Dibenzofurans from nature: Biosynthesis, structural diversity, sources, and bioactivities.

Dibenzofurans are a small class of natural products with versatile biological activities that used to be thought to come mainly from lichens and ascomycetes. In fact, they are also distributed widely in higher plants, especially in the families Rosaceae and Myrtaceae. Dibenzofurans and derivatives from lichens and ascomycetes have been well reviewed, but dibenzofurans from all biological sources in nature have not been reviewed. In this review, dibenzofurans from all natural sources have been comprehensively reviewed, and a total of 211 dibenzofurans isolated and identified from organisms between 1843 and March 2023 are categorized and discussed, including their biosynthesis, structural diversity, sources, and bioactivities.

Phloridzin Highly Accumulated in Malus rockii Rehder and Its Structure Revision and Hypolipidemic Activity.

Phloridzin is a lead compound of the prestigious antidiabetic gliflozins. The present study found that phloridzin highly accumulated in Malus rockii Rehder. The content of phloridzin in M. rockii was the highest among wild plants, with the percentage of 15.54% in the dry leaves. The structure of phloridzin was revised by proton exchange experiments and extensive 2D NMR spectra. Phloridzin exhibited significant hypolipidemic activity in golden Syrian hamsters maybe by increasing the expression of CYP7A1, at the doses of 50 mg/kg and 200 mg/kg. The total performance of anti-hyperlipidemic effect of phloridzin may be superior to that of lovastatin, though lovastatin was more active than phloridzin. In addition, phloridzin exhibited moderate antimalarial activity with inhibition ratio of 31.3 ± 10.9% at a dose of 25 mg/kg/day, and showed moderate analgesic activity with 28.0% inhibition at a dose of 50 mg/kg.

A new prenylated coumestan from the roots of Campylotropis hirtella.

A new prenylated coumestan, campylohirtin A (1), along with fifteen phenolic known compounds (2‒16) and four other known compounds (17‒20), was obtained from the 95% ethanol extract of roots of Campylotropis hirtella. Their structures were elucidated based on extensive spectroscopic analysis (1 D and 2 D-NMR, MS, UV and IR). In vitro antimalarial activities of compounds 1-3, 5-14 and 16 were evaluated by ß-hematin formation inhibition assay. Compared with the positive control chloroquine diphosphate, compounds 8, 11 and 16 exhibited strong antimalarial activity with the IC50 values of 69.9, 33.2 and 75.4 µM, respectively. Compounds 1-3, 5-7 and 12 showed moderate antimalarial activities with IC50 values ranging from 134.6 µM to 578.6 µM.[Formula: see text].

Antimalarial Eudesmane Sesquiterpenoids from Dobinea delavayi.

Eleven new angeloylated eudesmane sesquiterpenoids, dobinins D-N (2, 3, 5, 6, 8, 9, and 11-15), and four known compounds (1, 4, 7, and 10) were isolated from the roots of Dobinea delavayi. A new oxidation product (8a) was also obtained from dobinin H (8). Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction analyses. Dobinins K-N (12-15) are the first examples of rearrangement noreudesmane analogue sesquiterpenoids with a unique 6/5-fused carbon skeleton. A putative biosynthetic pathway of compounds 12-15 is proposed. Compound 12 exhibited significant antimalarial activity superior to artemisinin with the inhibition ratio of 59.1%, and compounds 3, 5, and 15 exhibited moderate antimalarial activities against Plasmodium yoelii BY265RFP with inhibition ratios ranging from 14.5% to 18.5% at a dose of 30 mg/kg/day. In addition, the apoptosis of P. yoelii BY265RFP by the depolarization of mitochondrial membrane potential with striking ROS production, after parasitized erythrocyte lysis mediated by cytokines IL-12 and IFN-γ, may be a possible mechanism of antimalarial action of compound 12 against P. yoelii BY265RFP.

Dodelates A-E: Five dimeric eudesmane sesquiterpenoids from Dobinea delavayi.

Dodelates A-E (1-5), five angeloylated eudesmane sesquiterpenoid dimers were isolated from the roots of Dobinea delavayi. Their structures were elucidated by extensive spectroscopic data and single-crystal X-ray diffraction analyses. A possible biosynthetic pathway of these five compounds was proposed. Compounds 1 and 3 exhibited moderate antimalarial activities against Plasmodium yoelii BY265RFP.

