Natural product-derived ferroptosis mediators.

It has been 11 years since ferroptosis, a new mode of programmed cell death, was first proposed. Natural products are an important source of drug discovery. In the past five years, natural product-derived ferroptosis regulators have been discovered in an endless stream. Herein, 178 natural products discovered so far to trigger or resist ferroptosis are classified into 6 structural classes based on skeleton type, and the mechanisms of action that have been reported are elaborated upon. If pharmacodynamic data are sufficient, the structure and bioactivity relationship is also presented. This review will provide medicinal chemists with some effective ferroptosis regulators, which will promote the research of natural product-based treatment of ferroptosis-related diseases in the future.

Rare 7,9'-dinorlignans with neuroprotective activity from the roots of Lindera aggregata (Sims) Kosterm.

Linderagatins C-F (1-4), the first examples of naturally occurring diaryltetrahydrofuran-type 7,9'-dinorlignans, were characterized from the roots of Lindera aggregata (Sims) Kosterm. The structures of these dinorlignans were elucidated by extensive spectroscopic analysis. The absolute configurations were determined based on calculated and experimental ECD data. A biosynthetic pathway for these dinorlignans was hypothetically proposed. Compounds 2 and 3 showed significant neuroprotective effects on erastin-induced ferroptosis in HT-22 cells with EC50 values of 23.4 and 21.8 µM, respectively.

Structurally Diverse Sesquiterpenoids from the Genus of Ainsliaea.

The genus of Ainsliaea embraces approximately 70 recognized species, many of which have been used to treat various diseases in folklore medicines. As the main metabolites of Ainsliaea plants, Ainsliaea sesquiterpenoids have drawn considerable attention in related scientific communities due to their intriguing structures and a variety of bioactivities. In this review, we intend to provide a full-aspect coverage of sesquiterpenoids reported from the genus of Ainsliaea, including 145 monomeric sesquiterpenoids and 30 oligomeric ones. Multiple aspects will be summarized, including their classification, distributions, structures, bioactivities, and biomimetic syntheses. In addition, their possible biosynthetic pathway will be discussed in detail.

Discovery of phenylcarbamoyl xanthone derivatives as potent neuroprotective agents for treating ischemic stroke.

Compounds of natural sources are widespread discovered in the treatment of ischemic stroke. Alpha-mangostin, a natural prenylated xanthone, has been found to display a therapeutic potential to treat ischemic stroke. However, the direct application of α-mangostin is limited due to its cytotoxicity and relatively low efficacy. Herein, structural modification of α-mangostin was necessary to improve its drug-ability. Currently, 34 α-mangostin phenylcarbamoyl derivatives were synthesized and evaluated for their neuroprotective activities by glutamate-induced excitotoxicity and H2O2-induced oxidative damage models in vitro. The results showed that compound 2 had the most therapeutic potential in both models. Whereafter, 2 has been proved to have powerful therapeutic effects by the MCAO ischemic stroke model in rats, which might be due to inhibition of inflammatory reaction and free radical accumulation. Besides, acute toxicity assay in rats showed that compound 2 had excellent safety. Overall, 2 could be a promising neuroprotective agent for the treatment of ischemic stroke deserving further investigations.

Coordination of Polyketide Release and Multiple Detoxification Pathways for Tolerable Production of Fungal Mycotoxins.

Efficient biosynthesis of microbial bioactive natural products (NPs) is beneficial for the survival of producers, while self-protection is necessary to avoid self-harm resulting from over-accumulation of NPs. The underlying mechanisms for the effective but tolerable production of bioactive NPs are not well understood. Herein, in the biosynthesis of two fungal polyketide mycotoxins aurovertin E (1) and asteltoxin, we show that the cyclases in the gene clusters promote the release of the polyketide backbone, and reveal that a signal peptide is crucial for their subcellular localization and full activity. Meanwhile, the fungus adopts enzymatic acetylation as the major detoxification pathway of 1. If intermediates are over-produced, the non-enzymatic shunt pathways work as salvage pathways to avoid excessive accumulation of the toxic metabolites for self-protection. These findings provided new insight into the interplay of efficient backbone release and multiple detoxification strategies for the production of fungal bioactive NPs.

New Jatrophane-Type Diterpenoids from Euphorbia kansui as Potential MDR Reversal Agents.

