realized without interference from the coupling to an MS system. Several significantly interacting parameters were revealed, which are not accessible with classical univariate optimization approaches. With this optimization, alkaloid mixtures from a plant extract of Mitragyna speciosa, containing a large number of diastereomeric compounds were successfully separated.

Isolation and structural elucidation of indole alkaloids from Geissospermum vellosii by mass spectrometry

Alkaloids from the stem bark of Geissospermum vellosii possess a variety of therapeutic properties including antimalarial activities, activity as a sexual stimulant and inhibition of the proliferation of HIV and herpes viruses. Methods currently used to isolate the active components from G. vellosii are time-consuming, labor intensive, and result in low recovery. In addition, there is a lack of sensitive and accurate analytical methods for the structural characterization and identification of alkaloid components in minor quantities. A combination of high performance counter-current chromatography and ESI tandem mass spectrometry (MSn) was established to isolate alkaloids from the stem bark of G. vellosii, and study their electrospray ionization mass spectrometry fragmentation behavior. Five indole alkaloids were successfully isolated and identified by nuclear magnetic resonance and mass spectrometry. The multi-stage tandem mass spectrometric data were used to study their fragmentation pattern and set a model for detailed structure characterization of related indole alkaloids. The presence of the even mass fragment ion suggestive of an odd number of nitrogen at m/z 144 corresponding to C10H9N was characteristic to indole alkaloids. The results of the experiments demonstrated that the combination of high performance counter current chromatography and ESI-MSn is a sensitive, selective and effective approach for rapid isolation and characterization of alkaloids from G. vellosii.

ChemInform Abstract: Enantiospecific Total Synthesis of the Sarpagine Related Indole Alkaloids Talpinine (X) and Talcarpine (XII) as Well as the Improved Total Synthesis of Alstonerine (XIII) and Anhydromacrosalhine-methine (XIV) via the Asymmetric Pictet

ChemInform Abstract: Enantiospecific Total Synthesis of the Sarpagine Related Indole Alkaloids Talpinine (X) and Talcarpine (XII) as Well as the Improved Total Synthesis of Alstonerine (XIII) and Anhydromacrosalhine-methine (XIV) via the Asymmetric Pictet

Not so strictosidine

Plant cell cultures expressing a mutated form of a key alkaloid-producing enzyme could enable the biosynthesis of vinblastine and related indole alkaloids that are used to treat cancer. In addition, the technique could be used to produce new alkaloids.

Total Synthesis of Indole Alkaloid (±)-Subincanadine F via SmI2-Mediated Ring Opening and Bridge-Forming Mannich Reaction

The first total synthesis of (+/-)-subincanadine F, a bioactive indole alkaloid structurally featuring a 1-azabicyclo[4.3.1]decane unit, has been realized from 1-(para-methoxybenzyl)tryptamine in six steps. The bridge-containing tetracyclic framework of subincanadine F was efficiently assembled by a SmI2-mediated ring opening followed by an acid-mediated Mannich reaction. In addition, the tetracyclic ketoester 6, a key intermediate potentially useful for synthesizing structurally related indole alkaloids as well, was obtained in one step from alpha,beta-diketoester 5.

Cytotoxic effects and reversal of multidrug resistance by ibogan and related indole alkaloids

A series of indole alkaloids of the ibogan-type was assessed for their cytotoxic effects as well as their potential in reversing MDR in vincristine-resistant KB cells. Of a total of 25 compounds tested, 3( S)-cyanocoronaridine, 3( S)-cyanoisovoacangine, 3( S)-cyanovoacangine, and 10,11-demethoxychippiine were found to show appreciable cytotoxicity toward KB cells, while coronaridine, heyneanine, 19- epi-heyneanine, dippinine B, and dippinine C, were found to reverse MDR in vincristine-resistant KB cells.