A new lignan glycoside from Astragalus yunnanensis.

A new lignan glycoside, astrayunoside A (1), along with eight known compounds (2-9), were obtained from the methanol extract of roots of Astragalus yunnanensis. All the compounds were obtained from A. yunnanensis for the first time. Their structures were elucidated by extensive spectroscopic analysis (1D and 2D-NMR, MS, UV, CD, and IR). The weak antibacterial activities of the crude extracts of A. yunnanensis against Staphyloccocus aureus, Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Shigella dysenteriae, Salmonella typhi H901, Candida albicans, Streptococcus mutans, and Actinomyces viscosus were observed.

New abietane diterpenoid glucosides from underground parts of Isodon taliensis.

Two new abietane diterpenoid glucosides, talienosides A and B (1 and 2), along with four known compounds (3 - 6), were isolated from the ethyl acetate soluble portion of 70% acetone extract of the underground parts of Isodon taliensis. Their structures were elucidated based on the analyses of extensive spectroscopic data and physicochemical properties. The two new compounds were tested for their bioactivities against malaria and diabetes by ß-hematin formation inhibition and α-glycosidase inhibition experiments, respectively. However, only 2 showed weak ß-hematin formation inhibitory activity. [Formula: see text].

New Bioactive Macrocyclic Diterpenoids from Euphorbia helioscopia.

Three new macrocyclic diterpenoids, euphoscopoids A - C (1 - 3), including two new jatrophanes and a new lathyrane, were isolated from the whole plant of Euphorbia helioscopia. Their structures were elucidated by spectroscopic methods. Antifeedant and cytotoxic activities of these isolates were evaluated. All compounds showed significant antifeedant activity against a generalist plant-feeding insect, Helicoverpa armigera, with EC50 values ranging from 2.05 to 4.34 µg/cm2 . In addition, compound 2 showed moderate cytotoxicity against tumor cell lines NCI-H1975, HepG2, and MCF-2, while compounds 1 and 3 were not active at 80 µm. The results suggested not only the defensive function of macrocyclic diterpenoids in E. helioscopia against insect herbivores, but also their potential applications as new natural insect antifeedants.

Localisation of Two Bioactive Labdane Diterpenoids in the Peltate Glandular Trichomes of Leonurus japonicus by Laser Microdissection Coupled with UPLC-MS/MS.

INTRODUCTION: Glandular trichomes of plants are biochemical factories that could produce, store and secrete copious pharmaceutically important natural products. The Labiatae plant Leonurus japonicus is an important traditional Chinese medicine used to treat gynecological diseases, and has abundant peltate glandular trichomes (PGTs), in which the secondary metabolites accumulated are still unknown. OBJECTIVE: To study the secondary metabolites specifically accumulated in the PGTs of L. japonicus and their biological activities, and provide a new way to pinpoint bioactive natural products from plants. METHODOLOGY: Morphology of the trichomes on L. japonicus were observed under a scanning electron microscope. The PGTs of L. japonicus were precisely collected using laser microdissection (LMD) and analysed for their secondary metabolites with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Targeted compounds were isolated with classical phytochemical methods, and their structures were elucidated by spectroscopic analysis. Biological activities were evaluated by in vitro assays. RESULTS: Two labdane diterpenoids, leoheterin (1) and galeopsin (2), were localised in the PGTs of L. japonicus. Antithrombotic activity of 1 in anti-platelet aggregation assay induced by arachidonic acid was observed. Both compounds showed potential anti-inflammatory activity by inhibiting proinflammatory cytokine TNF-α. In addition, anti-proliferative effect of both compounds on several cancer cell lines was also detected. CONCLUSION: Two bioactive labdane diterpenoids were localised in the PGTs of L. japonicus. The findings suggested that it might be an efficient approach to explore bioactive natural products from the glandular trichomes of medicinal plants with LMD-UPLC/MS/MS. Copyright © 2017 John Wiley & Sons, Ltd.

New Labdane Diterpenes and Their Glycoside Derivatives from the Roots of Isodon adenantha.

Two new labdane-type diterpenes (adenanthic acids A and B; 1 and 2, resp.) and three new labdane diterpene glycosides (adenanthosides A-C; 3-5, resp.) were isolated from the roots of Isodon adenantha, together with 23 known constituents including seven diterpenoids (6-12), eight triterpenoids (13-20), one lignan glycoside (21), six steroids (22-27), and one ceramide (28). Their structures were elucidated by spectroscopic methods including extensive 2D-NMR techniques. Cytotoxicity and antibacterial activities of the samples were measured by the MTT method and the filter paper disc agar diffusion method. But none of them showed significant activities.

