Cyclopiazonic Acid and Okaramine Analogues, Including Chlorinated Compounds, from Chrysosporium undulatum YT-1.

Eight new cyclopiazonic acid (1-8) and five new okaramine (9-13) alkaloids together with 13 known compounds were isolated from the fungus Chrysosporium undulatum YT-1. Compounds 2, 4, 5, 7, 10, 11, and 13 were chlorinated indole alkaloids. The structures of compounds 1-13 were elucidated by HRESIMS and NMR spectroscopic data. Their relative and absolute configurations were established by J-based configuration analysis, NOESY, NOEDIFF experiments, ECD spectroscopic data, and biogenetic considerations. Compound 4 inhibited the growth of Bacillus subtilis with an MIC value of 6.3 µg/mL. Compounds 9-11 exhibited strong insecticidal capacity against the third instar larvae of silkworm and cotton bollworm (LD50: ≤7.56 µg/g). At 40 µM, compound 1 showed obvious neuroprotection to the PC12 cells with 6-OHDA treatment.

Neoechinulin A as a Promising SARS-CoV-2 Mpro Inhibitor: In Vitro and In Silico Study Showing the Ability of Simulations in Discerning Active from Inactive Enzyme Inhibitors.

The COVID-19 pandemic and its continuing emerging variants emphasize the need to discover appropriate treatment, where vaccines alone have failed to show complete protection against the new variants of the virus. Therefore, treatment of the infected cases is critical. This paper discusses the bio-guided isolation of three indole diketopiperazine alkaloids, neoechinulin A (1), echinulin (2), and eurocristatine (3), from the Red Sea-derived Aspergillus fumigatus MR2012. Neoechinulin A (1) exhibited a potent inhibitory effect against SARS-CoV-2 Mpro with IC50 value of 0.47 µM, which is comparable to the reference standard GC376. Despite the structural similarity between the three compounds, only 1 showed a promising effect. The mechanism of inhibition is discussed in light of a series of extensive molecular docking, classical and steered molecular dynamics simulation experiments. This paper sheds light on indole diketopiperazine alkaloids as a potential structural motif against SARS-CoV-2 Mpro. Additionally, it highlights the potential of different molecular docking and molecular dynamics simulation approaches in the discrimination between active and inactive structurally related Mpro inhibitors.

Voatriafricanines A and B, Trimeric Vobasine-Aspidosperma-Aspidosperma Alkaloids from Voacanga africana.

Voatriafricanines A and B (1 and 2), the first examples of vobasine-aspidosperma-aspidosperma monoterpene trisindole alkaloids, were isolated from the stem barks of Voacanga africana, guided by a molecular networking strategy. Their structures, including absolute configurations, were elucidated by spectroscopic methods and ECD calculations. Compounds 1 and 2 possess intramolecular hydrogen bonding, sufficiently robust to transfer homonuclear and heteronuclear magnetizations. Compound 1 exhibited potent antimycobacterial activity with no discernible cytotoxic activity.

Indole Alkaloids from a Soil-Derived Clonostachys rosea.

Clonorosins A (1) and B (2), two novel indole alkaloids featuring unprecedented 6/5/6/6/5 and 6/5/5 cores, together with seven known indole-linked 2,5-diketopiperazine alkaloids (3-9), were isolated from the soil-derived fungus Clonostachys rosea YRS-06. The new structures were proposed through HR-MS, NMR, and ECD spectroscopic data. They were established by comparing the calculated NMR, ECD, and specific rotation data with the experimental. To assist in determining the absolute configuration of the chiral carbon in the side chain of 2,5-diketopiperazine derivatives, flexible analogues 3i-3iv were synthesized and analyzed. 1 was active against Fusarium oxysporum with an MIC value of 50 µg/mL. 7 and 8 showed excellent activity against human HeLa and HepG2 cells with IC50 values of 0.12-0.60 µM.

[11]-Chaetoglobosins from Pseudeurotium bakeri Induce G2/M Cell Cycle Arrest and Apoptosis in Human Cancer Cells.

Twelve new [11]-chaetoglobosins, chaetopseudeurins A-L (1-12), were identified from the fermentation of the endophytic fungus Pseudeurotium bakeri P1-1-1. Their structures with absolute configurations were elucidated by detailed interpretation of NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. Compounds 2 and 5-7 exhibited significant cytotoxicities against seven human cancer cell lines, with IC50 values ranging from 4.7 ± 1.0 to 12.2 ± 0.7 µM, and induced G2/M cell cycle arrest and apoptosis in MCF-7 and A427 cells dose dependently. Western blot analysis showed that compound 2 induced apoptosis of MCF-7 cells via the Bcl-2/caspase-3/PARP pathway.

