Dauferulins A-L, daucane-type sesquiterpenes from the roots of Ferula communis: Their structures and biological activities


Meroterpenes and prenylated benzoylphloroglucinol from the flowers of Hypericum formosanum


Acylated iridoid glucoside and xanthones from Canscora lucidissima: Their structures and ferroptosis inhibitory activity

Phytochemical study on the whole plants of a Gentianaceous medicinal plant, Canscora lucidissima, gave one new acylated iridoid glucoside, canscorin A (1), and two new xanthone glycosides (2 and 3) together with 17 known compounds including five xanthones, eight xanthone glycosides, two benzophenone glucosides, caffeic acid, and loganic acid. Canscorin A (1) was assigned as a loganic acid derivative having a hydroxyterephthalic acid moiety by spectroscopic analysis together with chemical evidence, while 2 and 3 were elucidated to be a rutinosylxanthone and a glucosylxanthone, respectively. The absolute configurations of the sugar moieties of 2 and 3 were determined by HPLC analysis. The isolated compounds were evaluated for their inhibitory activities against erastin-induced ferroptosis on human hepatoma Hep3B cells and LPS-stimulated IL-1β production from murine microglial cells.


Communiferulins, farnesylated coumarins from the roots of Ferula communis and their anti-neuroinflammatory activity

Three new farnesylated coumarins, communiferulins A-C (1-3), and a farnesylated chromone, ferchromone (4), were isolated from the roots of an Apiaceous plant Ferula communis. Their structures including the relative configurations were elucidated by a combination of spectroscopic analyses and calculations of the NMR data. Communiferulins A-C (1-3) had dihydrofuran rings fused to C-3 and C-4 of their coumarin moieties, while 3 possessed one additional furan ring. HPLC analyses using a chiral column showed 1-4 to be racemates, and the absolute configurations of (+)-1, (-)-1, (+)-2, and (-)-2 were deduced by comparison of their ECD spectra with TDDFT-calculated spectra. Communiferulins A (1) and B (2), and ferchromone (4) showed inhibitory activities on IL-1β production from LPS-stimulated microglial cells.


Tigliane-type diterpene esters from the fruits of Shirakiopsis indica and their anti-HIV activity


Rhodomollosides A and B, glycosides of methyl everninate from the aerial parts of Rhododendron molle

Journal of Asian Natural Products Research


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.


The novel preventive effect of a Japanese ethical Kampo extract formulation TJ-90 (Seihaito) against cisplatin-induced nephrotoxicity


Lanicepines A and B, sesquiterpenes with amino acid-derived substituents from the flowering aerial parts of Saussurea laniceps


Hyperdioxanes, dibenzo-1,4-dioxane derivatives from the roots of Hypericum ascyron

Six dibenzo-1,4-dioxane derivatives (1-6) were isolated from the roots of a Hypericaceous plant Hypericum ascyron. Spectroscopic analyses revealed 2 and 4-6 to be new compounds. The partial racemic natures of 1-3 were concluded by chiral HPLC analyses, while 5 was confirmed to be a racemate. The absolute configurations 1-4 were deduced on the basis of ECD calculations. Biological activity evaluation of the dibenzo-1,4-dioxane derivatives along with two related compounds: hyperdioxanes A (7) and B (8), previously isolated from the same plant material by our group demonstrated that 7 exhibit an anti-HIV activity (IC 5.3 μM, TI 7.2) while 8 showed an inhibitory effect on IL-1β production (inhibition rate: 72.3% at 6.3 μM) from LPS-stimulated microglial cells.


Studies on non-medicinal parts of plant materials: Triterpenes from the roots of Schisandra chinensis


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


Diterpenes from an Uzbek medicinal plant Perovskia scrophulariifolia: their structures and anti-neuroinflammatory activity

Phytochemical investigation on the aerial parts of a Lamiaceous medicinal plant Perovskia scrophulariifolia collected in Uzbekistan resulted in the isolation of two new 20-norabietane diterpenes, along with thirteen known diterpenes including one 20-norabietane, eight abietanes, one 6,7-secoabietane, and three icetexanes. The structures of new 20-norabietane diterpenes, perovsfolins C (1) and D (2), were elucidated by spectroscopic analyses aided with calculations of ECD spectra. Perovsfolin C (1) is the first 20-norabietane diterpene possessing a 1,11-epoxy moiety, while perovsfolin D (2) is a 20-norabitetane diterpene with a 2-hydroxy-1,4-quinone moiety as C-ring. Anti-neuroinflammatory activity of the isolated diterpenes on microglial cells was evaluated.


