Characteristic metabolites of Hypericum plants : their chemical structures and biological activities

Plants belonging to the genus Hypericum (Hypericaceae) are recognized as an abundant source of natural products with interesting chemical structures and intriguing biological activities. In the course of our continuing study on constituents of Hypericum plants, aiming at searching natural product-based lead compounds for therapeutic agents, we have isolated more than 100 new characteristic metabolites classified as prenylated acylphloroglucinols, meroterpenes, ketides, dibenzo-1,4-dioxane derivatives, and xanthones including prenylated xanthones, phenylxanthones, and xanthonolignoids from 11 Hypericum plants and one Triadenum plant collected in Japan, China, and Uzbekistan or cultivated in Japan. This review summarizes their chemical structures and biological activities

Phytochemical studies on traditional herbal medicines based on the ethnopharmacological information obtained by field studies

Traditional herbal medicines, which have been used in the matured traditional medical systems as well as those have been used in ethnic medical systems, are invaluable resources of drug seeds. Ethnobotanical and ethnopharmacological survey may provide useful information of these herbal medicines, which are valuable for searching new bioactive molecules. From this viewpoint, we have been performing the ethnobotanical and ethnopharmacological field studies in Yunnan Province and Guangxi Zhuang Autonomous Region, China, and Mongolia. Phytochemical studies on traditional herbal medicines were performed based on the information obtained by our ethnobotanical survey. Herbal medicines used in Uzbekistan and Bangladesh were also investigated on the basis of the ethnopharmacological information obtained from collaborative researchers in the respective regions. Some studies were carried out for searching active substance(s) based on bioassay-guided fractionation and isolation. Over 150 new molecules were isolated in these studies, and their various biological activities were also demonstrated. This review summarizes the results of phytochemical studies of those traditional herbal medicines as well as biological activities of the isolated molecules

Betuletol, a Propolis Component, Suppresses IL-33 Gene Expression and Effective against Eosinophilia

Propolis, a resinous substance produced by honeybees, has been used in folk medicine since ancient times due to its many biological benefits such as antitumor, antioxidant, antimicrobial, anti-inflammatory, and immunomodulatory effects. Propolis contains flavonoids, terpenoids, aromatic aldehydes, and alcohols, which vary with different climate and environmental conditions. In our study, we examined the antiallergic activity of Brazilian green propolis (BGP) and isolated the active compound that can suppress an allergy-sensitive gene, IL-33, expression and eosinophilia. Ethanolic extract of BGP freeze-dried powder was fractionated with several solvent systems, and the active fractions were collected based on activity measurement. The single active compound was found by thin-layer chromatography. Using column chromatography and NMR, the active compound was isolated and identified as 3,5,7-trihydroxy-6,4’-dimethoxyflavone, also known as betuletol. Further, the antiallergic activity of that has been examined in PMA-induced up-regulation of IL-33 gene expression in Swiss 3T3 cells. Our data showed the IL-33 gene suppression both by BGP and the isolated active compound, betuletol. We also found that betuletol suppressed ERK phosphorylation, suggesting it could be effective in suppressing IL-33 mediated eosinophilic chronic inflammation and will provide new insights to develop potent therapeutics against allergic inflammations

Pyrogallol inhibits NFAT signal

As the expression level of allergic disease sensitive genes are correlated with the severity of allergic symptoms, suppression of these gene expressions could be promising therapeutics. We demonstrated that protein kinase Cδ / heat shock protein 90-mediated H1R gene expression signaling and nuclear factor of activated T-cells (NFAT)-mediated IL-9 gene expression signaling are responsible for the pathogenesis of pollinosis. Treatment with Awa-tea combined with wild grape hot water extract suppressed these signaling and alleviated nasal symptoms in toluene-2,4-diisocyanate (TDI)-sensitized rats. However, the underlying mechanism of its anti-allergic activity is not elucidated yet. Here, we sought to identify an anti-allergic compound from Awa-tea and pyrogallol was identified as an active compound. Pyrogallol strongly suppressed ionomycin-induced up-regulation of IL-9 gene expression in RBL-2H3 cells. Treatment with pyrogallol in combination with epinastine alleviated nasal symptoms and suppressed up-regulation of IL-9 gene expression in TDI-sensitized rats. Pyrogallol itself did not inhibit calcineurin phosphatase activity. However, pyrogallol suppressed ionomycin-induced dephosphorylation and nuclear translocation of NFAT. These data suggest pyrogallol is an anti-allergic compound in Awa-tea and it suppressed NFAT-mediated IL-9 gene expression through the inhibition of dephosphorylation of NFAT. This might be the underlying mechanism of the therapeutic effects of combined therapy of pyrogallol with antihistamine

Agesasines A and B, Bromopyrrole Alkaloids from Marine Sponges Agelas spp.