A new schistosomicidal and antioxidative phenylpropanoid from Astragalus englerianus.

A new phenylpropanoid, (E)-2,3,4-trimethoxy-5-(1-propenyl)phenol (1), along with five known aromatic compounds (2-6), was isolated from the methanol extract of roots of Astragalus englerianus. Their structures were elucidated based on the analyses of extensive spectroscopic data and comparison of their physicochemical properties. Compounds 1 and 2 were evaluated schistosomicidal activities, and all the isolated compounds were tested for their antioxidant activities in vitro. Compound 1 showed significant schistosomicidal activity with worm mortality rates of 66.7% and 83.3% within 12 and 24 h in a drug-containing (1.16 mM) RPMI 1640 medium, respectively. Also, compound 1 exhibited excellent antioxidant activity (2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl free radical-scavenging capability) with an IC50 value of 81.3 ± 1.3 µM.

Schistosomicidal and antioxidant flavonoids from Astragalus englerianus.

Astragalus englerianus is a close relative of the traditional Chinese medicine plant Radix Astragali (Huang-qi) and is mainly distributed in Yunnan. It has been traditionally used as a substitute of "Huang-qi" for reducing fatigue and enhancing immunity by local folks. A phytochemical study of the methanol extract of the roots led to the isolation of three new flavonoids including one aurone (1) and two chalcones (2 and 3), as well as two known flavonoids (4 and 5). Their structures were elucidated based on the analyses of extensive spectroscopic data and comparison of their physicochemical properties. This is the first report on the occurrence of ß-hydroxydihydrochalcone, 2',5'-dioxygenchalcones, and 2',5'-dioxygenaurone in the genus Astragalus. All the isolated compounds were tested in vitro for their schistosomicidal and antioxidant activities. Compounds 2 and 4 showed schistosomicidal activities with worm mortality rates of 100 % within 12 h in a drug-containing (0.70 and 0.77 mM, respectively) RPMI 1640 medium. Compounds 1 and 2 exhibited antioxidant activities in 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl free radical scavenging assays, with IC50 values of 35.9 ± 1.1 and 12.2 ± 1.1 µM, respectively.

Five new terpenoids from the rhizomes of Isodon adenantha.

Five new terpenoids including 2 labdane diterpenoids (1 and 2), 2 ent-kaurane diterpenoids (3 and 4), and a new oleanane triterpenoid (5), along with 13 known compounds (6-18), were isolated from the ethyl acetate fraction of 70% acetone extract of the rhizomes of Isodonadenantha. Their structures were elucidated based on the analyses of spectroscopic data and comparison of their physicochemical properties. The structure of 1 was further confirmed by single-crystal X-ray diffraction. Cytotoxicity and antibacterial activities of the samples were measured by MTT method and the filter paper disk agar diffusion method. But none of them showed significant activities.

Four new phenolic glycosides from Dobinea delavayi.

Three new benzophenone glycosides, 2-O-ß-D-glucopyranosyl-6,3',4'-trihydroxy-4-methoxybenzophenone (1), 4'-O-ß-D-glucopyranosyl-2,4,6,3'-tetramethoxybenzophenone (2) and 2-O-ß-D-glucopyranosyl-4'-hydroxy-6-methylbenzophenone (3), and a new flavonoid glycoside 5'-hydroxyombuoside (6), along with three known phenolic glycosides 4-O-ß-D-glucopyranosyl-2,6,4'-trihydroxybenzophenone (4), mangiferin (5), and ombuoside (7), were isolated from the 80% ethanol extract of roots of Dobinea delavayi. Their structures were determined by the comprehensive analyses of the physicochemical properties and spectroscopic data (1D NMR, 2D NMR, and HR-ESI-MS). Cytotoxicity and in vitro antimalarial activity of compounds 1, 3, 4, 6, and 7 were evaluated by MTT colorimetric assay and ß-hematin formation inhibition assay, respectively.

Farnesane sesquiterpenoids from Rubus delavayi and their anti-Trichinella spiralis activities.