C28 Terpenoids from Lamiaceous plant Perovskia scrophulariifolia: their structures and anti-neuroinflammatory activity

Structurally unique C terpenoids, perovsfolins A () and B (), were isolated from the aerial parts of an Uzbek medicinal plant, (Lamiaceae). Their chemical structures including an unprecedented 6/8/6/6/6 pentacyclic carbon skeleton with a C-C ester moiety were elucidated on the basis of spectroscopic analyses aided by density functional theory calculations as well as chemical evidence. Perovsfolin B () exhibited an anti-neuroinflammatory activity.


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

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


Lophachinins A-E, abietane diterpenes from a Mongolian traditional herbal medicine Lophanthus chinensis

Five new abietane diterpenes, lophachinins A-E (1-5), and eleven known related diterpenes were isolated from a Mongolian traditional herbal medicine, the aerial parts of Lophanthus chinensis (Lamiaceae). The structures of new diterpenes were assigned by spectroscopic analyses. Lophachinins A (1) and B (2) were abietane diterpene possessing an endoperoxy bridge at C-ring. In contrast, lophachinins C-E (3-5) had an abietane skeleton with an aromatized C-ring. The absolute configuration of 1 was elucidated by application of the modified Mosher's method, while those of 2, 3, and 5 were assigned by chemical conversions. The absolute configuration of lophachinin D (4) was deduced by ECD calculation. Anti-inflammatory activity of isolated diterpenes on microglial cells were evaluated.


Sarcaglabrin A, a conjugate of C15 and C10 terpenes from the aerial parts of Sarcandra glabra


Prenylated benzophenone derivatives from Hypericum patulum

A new prenylated benzophenone, hypatulin C (1), was isolated from the leaves of Hypericum patulum together with a biogenetically related analog, hypelodin B (2). Hypatulin C (1) had a tricyclic [4.3.1.0]-decane moiety substituted by four prenyl groups. The structure of 1 was elucidated by detailed spectroscopic analyses, while the absolute stereochemistries of 1 and 2 were assigned by comparison of their ECD spectra with TDDFT calculated spectra.


Linaburiosides A-D, acylated iridoid glucosides from Linaria buriatica


Limonoids from the aerial parts of Munronia pinnata


Hypascyrins A-E, prenylated acylphloroglucinols from Hypericum ascyron

Six new prenylated acylphloroglucinols with menthane moieties, hypascyrins A-E (-) and -hyphenrone J (), together with four known analogues, were isolated from roots. Detailed spectroscopic data analyses resulted in the assignment of their structures. The absolute configuration of was deduced by experimental and calculated ECD data, while those of - were assigned by ECD data analyses as well as chemical conversions. Hypascyrins A (), C (), and E () and -hyphenrone J () exhibited antimicrobial activity against MRSA (MIC values of 4.0, 8.0, 2.0, and 4.0 μM, respectively) and (MIC values of 4.0, 4.0, 2.0, and 4.0 μM, respectively).


Marylosides A-G, Norcycloartane Glycosides from Leaves of Great Flower 'Marylaurencin'.

Seven novel norcycloartane glycosides, maryloside A-G (-), were isolated from the leaves of Great Flower 'Marylaurencin', along with a known norcycloartane glycoside, cymbidoside (). These structures were determined on the basis of mainly NMR experiments as well as chemical degradation and X-ray crystallographic analysis. The isolated compounds (- and ) 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, and exhibited moderate activity.


Lanostane-type triterpnes from the sclerotium of Inonotus obliquus (Chaga mushrooms) as proproliferative agents on human follicle dermal papilla cells

Chaga mushrooms, the sclerotium of Inonotus obliquus, have been used in Mongolia as a traditional hair shampoo to maintain healthy hair. Bioassay-guided fractionations of the extract of Chaga mushrooms using a proliferation assay on human follicle dermal papilla cells (HFDPCs) gave five lanostane-type triterpenes (1-5), whose structures were identified by spectroscopic evidence. Among these, lanosterol (1), inotodiol (3), lanost-8,24-diene-3β,21-diol (4), and trametenolic acid (5) demonstrated proproliferative effects on HFDPCs more potent than minoxidil, an anti-alopecia agent, used as the positive control. The lanostane-type triterpenes (1, 3, 4, and 5) appeared to be potential candidates of new agents possibly used for hair-care with a stimulative effect on hair growth.