A serial jatrophane-type diterpenoids, comprised with three undescribed compounds kanesulones C-E (1-3) and four known ones (4-7), were obtained from the roots of Euphorbia kansui. The structures of compounds 1-3 were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS, the absolute configuration of 1 was revealed by single crystal X-ray diffraction. These isolates were assayed for their multidrug resistance reversing activities on human breast adenocarcinoma cell line MCF-7/ADR. Compound 1 possessed potential as low toxic MDR modulator that could promote the efficacy of anticancer drug adriamycin ca. 85-fold at 5 µM, as 12 times stronger than the positive drug verapamil.

Lignans and sesquiterpenes from Schisandra tomentella A. C. Smith.

This is the first phytochemical investigation of Schisandra tomentella A. C. Smith. 11 lignans and 8 sesquiterpenoids, were isolated from the stems of S. tomentella, including two undescribed lignans, tomentaschinins A-B (1-2), and two new sesquiterpenoids, tomentaschinnes A-B (3-4). Their structures were elucidated based on the interpretation of their spectroscopic data. Cytotoxicity and MDR reversal effect of these compounds were screened on multidrug resistance cancer cell line MCF-7/ADR, and results showed gomisin M2 (7) could promote the efficacy of adriamycin against MCF-7/ADR.

Tetrodecadazinone, a novel tetrodecamycin-pyridazinone hybrid with anti-liver fibrosis activity from Streptomyces sp. HU051.

Tetrodecadazinone (1), a novel tetrodecamycin-pyridazinone hybrid possessing a new 1,2-dimethyl-1-(2-methylnonyl)decahydronaphthalene skeleton, and 4-hydroxydihydrotetrodecamycin (2) were separated from a culture of Streptomyces sp. HU051, together with a known compound, dihydrotetrodecamycin (3). Diverse spectroscopic approaches were applied to assign the structures of 1-3, and the structure of 1 was further confirmed by single crystal X-ray diffraction analysis. Compound 1 is the first example of a pyridazinone-containing natural product. Biosynthetically, 1 is proposed to be derived from a Michael addition reaction of a PKS-derived tetrodecamycin and a piperazic-acid-derived pyridazinone. Biological evaluation revealed 1 could reduce the expressions of extracellular matrix proteins (fibronectin and collagen I) and α-smooth muscle actin (α-SMA) in transforming growth factor-ß (TGF-ß1)-activated LX-2 cells. Preliminary mechanism study showed 1 exerted its anti-liver fibrosis effect by regulating TGF-ß1/Smad2/3 signaling pathway.

New Insights Into the Antibacterial Mechanism of Cryptotanshinone, a Representative Diterpenoid Quinone From Salvia miltiorrhiza Bunge.

The rapid rise of antibiotic resistance causes an urgent need for new antimicrobial agents with unique and different mechanisms of action. The respiratory chain is one such target involved in the redox balance and energy metabolism. As a natural quinone compound isolated from the root of Salvia miltiorrhiza Bunge, cryptotanshinone (CT) has been previously demonstrated against a wide range of Gram-positive bacteria including multidrug-resistant pathogens. Although superoxide radicals induced by CT are proposed to play an important role in the antibacterial effect of this agent, its mechanism of action is still unclear. In this study, we have shown that CT is a bacteriostatic agent rather than a bactericidal agent. Metabolome analysis suggested that CT might act as an antibacterial agent targeting the cell membrane. CT did not cause severe damage to the bacterial membrane but rapidly dissipated membrane potential, implying that this compound could be a respiratory chain inhibitor. Oxygen consumption analysis in staphylococcal membrane vesicles implied that CT acted as respiratory chain inhibitor probably by targeting type II NADH:quinone dehydrogenase (NDH-2). Molecular docking study suggested that the compound would competitively inhibit the binding of quinone to NDH-2. Consistent with the hypothesis, the antimicrobial activity of CT was blocked by menaquinone, and the combination of CT with thioridazine but not 2-n-heptyl-4-hydroxyquinoline-N-oxide exerted synergistic activity against Staphylococcus aureus. Additionally, combinations of CT with other inhibitors targeting different components of the bacterial respiratory chain exhibit potent synergistic activities against S. aureus, suggesting a promising role in combination therapies.

Effects of α-Mangostin Derivatives on the Alzheimer's Disease Model of Rats and Their Mechanism: A Combination of Experimental Study and Computational Systems Pharmacology Analysis.