Two new farnesane sesquiterpenoid glycosides, rubusdelosides A and B (1 and 4), together with five known farnesane sesquiterpenoids (2, 3, and 5-7), and two known meroterpenoids (8 and 9), were isolated from water extract of the herbs of R. delavayi. Their structures were identified by the comprehensive analyses of physicochemical properties and spectroscopic data (NMR and HR-ESI-MS). Compounds 1-8 showed moderate in vivo anti-T. spiralis activities.

Crystal structure of phloridzin and its distribution changes in flowering and fruiting stage of Malus rockii.

The exact structure of phloridzin was further confirmed as phloretin 6'-O-glucopyranoside by a single-crystal X-ray diffraction experiment. The distribution changes of phloridzin in flowering, fruitlet, and fruit ripening phases of Malus rockii were quantified by an HPLC with an external standard. The concentrations of phloridzin in leaves, twigs, and bark and xylem of twigs increased at first and then decreased, and reached the highest value in the fruitlet period. The highest concentration of phloridzin was found in leaves, with the percentage contents of 10.92-14.43 %. What is more, the decreased value of the concentration of phloridzin in leaves from fruit ripening period was almost equivalent to the increased value of the concentration of phloretin. This interesting physiological phenomenon should be able to provide the readers, especially plant physiologists, with a new perspective for the development and utilization of phloridzin.

Discovery of diversified cassane diterpenoids as potent antibacterial agents from Caesaplinia pulcherrima and their mechanisms.

BACKGROUND: Natural products play a significant role in the development of novel bactericide candidates. Caesalpinia pulcherrima, a traditional medicine, had anti-inflammatory, antimicrobial, and antifeedant activities, therefore the previous bioassay results of C. pulcherrima implied that its main active ingredients may have potential to be used as botanical bactericides. RESULTS: Bio-guided isolation of C. pulcherrima was conducted to obtain 11 novel cassane diterpenoids (capulchemins A-K) and 10 known sesquiterpenes. Their structures were established by extensive spectroscopic methods and single-crystal X-ray diffraction analyses. Capulchemins A-F possess a rare aromatic C ring, while capulchemin K with a 15,16-degradative carbon skeleton represents a rare group of cassane diterpenes. Capulchemin A exhibited remarkable antibacterial activity against four phytopathogenic bacteria, particularly against Pseudomonas syringae pv. actinidae and Bacillus cereus, with minimal inhibitory concentration values of 3.13 µM. Meanwhile, capulchemin A showed significant control effect on kiwifruit canker in vivo. Further investigation of its mechanism of antibacterial activity revealed that compound 1 was closely related to destroy cell membrane to cause cell death. Additionally, some of those cassane diterpenoids showed potential antifeedant against Mythimna separate walker and Plutella xylostella. Consequently, capulchemin A could have the potential to be used as a template for the development for new eco-friendly NP-based bactericides. CONCLUSION: These data contribute to a better understanding of the antibacterial activity of cassane diterpenes. Cassane diterpenes have been discovered to be leading to broad application prospects in the development as novel botanical bactericides. © 2023 Society of Chemical Industry.

Flavonoids from Scutellaria likiangensis Diels and their antimalarial activities.

Two new flavonoid glycosides scutelikiosides A and B (13 and 23), along with twenty-one known compounds from the 75% ethanol extract of roots of Scutellaria likiangensis Diels. Their structures were determined by the comprehensive analyses of the spectroscopic data (1D NMR, 2D NMR, HRESIMS, and CD) and physicochemical properties. Compounds 4-14, 17-19, 21, and 22 were evaluated for their in vivo antimalarial activities against Plasmodium yoelii BY265RFP in mice. Compound 17 exhibited significant activity close to artemisinin with an inhibition ratio of 29.2%, and compounds 6, 9-12, 14, 18, 19, and 22 exhibited moderate antimalarial activities with inhibition ratios ranging from 10.2% to 20.0% at a dose of 25 mg/kg/day. In addition, a summary of preliminary structure-activity relationship of isolated flavonoids for in vivo antimalarial activity was described.

Diversified cassane family diterpenoids from the leaves of Caesalpinia minax exerting anti-neuroinflammatory activity through suppressing MAPK and NF-κB pathways in BV-2 microglia.

