Insights into Ganoderma fungi meroterpenoids opening a new era of racemic natural products in mushrooms.

Ganoderma meroterpenoids (GMs) containing 688 structures to date were discovered to have multiple remarkable biological activities. 65.6% of meroterpenoids featuring stereogenic centers from Ganoderma species are racemates. Further, GMs from different Ganoderma species seem to have their own characteristics. In this review, a comprehensive summarization of GMs since 2000 is presented, including GM structures, structure corrections, biological activities, physicochemical properties, total synthesis, and proposed biosynthetic pathways. Additionally, we especially discuss the racemic nature, species-related structural distribution, and structure-activity relationship of GMs, which will provide a likely in-house database and shed light on future studies on GMs.

Medicinal plant resin natural products: structural diversity and biological activities.

Covering: up to the mid of 2023Plants secrete defense resins rich in small-molecule natural products under abiotic and biotic stresses. This comprehensive review encompasses the literature published up to mid-2023 on medicinal plant resin natural products from six main contributor genera, featuring 275 citations that refer to 1115 structurally diverse compounds. The scope of this review extends to include essential information such as the racemic nature of metabolites found in different species of plant resins, source of resins, and revised structures. Additionally, we carefully analyze the reported biological activities of resins, organizing them based on the their structures. The findings offer important insights into the relationship between their structure and activity. Furthermore, this detailed examination can be valuable for researchers and scientists in the field of medicinal plant resin natural products and will promote continued exploration and progress in this area.

Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans.

Twelve new alkaloids, scolopenolines A-L (1-7, 9-11, 13, 14), along with six known analogues, were isolated from Scolopendra subspinipes mutilans, identified by analysis of spectroscopic data and quantum chemical and computational methods. Scolopenoline A (1), a unique guanidyl-containing C14 quinoline alkaloid, features a 6/6/5 ring backbone. Scolopenoline B (2) is a novel sulfonyl-containing heterodimer comprising quinoline and tyramine moieties. Scolopenoline G (7) presents a rare C12 quinoline skeleton with a 6/6/5 ring system. Alkaloids 1, 8, 10, and 15-18 display anti-inflammatory activity, while 10 and 16-18 also exhibit anti-renal-fibrosis activity. Drug affinity responsive target stability and RNA-interference assays show that Lamp2 might be a potentially important target protein of 16 for anti-renal-fibrosis activity.

Isolation and target identification of anti-renal fibrosis compounds from Cordyceps militaris.

Four undescribed compounds including one aromatic glucoside derivative, cordyceglycoside A (1), one new isoleucine derivative inner salt, cordycepisosalt A (2), a rare four-membered lactam, cinerealactam B (3), and one sesquiterpene derivative, cordycepsetp A (4), together with six known compounds were isolated from Cordyceps militaris. The structures including absolute configurations of these new compounds, were unambiguously elucidated by spectroscopic data analysis and single crystal X-ray diffraction. Biological evaluation of compounds 1-4 showed that 3 displays anti-renal fibrotic activities in TGF-ß1 induced NRK-52e cells. Furthermore, DARTS coupled with LC-MS/MS analysis was used to identify candidate target proteins for 3. Subsequently, C1qbp knockdown using siRNA allowed us to validate the target protein of 3.

Investigation of the Inhibitory Effects of Illicium verum Essential Oil Nanoemulsion on Fusarium proliferatum via Combined Transcriptomics and Metabolomics Analysis.

Fusarium proliferatum is the main pathogen that causes Panax notoginseng root rot. The shortcomings of strong volatility and poor water solubility of Illicium verum essential oil (EO) limit its utilization. In this study, we prepared traditional emulsion (BDT) and nanoemulsion (Bneo) of I. verum EO by ultrasonic method with Tween-80 and absolute ethanol as solvents. The chemical components of EO, BDT, and Bneo were identified by gas chromatography-mass spectrometry (GC-MS) and the antifungal activity and mechanism were compared. The results show that Bneo has good stability and its particle size is 34.86 nm. The contents of (-) -anethole and estragole in Bneo were significantly higher than those in BDT. The antifungal activity against F. proliferatum was 5.8-fold higher than BDT. In the presence of I. verum EO, the occurrence of P. notoginseng root rot was significantly reduced. By combining transcriptome and metabolomics analysis, I. verum EO was found to be involved in the mutual transformation of pentose and glucuronic acid, galactose metabolism, streptomycin biosynthesis, carbon metabolism, and other metabolic pathways of F. proliferatum, and it interfered with the normal growth of F. proliferatum to exert antifungal effects. This study provide a theoretical basis for expanding the practical application of Bneo.