α-Mangostin (α-M) is a natural xanthone from the pericarp of fruit Garcinia mangostana and possesses versatile biological activities. α-M has a therapeutic potential to treat Alzheimer's disease (AD) because of its anti-inflammatory, antioxidative, and neuroprotective activities. However, the use of α-M for AD treatment is limited due to its cytotoxic activities and relatively low potency. Modifications of its chemical structure were needed to reduce its cytotoxicity and improve its therapeutic potential against AD. For this purpose, 16 α-M carbamate derivatives were synthesized. An animal model of AD was established, and the effects of AMG-1 on the spatial learning ability and memory ability were evaluated using behavioral tests. The effect on neuropathology was tested by histopathological evaluation, Nissl staining, and silver staining. Computational systems pharmacology analysis using the chemogenomics knowledgebase was applied for network studies. Compound-target, target-pathway, and target-disease networks were constructed, integrating both in silico analysis and reported experimental data. The results show that AMG-1 can demonstrate its therapeutic effects in a one-molecule, multiple-targets manner to remarkably ameliorate neurological changes and reverse behavioral deficits in AD model rats. The improved cognitive function and alleviated neuronal injury can be observed. The ability of AMG-1 to scavenge ß-amyloid in the hippocampus was validated in AD model rats.

Streptomyces albogriseolus SY67903 Produces Eunicellin Diterpenoids Structurally Similar to Terpenes of the Gorgonian Muricella sibogae, the Bacterial Source.

Microeunicellols A (1) and B (2), two undescribed eunicellin diterpenoids, were isolated from the culture of a bacterial symbiont, Streptomyces albogriseolus SY67903. Their structures, including absolute configurations revealed by spectroscopic data and single-crystal X-ray diffraction analysis, are closely related with the diterpenoids from its host, a South China Sea gorgonian, Muricella sibogae. This is the first report of eunicellin diterpenoids, commonly coral-derived, from a bacterial symbiont of coral. The chemical metabolic relationship between the bacterium and its host is discussed. Biological evaluation revealed that compound 1 possessed cytotoxicities against several human cancer cell lines.

Natural disesquiterpenoids: an update.

Covering: July 2010 to August 2019. Previous review: Nat. Prod. Rep., 2011, 28, 594The review covers recent progress on the isolation, identification, bioactivity and biomimetic synthesis of natural dimeric sesquiterpenoids, along with a detailed discussion of the biogenesis of these metabolites. Structural revisions are included.

Morindolestatin, Naturally Occurring Dehydromorpholinocarbazole Alkaloid from Soil-Derived Bacterium of the Genus Streptomyces.

Novel antilipid peroxidative carbazole alkaloids, antiostatin A5 (1), antiostatin A6 (2), and (±)-morindolestatin (3), were isolated from a new soil-derived Streptomyces sp. Compound 2 possesses an unusual cyclohexene side chain. Compound 3 was a pair of enantiomers featuring an unprecedented [1,4]oxazino[2,3-c]carbazole ring system. The absolute configuration of 3 was determined by online HPLC-ECD and ECD calculation. A racemization mechanism and putative biosynthetic pathway are discussed.

Cytotoxic Spliceostatin Analogs from Pseudomonas sp.

Two new spliceostatin analogs, designed as spliceostatins J and K (1 and 2), were isolated and identified from the culture of Pseudomonas sp., along with two known ones, FR901464 (3) and spliceostatin E (4). Their structures were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS. Spliceostatin J (1) represented the first example of spliceostatins bearing an unusual hexahydrofuro[3,4-b]furan moiety. Biological assay showed all the isolated compounds except 1 displayed potent cytotoxic activities against two cancer cell lines (MDA-MB-231 and A-549). Structure-activity-relationship studies revealed that the tetrahydropyran ring in spliceostatin analogs was necessary for their bioactive retention.

New Immunomodulating Polyhydroxypregnane Glycosides from the Roots of Cynanchum otophyllum C.K.Schneid.

Seven new polyhydroxypregnane glycosides, named cynotophyllosides P-V, together with three known analogs were isolated from the roots of Cynanchum otophyllum C.K.Schneid. Their structures were elucidated by a variety of spectroscopic techniques, as well as acid-catalyzed hydrolysis. All isolates were tested for their immunological activities in vitro against Con A- and LPS-induced proliferation of mice splenocytes. Immunoenhancing (for 1, 9) and immunosuppressive (for 2) activities were observed. Furthermore, cynotophylloside R (3) showed immunomodulatory as it enhanced the proliferation of splenocytes in low concentration and suppressed immune cells in concentration more than 1.0 µg/ml.

Synthesis and anti-tumor activity study of water-soluble PEG-celastrol coupling derivatives as self-assembled nanoparticles.