ETHNOPHARMACOLOGICAL RELEVANCE: Caesalpinia minax Hance, whose seeds are known as "Ku-shi-lian" in China, have been used in Chinese folk medicine for treatment of rheumatism, dysentery, and skin itching. However, the anti-neuroinflammatory constituents of its leaves and their mechanism are rarely reported. AIM OF THE STUDY: To search for new anti-neuro-inflammatory compounds from the leaves of C. minax and elucidate their mechanism on anti-neuroinflammatory effect. MATERIALS AND METHODS: The main metabolites of the ethyl acetate fraction from C. minax were analyzed and purified via HPLC and various column chromatography techniques. Their structures were elucidated on the basis of 1D and 2D NMR, HR-ESI-MS, and single crystal X-ray diffraction analysis. Anti-neuroinflammatory activity was evaluated in BV-2 microglia cells induced by LPS. The expression levels of molecules in NF-κB and MAPK signaling pathways were analyzed through western blotting. Meanwhile, the time- and dose-dependent expression of associated proteins such as iNOS and COX-2 were detected by western blotting. Furthermore, Compounds 1 and 3 were performed on the NF-κB p65 active site using molecular docking simulation to elucidate the molecular level inhibition mechanism. RESULTS: 20 cassane diterpenoids, including two novel ones (caeminaxins A and B) were isolated from the leaves of C. minax Hance. Caeminaxins A and B possessed a rare unsaturated carbonyl moiety in their structures. Most of the metabolites exhibited potent inhibition effects with IC50 values ranging from 10.86 ± 0.82 to 32.55 ± 0.47 µM. Among them, caeminaxin A inhibited seriously the expression of iNOS and COX-2 proteins and restrained the phosphorylation of MAPK and the activation of NF-κB signaling pathways in BV-2 cells. The anti-neuro-inflammatory mechanism of caeminaxin A has been studied systematically for the first time. Furthermore, biosynthesis pathways for compounds 1-20 were discussed. CONCLUSIONS: The new cassane diterpenoid, caeminaxin A, alleviated the expression of iNOS and COX-2 protein and down-regulated of intracellular MAPK and NF-κB signaling pathways. The results implied that cassane diterpenoids had potential to be developed into therapeutic agents for neurodegenerative disorders such as Alzheimer's disease.

Antinociceptive effect of ethanolic extract of Bauhinia brachycarpa Benth on neuropathic pain model induced by partial sciatic nerve ligation.

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Bauhinia brachycarpa Benth (BBB) has been traditionally used for treating muscle aches such as bone pain, and neuralgia for a long time, on account of its sedative and antinociceptive activities in Yunnan province of China. However, there was no experimental evidence to confirm its traditional medicinal use. AIM OF THE STUDY: The antinociceptive effect and possible mechanism of ethanolic extract of BBB on neuropathic pain was evaluated through a model of partial sciatic nerve ligation in mice. MATERIALS AND METHODS: A commonly employed animal model induced by partial sciatic nerve ligation (PSNL) in mice was established in the aim of studying neuropathic pain. Ethanolic extract of BBB (1000, 500, 250 mg/kg) and pregabalin (60 mg/kg) were intragastric administrated daily for 7 days post-PSNL. Mechanical and thermal hyperalgesia were assessed throughout the experimental period. After the experiment, the levels of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in serum were determined by ELISA. The mRNA expressions of ionized calcium binding adaptor molecule 1 (Iba-1), CD16, CD206, arginine-1 (Arg-1), interleukin-1ß (IL-1ß), and inducible nitric oxide synthase (iNOS) in the spinal cord were detected by qPCR. The protein levels of Iba-1, CD16, CD206, and p38 phosphorylation in the spinal cord were detected by immunohistochemistry and western blotting. The phytochemical analysis of BBB was performed through the colorimetric test. RESULTS: Neuropathic pain induced by PSNL was significantly alleviated by BBB treatment, which decreased pro-inflammatory cytokines such as TNF-α, IL-1ß and iNOS, increased anti-inflammatory cytokine such as IL-10 and Arg-1, and attenuated p38 phosphorylation. BBB also reduced the number of Iba-1 and CD16 positive cells, but it enhanced the number of CD206 positive cells. n-Butanol portion that was partitioned from the ethanolic extract had the highest content of total flavonoids among all the portions, and the antinociceptive effect of n-butanol portion is better than that of other portions. CONCLUSIONS: Our findings indicate that the antinociceptive effect of BBB is mediated by inhibiting the inflammatory response and regulating the differentiation of microglia. The antinociceptive effect of BBB was related to the content of total flavonoids.