Ganoderma lucidum-Derived Meroterpenoids Show Anti-Inflammatory Activity In Vitro.

Ganoderma lucidum, known as the "herb of spiritual potency", is used for the treatment and prevention of various diseases, but the responsible constituents for its therapeutic effects are largely unknown. For the purpose of obtaining insight into the chemical and biological profiling of meroterpenoids in G. lucidum, various chromatographic approaches were utilized for the title fungus. As a result, six undescribed meroterpenoids, chizhienes A-F (1-6), containing two pairs of enantiomers (4 and 5), were isolated. Their structures were identified using spectroscopic and computational methods. In addition, the anti-inflammatory activities of all the isolates were evaluated by Western blot analysis in LPS-induced macrophage cells (RAW264.7), showing that 1 and 3 could dose dependently inhibit iNOS but not COX-2 expression. Further, 1 and 3 were found to inhibit nitric oxide (NO) production using the Greiss reagent test. The current study will aid in enriching the structural and biological diversity of Ganoderma-derived meroterpenoids.

X-ray Study of Cembranoids with Flexible Rings from Boswellia papyrifera Resins Allowing Structural Revision of Misleading Structures from the Past 70 Years.

Thirty new, highly oxygenated and stereogenic 14-membered macrocyclic diterpenoids, papyrifuranols A-Z (1-26) and AA-AD (27-30), and eight known analogs have been isolated from Boswellia papyrifera resins. All the structures were characterized by detailed spectral analyses, quantum calculations, X-ray diffraction, and modified Mosher's methods. Notably, six previously reported structures were revised. Our study points out misleading factors of macrocyclic cembranoid (CB) representation in the past seven decades by analyzing of 25 X-ray structures, lending a hand for the innately challenging structure identification of such flexible macrocyclic CBs and avoiding following the tracks of an overturned cart during future structure characterization and total synthesis. Biosynthetic conversions of all the isolates are proposed, and wound healing bioassays reveal that papyrifuranols N-P could significantly stimulate the proliferation and differentiation of umbilical cord mesenchymal stem cells.

Aquilariperoxide A, a Sesquiterpene Dimer from Agarwood of Aquilaria sinensis with Dual Antitumor and Antimalarial Effects.

Aquilariperoxide A (1), an unprecedented sesquiterpene dimer characterized by a dioxepane ring connecting two sesquiterpene units via a C-C bond, was isolated from agarwood of Aquilaria sinensis-containing resins. The structure was elucidated by spectroscopic and computational methods. A bioassay revealed that 1 significantly inhibits cell proliferation and migration in human cancer cells. The mechanism of 1 against cancer cells was briefly discussed by analysis of RNA sequence data and epithelial-mesenchymal transition. Besides, the antimalarial activity of 1 was also evaluated.

Novel spirooxindole alkaloid derivatives from the medicinal insect Blaps japanensis and their biological evaluation.

Blapspirooxindoles A-C (1-3), three novel spirooxindole alkaloids with a unique spiro[chromane-4,3'-indoline]-2,2'-dione motif, blapcumaranons A and B (4 and 5), two new 2-cumaranon derivatives, blapoxindoles A-J (6-15), ten new oxindole alkaloid derivatives, along with one known compound (16), were isolated from the whole bodies of Blaps japanensis. Their structures including absolute configurations were determined by using spectroscopic, X-ray crystallographic, and computational methods. Compounds 1-11 and 13 exist as racemic mixtures in nature, and their (-)- and (+)-antipodes were separated by chiral HPLC. Biological evaluations of these compounds were determined with multiple assays including anti-tumor, anti-inflammatory, and renal protection activities in vitro. Several compounds displayed effective activity in one or more assays.

Design and synthesis of photoaffinity-based probes for labeling ß-glucuronidase.

ß-Glucuronidase (GUSB) plays an important role in human physiological and pathological activities. The activity level of GUSB is closely related to human health and diseases. It is imperative to detect the activity of GUSB for related disease diagnosis and treatment. However, exactly evaluating the activity of GUSB in complicated biological system remains a challenge. In this study, we developed photoaffinity-based probes (AfBPs) equipped with photosensitive benzophenone group for labeling active GUSB. Through molecule docking, we predicted the binding model of the AfBPs and GUSB, and the obtained results suggested thermodynamically favorable binding. The AfBPs indicated high efficiency and showed dose-/time-dependent labeling of Escherichia coli (E. coli) GUSB. The application of AfBPs toward GUSB provides a powerful tool to study the activity of target enzymes and contributes to huge potential of enzyme inhibitor discovery and biomedical diagnostics.

Structural Optimization, Fungicidal Activities Evaluation, DFT Study and Structure-Activity Relationship of Dopamine Derivatives with Benzothiazole Fragment from Polyrhachis dives.