To improve the drug-ability of celastrol, a series of PEGylation celastrol (PEGC) were designed and synthesized by conjugation with different kinds of polyethylene glycols (PEGs) with celastrol. Most of PEGCs could easily dissolve in water. In particular, one of them (DC1000) could be dispersed in water to form nanoparticles by self-assembly. The cytotoxic evaluation of PEGCs revealed that some of PEGCs showed more potent cytotoxicity than celastrol, and the molecular weight of PEG parts in PEGCs had apparent influence on their cytotoxic activity. Anti-tumor evaluation in vivo showed DC1000 had higher tumor inhibition rate and better safety than celastrol by intravenous administration with equivalent molar weight. These results revealed PEGylation might be an efficient and economical method to improve the water solubility and safety of celastrol and similar natural products.

Studies on the Chemical Diversities of Secondary Metabolites Produced by Neosartorya fischeri via the OSMAC Method.

The One Strain Many Compounds (OSMAC) method was applied to explore the chemical diversities of secondary metabolites produced by Neosartorya fischeri NRRL 181. Four pyripyropenes 1⁻4, eight steroids 5⁻11, and four prenylated indole alkaloids 12⁻15, were obtained from the fungus cultured in petri dishes containing potato dextrose agar (PDA). 1,7,11-trideacetylpyripyropene A (1) and 1,11-dideacetyl pyripyropene A (2) were obtained and spectroscopically characterized (1D, 2D NMR, and HR-ESI-MS) from a natural source for the first time. It offered a sustainable source of these two compounds, which were usually used as starting materials in preparing pyripyropene derivatives. In addition, as compared with all the other naturally occurring pyripyropenes, 1 and 2 possessed unique acetylation patterns that did not follow the established late-step biosynthetic rules of pyripyropenes. The natural occurrence of 1 and 2 in the fungus implied that the timing and order of hydroxylation and acetylation in the late-step biosynthetic pathway of pyripyropenes remained to be revealed. The isolation and identification of 1⁻15 indicated that the OSMAC method could remarkably alter the metabolic profile and enrich the chemical diversities of fungal metabolites. Compounds 1⁻4 exhibited no obvious cytotoxicity against the triple-negative breast cancer cell line MDA-MB-231 as compared with taxol.

New Eudesmane Sesquiterpenoids from Salvia plebeia R. Br.

Three new sesquiterpenoids, salplebeones A - C (1 - 3), were isolated from the ethanol-soluble extract of the aerial part of Salvia plebeia R. Br. Their structures were established by detailed analysis of NMR and MS spectra. Salplebeone A was an eudesmane lactone, while salplebeones B and C were rare eudesmane sesquiterpenoids, containing 12,8-lactam groups. Antiproliferative activities of salplebeones A - C to myeloid leukemia cell lines were evaluated.

α-Glucosidase Inhibitors from the Fungus Aspergillus terreus 3.05358.

One new diketopiperazine alkaloid amauromine B (1), along with three known meroterpenoids, austalide B (2), austalides N and O (3 and 4), and two known steroids (5 and 6), was isolated and identified from the culture broth of the fungus Aspergillus terreus 3.05358. Their structures were elucidated by extensive spectroscopic techniques, including 2D-NMR and MS analysis, the absolute configuration of 1 was unambiguously established by single crystal X-ray diffraction analysis. All the isolates were evaluated for their inhibitory effects on α-glucosidase. Amauromine B (1) and austalide N (3) exhibited more potent α-glucosidase inhibitory activities than the positive control acarbose.

Terpenoids with alpha-glucosidase inhibitory activity from the submerged culture of Inonotus obliquus.

Lanostane-type triterpenoids, inotolactones A and B, a drimane-type sesquiterpenoid, inotolactone C, and five known terpenoids 6ß-hydroxy-trans-dihydroconfertifolin, inotodiol, 3ß,22-dihydroxyanosta-7,9(11),24-triene, 3ß-hydroxycinnamolide, and 17-hydroxy-ent-atisan-19-oic acid, were isolated from the submerged culture of chaga mushroom, Inonotus obliquus. Their structures were characterized by spectroscopic methods, including MS and NMR (1D and 2D) spectroscopic techniques. Inotolactones A and B, examples of lanostane-type triterpenoids bearing α,ß-dimethyl, α,ß-unsaturated δ-lactone side chains, exhibited more potent alpha-glucosidase inhibitory activities than the positive control acarbose. This finding might be related to the anti-hyperglycemic properties of the fungus and to its popular role as a diabetes treatment. In addition, a drimane-type sesquiterpenoid and an atisane-type diterpenoid were isolated from I. obliquus.