Targeted Isolation of Hemitheion from Mostuea brunonis, a Proposed Biosynthetic Intermediate of Theionbrunonines.

Hemitheion (1), a new sulfur-containing vobasane-type indole alkaloid, was isolated, together with three known compounds, vobasine (2), gelsedine (3), and gelsemicine (4), from the alkaloid extract of the stems of Mostuea brunonis Didr. (Gelsemiaceae). Compound 1 could be straightforwardly isolated. Its structure was elucidated by a combination of spectroscopic methods. Besides corresponding to a formerly postulated biosynthetic intermediate toward theionbrunonines, hemitheion (1) stands among the few monomeric vobasanes lacking an oxygen at C-3. Hemitheion (1) showed moderate antiplasmodial activity in the micromolar range against the strain FcB1 of Plasmodium falciparum and no cytotoxic activity against the MRC-5 cell line at 20 µM.

Gelstriamine A, a Triamino Monoterpene Indole Alkaloid with a Caged 6/5/7/6/6/5 Scaffold and Analgesic Alkaloids from Gelsemium elegans Stems.

A novel triamino monoterpene indole alkaloid with an unprecedented skeleton, gelstriamine A (1), four new monoterpene indole alkaloids (2-5), and 12 known analogues (6-17) were isolated from Gelsemium elegans. The structures of 1-5 were established using extensive spectroscopic techniques, NMR calculations with iJ/dJ-DP4 and 2D C-H COSY ANNs analysis, ECD calculations, chemical methods, and single crystal X-ray diffraction analysis. Gelstriamine A (1) possesses an unprecedented 6/5/7/6/6/5 heterohexacyclic scaffold bearing a unique hexahydrooxazolo[4,5-b]pyridin-2(3H)-one motif, and a plausible biosynthetic pathway was proposed. All the isolated alkaloids 1-17 showed discernible analgesic activities in an acetic acid-induced writhing test in mice, and N-desmethoxyhumantenine N4-oxide (3) exhibited more potent analgesic activities than those of morphine at doses of 0.04 and 0.2 mg/kg.

New Prenylated Indole Homodimeric and Pteridine Alkaloids from the Marine-Derived Fungus Aspergillus austroafricanus Y32-2.

Chemical investigation of secondary metabolites from the marine-derived fungus Aspergillus austroafricanus Y32-2 resulted in the isolation of two new prenylated indole alkaloid homodimers, di-6-hydroxydeoxybrevianamide E (1) and dinotoamide J (2), one new pteridine alkaloid asperpteridinate A (3), with eleven known compounds (4-14). Their structures were elucidated by various spectroscopic methods including HRESIMS and NMR, while their absolute configurations were determined by ECD calculations. Each compound was evaluated for pro-angiogenic, anti-inflammatory effects in zebrafish models and cytotoxicity for HepG2 human liver carcinoma cells. As a result, compounds 2, 4, 5, 7, 10 exhibited pro-angiogenic activity in a PTK787-induced vascular injury zebrafish model in a dose-dependent manner, compounds 7, 8, 10, 11 displayed anti-inflammatory activity in a CuSO4-induced zebrafish inflammation model, and compound 6 showed significant cytotoxicity against HepG2 cells with an IC50 value of 30 µg/mL.

Neuronal Modulators from the Coral-Associated Fungi Aspergillus candidus.

Three new p-terphenyl derivatives, named 4″-O-methyl-prenylterphenyllin B (1) and phenylcandilide A and B (17 and 18), and three new indole-diterpene alkaloids, asperindoles E-G (22-24), were isolated together with eighteen known analogues from the fungi Aspergillus candidus associated with the South China Sea gorgonian Junceela fragillis. The structures and absolute configurations of the new compounds were elucidated on the basis of spectroscopic analysis, and DFT/NMR and TDDFT/ECD calculations. In a primary cultured cortical neuronal network, the compounds 6, 9, 14, 17, 18 and 24 modulated spontaneous Ca2+ oscillations and 4-aminopyridine hyperexcited neuronal activity. A preliminary structure-activity relationship was discussed.

Bioactive Indole Diketopiperazine Alkaloids from the Marine Endophytic Fungus Aspergillus sp. YJ191021.