In our previous work, two dopamine derivatives with benzothiazole fragment were isolated and identified from Polyrhachis dives (P. dives). Based on their characteristic structure, we used them as lead compound to carry out structural optimization and subsequent fungicidal evaluation. Here 20 dopamine derivatives with benzothiazole fragment were designed and synthesized by a facile method, and their structures were characterized by 1 H-NMR, 13 CNMR and HMRS. In bioassays, most of the title compounds possess potential fungicidal activities against Altenaia alternala (A. alternala) and Botrytis cinerea (B. cinerea). Especially, (E)-N-(2-(benzo[d]thiazol-6-yl)ethyl)-3-(p-tolyl)acrylamide and (E)-N-(2-(benzo[d]thiazol-6-yl)ethyl)-3-(4-(trifluoromethyl)phenyl)acrylamide displayed 29.3 mg/L and 10.7 mg/L EC50 value against A. alternala, respectively, which possessed equivalent fungicidal activities level to hymexazol.

Isolation and Characterization of trans-p-Hydroxycinnamoyl Meroterpenoids from Ganoderma sinensis.

Zizhines V, W, Y, Z, (±)-zizhines X, and Z1-Z3, and (±)-ganosinensol L, thirteen new compounds including four pairs of enantiomers and a known compound (-)-ganosinensol L, were isolated from the fruiting bodies of Ganoderma sinensis. Their structures were identified by spectroscopic, computational methods, and CD (circular dichroism spectroscopy) comparisons. Zizhines V-Z and Z1-Z3 are meroterpenoids consisting of the phenolic and the terpenoidal parts. All the compounds except zizhine Z3 bear a common trans-p-hydroxycinnamoyl group. Biological evaluation shows that (-)-zizhine Z1 inhibits cell migration in the MDA-MB-231 cell lines. The present study discloses the chemical profiling of G. sinensis and paves the way for its development as functional products to benefit chronic disorders.

Five New Cantharidin Derivatives from the Insect Mylabris cichorii L. and Their Potential against Kidney Fibrosis In Vitro.

Five new monoterpenoids including three 1-hydroxymethyl-2-methyl cantharimide-type derivatives (1, 2, and 5) and two 1,2-dimethyl cantharimide-type derivatives (3 and 4), together with three known compounds (6-8) were isolated from the insect Mylabris cichorii Linnaeus. The structures of these new compounds, including their absolute configurations, were characterized by detailed analysis of NMR, chemical derivatization, and quantum chemical ECD calculations. All of the compounds were tested for their biological activity against kidney fibrosis. The results revealed that compounds 2, 4, and 7 could inhibit kidney fibrosis in vitro at 40 µM by inhibiting the expression of fibronectin and collagen I in TGF-ß1-induced NRK-52e cells.

Five new sesquiterpenoids from agarwood of Aquilaria sinensis.

Five new eudesmane-type sesquiterpenoids (aquisinenoids F-J (1-5)) and five known compounds (6-10) were isolated from the agarwood of Aquilaria sinensis. Their structures, including absolute configurations, were identified by comprehensive spectroscopic analyses and computational methods. Inspired by our previous study on the same kinds of skeletons, we speculated that the new compounds have anticancer and anti-inflammatory activities. The results did not show any activity, but they revealed the structure-activity relationships (SAR).

Non-peptide compounds from Kronopolites svenhedini (Verhoeff) and their antitumor and iNOS inhibitory activities.

Six new compounds, including a tetralone 1, two xanthones 2 and 3, a flavan derivative 4, and two nor-diterpenoids 7 and 8, accompanied by two known flavan derivatives 5 and 6 and a known olefine acid (9) were isolated from whole bodies of Kronopolites svenhedini (Verhoeff). The structures of the new compounds were determined by 1D and 2D nuclear magnetic resonance (NMR) and other spectroscopic methods, as well as computational methods. Selected compounds were evaluated for their biological properties against a mouse pancreatic cancer cell line and inhibitory effects on iNOS and COX-2 in RAW264.7 cells.

Correction: Non-peptide compounds from Kronopolites svenhedini (Verhoeff) and their antitumor and iNOS inhibitory activities.

[This corrects the article DOI: 10.3762/bjoc.19.59.].

Sesquiterpenoid-Chromone Heterohybrids from Agarwood of Aquilaria sinensis as Potent Specific Smad3 Phosphorylation Inhibitors.