Exploration for specialized metabolites of Okinawan marine sponges Agelas spp. resulted in the isolation of five new bromopyrrole alkaloids, agesasines A (1) and B (2), 9-hydroxydihydrodispacamide (3), 9-hydroxydihydrooroidin (4), and 9E-keramadine (5). Their structures were elucidated on the basis of spectroscopic analyses. Agesasines A (1) and B (2) were assigned as rare bromopyrrole alkaloids lacking an aminoimidazole moiety, while 3–5 were elucidated to be linear bromopyrrole alkaloids with either aminoimidazolone, aminoimidazole, or N-methylated aminoimidazole moieties

Marylosides A-G, Norcycloartane Glycosides from Leaves of Cymbidium Great Flower ‘Marylaurencin’

Seven novel norcycloartane glycosides, maryloside A–G (1–7), were isolated from the leaves of Cymbidium Great Flower ‘Marylaurencin’, along with a known norcycloartane glycoside, cymbidoside (8). These structures were determined on the basis of mainly NMR experiments as well as chemical degradation and X-ray crystallographic analysis. The isolated compounds (1–6 and 8) were evaluated for the inhibitory activity on lipopolysaccharide (LPS) and interferon-γ (IFN-γ)-stimulated nitric oxide (NO) production in RAW 264.7 cells. Consequently, 1 and 3 exhibited moderate activity

Mechanistic Support for Intramolecular Migrative Cyclization of Propargyl Sulfones Provided by Catalytic Asymmetric Induction with a Chiral Counter Cation Strategy

We previously reported an intramolecular migrative cyclization of propargylsufones and sulfonylalkynamides giving oxa- and azacycles, respectively. To confirm the postulated reaction mechanism, the reaction was conducted with chiral nucleophiles such as N-heterocyclic carbenes, phosphines, and pyridines, or with sulfinate anions and chiral cations. As expected, migrative cyclization proceeded to give the enantiomerically enriched products. These results strongly support the postulated mechanism and provide the first example of the asymmetric version of this reaction

Maackiain Suppresses H1R and IL-4 Gene Transcriptions

Kujin contains antiallergic compounds that inhibit upregulation of histamine H1 receptor (H1R) and interleukin (IL)‐4 gene expression. However, the underlying mechanism remains unknown. We sought to identify a Kujin‐derived antiallergic compound and investigate its mechanism of action. The H1R and IL‐4 mRNA levels were determined by real‐time quantitative RT‐PCR. To investigate the effects of maackiain in vivo, toluene‐2,4‐diisocyanate (TDI)‐sensitized rats were used as a nasal hypersensitivity animal model. We identified (−)‐maackiain as the responsible component. Synthetic maackiain showed stereoselectivity for the suppression of IL‐4 gene expression but not for H1R gene expression, suggesting distinct target proteins for transcriptional signaling. (−)‐Maackiain inhibited of PKCδ translocation to the Golgi and phosphorylation of Tyr311 on PKCδ, which led to the suppression of H1R gene transcription. However, (−)‐maackiain did not show any antioxidant activity or inhibition of PKCδ enzymatic activity per se. Pretreatment with maackiain alleviated nasal symptoms and suppressed TDI‐induced upregulations of H1R and IL‐4 gene expressions in TDI‐sensitized rats. These data suggest that (−)‐maackiain is a novel antiallergic compound that alleviates nasal symptoms in TDI‐sensitized allergy model rats through the inhibition of H1R and IL‐4 gene expression. The molecular mechanism underlying its suppressive effect for H1R gene expression is mediated by the inhibition of PKCδ activation

Anti-AIDS Agents 69. Moronic Acid and Other Triterpene Derivatives as Novel Potent Anti-HIV Agents

In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20 and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4−3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analog 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 μM against NL4−3, 0.021 μM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 μM against FHR-2 (an HIV strain resistant to 8), respectively. The promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted

Conjugates of betulin derivatives with AZT as potent anti-HIV agents

Fourteen novel conjugates of 3,28-di-O-acylbetulins with AZT were prepared as anti-HIV agents, based on our previously reported potent anti-HIV triterpene leads, including 3-O-acyl and 3,28-di-O-acylbetulins. Nine of the conjugates (49–53, 55, 56, 59, 60) exhibited potent anti-HIV activity at the submicromolar level, with EC50 values ranging from 0.040 to 0.098 µM in HIV-1NL4-3 infected MT-4 cells. These compounds were equipotent or more potent than 3-O-(3',3'-dimethylsuccinyl)betulinic acid (2), which is currently in Phase IIb anti-AIDS clinical trial