Six new prenylated indole diketopiperazine alkaloids, asperthrins A-F (1-6), along with eight known analogues (7-14), were isolated from the marine-derived endophytic fungus Aspergillus sp. YJ191021. Their planar structures and absolute configurations were elucidated by HR-ESI-MS, 1D/2D NMR data, and time-dependent density functional theory (TDDFT)/ECD calculation. The isolated compounds were assayed for their inhibition against three agricultural pathogenic fungi, four fish pathogenic bacteria, and two agricultural pathogenic bacteria. Compound 1 exhibited moderate antifungal and antibacterial activities against Vibrioanguillarum, Xanthomonas oryzae pv. Oryzicola, and Rhizoctoniasolani with minimal inhibitory concentration (MIC) values of 8, 12.5, and 25 µg/mL, respectively. Furthermore, 1 displayed notable anti-inflammatory activity with IC50 value of 1.46 ± 0.21 µM in Propionibacteriumacnes induced human monocyte cell line (THP-1).

NMR characterization of rearranged staurosporine aglycone analogues from the marine sponge Damiria sp.

The indolocarbazole family of bisindole alkaloids is best known for the natural product staurosporine, a protein kinase C inhibitor that belongs to the indolo[2,3-a]carbazole structural class. A large number of other indolo[2,3-a]carbazoles have subsequently been isolated and identified, but other isomeric forms of indolocarbazole natural products have rarely been reported. An extract of the marine sponge Damiria sp., which represents an understudied genus, provided two novel alkaloids named damirines A (1) and B (2). Their structures were assigned by comprehensive NMR spectroscopic analyses, and for compound 2, this included application of the LR-HSQMBC pulse sequence, a long-range heteronuclear correlation experiment that has particular utility for defining proton-deficient scaffolds. The damirines represent a new hexacyclic carbon-nitrogen framework comprised of an indolo[3,2-a]carbazole fused with either an aminoimidazole or a imidazolone ring. Compound 1 showed selective cytotoxic properties toward six different cell lines in the NCI-60 cancer screen.

Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3ß Signal Axis through a Cyclic Nucleotides/VASP-Independent Mechanism.

The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1-5 µM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3ß (GSK3ß) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3ß pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.

Gelsemium elegans Benth: Chemical Components, Pharmacological Effects, and Toxicity Mechanisms.

Gelsemium elegans Benth (GEB), also known as heartbreak grass, is a highly poisonous plant belonging to the family Loganiaceae and genus Gelsemium that has broad application prospects in medicine. This article reviews its chemical components, pharmacological effects, toxicity mechanisms, and research progress in clinical applications in recent years. Indole alkaloids are the main active components of GEB and have a variety of pharmacological and biological functions. They have anti-tumor, anti-inflammatory, analgesic, and immunomodulation properties, with the therapeutic dose being close to the toxic dose. Application of small-dose indole alkaloids fails to work effectively, while high-dose usage is prone to poisoning, aggravating the patient's conditions. Special caution is needed, especially to observe the changes in the disease condition of the patients in clinical practice. In-depth research on the chemical components and mechanisms of GEB is essential to the development of promising lead compounds and lays the foundation for extensive clinical application and safe usage of GEB in the future.

Tabernaesines A-I, Cytotoxic Aspidosperma-Aspidosperma-Type Bisindole Alkaloids from Tabernaemontana pachysiphon.

Twenty-one aspidosperma-aspidosperma alkaloids, including the new tabernaesines A-J (1-9), were obtained from Tabernaemontana pachysiphon. The structures and absolute configurations were elucidated using HRMS and NMR experiments. Compounds 1-9 possessed a rare spiro heterocycle moiety between the monomeric units, while compounds 4 and 5 were characterized by an indole ring fused with an (N,N-diethyl)methyl amino group. Compounds 1, 5-7, 15, and 16 exhibited moderate cytotoxic potency against various human cancer cell lines at IC50 2.5-9.8 µM.

Monoterpene indole alkaloids with acetylcholinesterase inhibitory activity from the leaves of Rauvolfia vomitoria.

Seventeen monoterpene indole alkaloids, including seven new alkaloids (1-7) and ten known analogues (8-17), were isolated and identified from the leaves of R. vomitoria. The structures of new alkaloids were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Rauvomitorine I (1) represents the first example of an unprecedented C22 yohimbine-type monoterpene indole alkaloid featuring a carboxymethyl at C-14. The exceedingly rare vobasenal (2-3) and affinisine oxindole (5-6) framework type alkaloids are first reported from the Rauvolfia genus. Most notably, the structure of vobasenal-type alkaloids (2-3) were first determined by single-crystal X-ray diffraction analyses. Alkaloids 1-17 were tested their cytotoxicity against five cancer cell lines, however, none of them showed significant cytotoxicity at a concentration of 40 µM. All the isolated alkaloids were evaluated their acetylcholinesterase (AChE) inhibitory activities. Alkaloid 3 exhibited significant anti-AChE activity with an IC50 value of 16.39 ± 1.41 µM and alkaloids 8 and 10 showed moderate anti-AChE activities whereas the others (2, 9, 13, and 17) were weak inhibitors. This is the first report of vobasenal-type alkaloids as AChE inhibitors, indicating this type of alkaloids may be important sources for the discovery of new AChE inhibitors. A preliminary structure-activity relationship for AChE inhibitory activities showed the presence of the N-methyl group in vobasenal-type alkaloids may be essential for anti-AChE activity. Further molecular docking studies of vobasenal-type alkaloids revealed that interaction with Trp133 and Trp86 residues at hydrophobic subsite are necessary for the AChE inhibitory activities. This study not only enriches the chemical diversity of alkaloids in Apocynaceae plants but also provides new potential leading compounds and versatile scaffolds for the design and development of new AChE inhibitors to treat AD.