Aquilarines A (1) and B (2), two unprecedented sesquiterpenoid-chromone heterohybrids, were isolated from Aquilaria sinensis agarwood. 1 is an alkaloid featuring an unusual pyridine nucleus, and 2 possesses a rare sesquiterpenoid-chromone skeleton via a C-C bond. A plausible biosynthetic pathway for 1 and 2 was proposed. Both 1 and 2 could significantly inhibit the expression of extracellular matrix components, and α-SMA at low concentrations in TGF-ß1 induced two types of kidney cells (NRK 52E and NRK 49F) featuring selective inhibition of Smad3 instead of Smad2 phosphorylation, showing their potential in renal fibrosis.

Unusual sesquilignans with anti-inflammatory activities from the resin of Ferula sinkiangensis.

Sinkianlignans A - D (1-4), four new sesquilignans with an unusual architectures was characterized with a rarely α-γ', ß-γ', and γ-γ' linkage pattern, and sinkianlignans E - F (5 and 6), two lignans, were isolated from the Ferula sinkiangensis. Hypothetic biosynthetic pathway of compound 3 contain a newly formed six-membered C-ring by Diels-Alder cycloaddition. The structures of isolates were established by spectroscopic techniques and computational methods. Biological evaluation of all the isolated compounds revealed that compounds 2a and 2b could inhibit IL-6 and TNF-α production in lipopolysaccharide (LPS) induced RAW264.7 cells in a dose-dependent manner.

Z16b, a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, lethal ventricular arrhythmia triggered by catecholamines. Mutations in genes that encode cardiac ryanodine receptor (RyR2) and proteins that regulate RyR2 activity cause enhanced diastolic Ca2+ release (leak) through the RyR2 channels, resulting in CPVT. Current therapies for CPVT are limited. We found that Z16b, a meroterpenoid isolated from Ganoderma cochlear, inhibited Ca2+ spark frequency (CaSF) in R2474S/ + cardiomyocytes in a dose-dependent manner, with an IC50 of 3.2 µM. Z16b also dose-dependently suppressed abnormal post-pacing Ca2+ release events. Intraperitoneal injection (i.p.) of epinephrine and caffeine stimulated sustained ventricular tachycardia in all R2474S/+ mice, while pretreatment with Z16b (0.5 mg/kg, i.p.) prevented ventricular arrhythmia in 9 of 10 mice, and Z16b administration immediately after the onset of VT abolished sVT in 9 of 12 mice. Of translational significance, Z16b significantly inhibited CaSF and abnormal Ca2+ release events in human CPVT iPS-CMs. Mechanistically, Z16b interacts with RyR2, enhancing the "zipping" state of the N-terminal and central domains of RyR2. A molecular docking simulation and point mutation and pulldown assays identified Z16b forms hydrogen bonds with Arg626, His1670, and Gln2126 in RyR2 as a triangle shape that anchors the NTD and CD interaction and thus stabilizes RyR2 in a tight "zipping" conformation. Our findings support that Z16b is a novel RyR2 stabilizer that can prevent CPVT. It may also serve as a lead compound with a new scaffold for the design of safer and more efficient drugs for treating CPVT.

Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway.

Cardiac hypertrophy is a common adaptive response to a variety of stimuli, but prolonged hypertrophy leads to heart failure. Hence, discovery of agents treating cardiac hypertrophy is urgently needed. In the present study, we investigated the effects of QF84139, a newly synthesized pyrazine derivative, on cardiac hypertrophy and the underlying mechanisms. In neonatal rat cardiomyocytes (NRCMs), pretreatment with QF84139 (1-10 µM) concentration-dependently inhibited phenylephrine-induced hypertrophic responses characterized by fetal genes reactivation, increased ANP protein level and enlarged cardiomyocytes. In adult male mice, administration of QF84139 (5-90 mg·kg-1·d-1, i.p., for 2 weeks) dose-dependently reversed transverse aortic constriction (TAC)-induced cardiac hypertrophy displayed by cardiomyocyte size, left ventricular mass, heart weights, and reactivation of fetal genes. We further revealed that QF84139 selectively activated the AMPK signaling pathway without affecting the phosphorylation of CaMKIIδ, ERK1/2, AKT, PKCε, and P38 kinases in phenylephrine-treated NRCMs and in the hearts of TAC-treated mice. In NRCMs, QF84139 did not show additive effects with metformin on the AMPK activation, whereas the anti-hypertrophic effect of QF84139 was abolished by an AMPK inhibitor Compound C or knockdown of AMPKα2. In AMPKα2-deficient mice, the anti-hypertrophic effect of QF84139 was also vanished. These results demonstrate that QF84139 attenuates the PE- and TAC-induced cardiac hypertrophy via activating the AMPK signaling. This structurally novel compound would be a promising lead compound for developing effective agents for the treatment of cardiac hypertrophy.