Total synthesis and isolation of citrinalin and cyclopiamine congeners.

Many natural products that contain basic nitrogen atoms--for example alkaloids like morphine and quinine-have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously.

Chaetoglobosins and azaphilones from Chaetomium globosum associated with Apostichopus japonicus.

Increasing attention has recently been focused on complex symbiotic associations, for instance coral and its symbionts. Sea cucumber, harboring diverse fungi, has also attracted more and more attention for their functional diversity. Here, secondary metabolites produced by Chaetomium globosum associated with sea cucumber, Apostichopus japonicus, were investigated using gene mining with third-generation sequencing technology (PacBio SMRT). Nine compounds, including one new compound cytoglobosin X (1), were isolated from cultures of Chaetomium globosum. Compound 1 was identified based on NMR data, HRESIMS, and ECD, and the absolute configurations were identified as 3S, 4R, 7S, 8R, 9R, 16S, 19S, 20S, and 23S. In an antimicrobial assay, compound 4 showed moderate activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus with MICs of 47.3 and 94.6 µM, respectively. Our results suggest that the microbiomes associated with sea cucumber could be an important resource for biodiversity and structural novelty, and the bioactive compounds may protect the host from pathogen microbial.

Antiplasmodial Bis-Indole Alkaloids from the Bark of Flindersia pimenteliana.

Three new (1: -3: ) and 2 known (4: -5: ) bis-indole alkaloids were identified from the bark of Flindersia pimenteliana (Rutaceae). The structures of 1: -3: were elucidated on the basis of their (+)-HRESESIMS and 2D NMR spectroscopic data. Antiplasmodial activity for 1: -3: against chloroquine sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum is also reported, with IC50 values ranging from 0.96 to 2.41 µg/mL. These results expand our knowledge of the structure-activity relationships of potently antiplasmodial isoborreverine-type alkaloids, the bioactivity of which have recently attracted significant attention in the literature.

Hapalindoles from the Cyanobacterium Hapalosiphon sp. Inhibit T Cell Proliferation.

Novel immunomodulating agents are currently sought after for the treatment of autoimmune diseases and cancers. In this context, a screening campaign of a collection of 575 cyanobacteria extracts for immunomodulatory effects has been conducted. The screening resulted in several active extracts. Here we report the results of subsequent studies on an extract from the cyanobacterium Hapalosiphon sp. CBT1235. We identified 5 hapalindoles as the compounds responsible for the observed immunomodulatory effect. These indole alkaloids are produced by several strains of the cyanobacterial family Hapalosiphonaceae. They are known for their anti-infective, cytotoxic, and other bioactivities. Modulation of the activity of human immune cells has not yet been described. The immunomodulatory activity of the hapalindoles was characterized in vitro using flow cytometry-based measurements of T cell proliferation after carboxyfluorescein diacetate succinimidyl ester staining, and apoptosis and necrosis induction after annexin V/propidium iodide staining. The most potent compound, hapalindole A, reduced T cell proliferation with an IC50 of 1.56 µM, while relevant levels of apoptosis were measurable only at 10-fold higher concentrations. Hapalindole A-formamide and hapalindole J-formamide, isolated for the first time from a natural source, had much lower activity than the nonformylated derivatives while, at the same time, being less selective for antiproliferative over apoptotic effects.

Bioactive Bis(indole) Alkaloids from a Spongosorites sp. Sponge.

Six new bis(indole) alkaloids (1-6) along with eight known ones of the topsentin class were isolated from a Spongosorites sp. sponge of Korea. Based on the results of combined spectroscopic analyses, the structures of spongosoritins A-D (1-4) were determined to possess a 2-methoxy-1-imidazole-5-one core connecting the indole moieties, and these were linked by a linear urea bridge for spongocarbamides A (5) and B (6). The absolute configurations of spongosoritins were assigned by electronic circular dichroism (ECD) computation. The new compounds exhibited moderate inhibition against transpeptidase sortase A and weak inhibition against human pathogenic bacteria and A549 and K562 cancer cell lines.