Hyperdioxane A, a conjugate of dibenzo-1,4-dioxane and sesquiterpene from Hypericum ascyron

Two new dibenzo-1,4-dioxane derivatives, hyperdioxanes A (1) and B (2), were isolated from the roots of a Hypericaceous plant, Hypericum ascyron. Hyperdioxane A (1) is a conjugate of dibenzo-1,4-dioxane and sesquiterpene with an unprecedented heptacyclic ring system. The structures of 1 and 2 were assigned by detailed spectroscopic analyses, including application of a modified Mosher's method. A possible biogenetic pathway of hyperdioxane A (1) from hyperdioxane B (2) and a sesquiterpene, eremophil-9,11(13)-dien-8β,12-olide (3), is presented.


Rigenolides D-H, norsecoiridoid and secoiridoids from Gentiana rigescens Franch

Five new compounds, rigenolides D-H (1-5), were isolated from the aerial parts of Gentiana rigescens Franch. Their structures were assigned by detailed spectroscopic analyses and chemical conversions. Rigenolides D (1) and E (2) were elucidated to be a secoiridoid and a norsecoiridoid, respectively, possessing a dienone moiety in common. Rigenolides F-H (3-5) were assigned as acylated secoiridoid glucosides.


Agelamasines A and B, diterpene alkaloids from an Okinawan marine sponge Agelas sp.


Phloroglucinol derivatives and a chromone gluycoside from the leaves of Myrtus communis


Methanol extraction fraction from Citrus Sudachi peel exerts lipid reducing effects in cultured cells.

Ectopic fat accumulation is associated with insulin resistance and type 2 diabetes mellitus. Citrus sudachi is an evergreen tree that is found mainly in Tokushima Prefecture in Japan. Previously, it was demonstrated that Citrus sudachi could inhibit the rising trend of blood glucose and fatty acid in human subjects. In the current study, we illustrated the function of methanol extracts from sudachi peel and investigated the mechanism of this effect. We got the five kinds of methanol extracts by using diaion HP-20, and those were named by hydrophobicity from M-F1 to M-F5. Among the 5 kinds of sudachi methanol extracts, only M-F4 significantly decreased the intracellular triglyceride of C2C12 cells. It augmented the AMPK activity and increased the transcription of PPARα and its downstream targets CPT-1b and UCP2. In conclusion, M-F4 improved the lipid metabolism possibly through AMPK, PPARα and their downstream targets like CPT-1b and UCP2. Furthermore, this extract may be useful for preventing obesity and diabetes related diseases. J. Med. Invest. 65:225-230, August, 2018.

The Journal of Medical Investigation : JMI


Stereochemical assignments of rubiaquinones A-C, naphthoquinone derivatives from Rubia yunnanensis


Antibiofilm and Anti-Inflammatory Activities of+ Houttuynia cordata Decoction for Oral Care

Dental biofilms that form in the oral cavity play a critical role in the pathogenesis of several infectious oral diseases, including dental caries, periodontal disease, and oral candidiasis. (HC, Saururaceae) is a widely used traditional medicine, for both internal and external application. A decoction of dried HC leaves (dHC) has long been consumed as a health-promoting herbal tea in Japan. We have recently reported that a water solution of HC poultice ethanol extract (wHCP) exerts antimicrobial and antibiofilm effects against several important oral pathogens. It also exhibits anti-inflammatory effects on human keratinocytes. In our current study, we examined the effects of dHC on infectious oral pathogens and inflammation. Our results demonstrated that dHC exerts moderate antimicrobial effects against methicillin-resistant (MRSA) and other oral microorganisms. dHC also exhibited antibiofilm effects against MRSA, (involved in dental plaque formation), and and inhibitory effects on interleukin-8, CCL20, IP-10, and GRO productions by human oral keratinocytes stimulated by lipopolysaccharide (a cause of periodontal disease), without cytotoxic effects. This suggests that dHC exhibits multiple activities in microorganisms and host cells. dHC can be easily prepared and may be effective in preventing infectious oral diseases.

Evidence-Based Complementary and Alternative Medicine : eCAM


Rigenolides B and C, conjugates of norsecoiridoid and secoiridoid glucoside from Gentiana rigescens Franch.


Frondhyperins A-D, short ketide-phenylketide conjugates from Hypericum frondosum cv. Sunburst


Hitorins A and B, hexacyclic C25 terpenoids from Chloranthus japonicus

Two novel C25 terpenoids with a 6/5/5/5/5/3 hexacyclic skeleton including one γ-lactone ring and two tetrahydrofuran rings, hitorins A (1) and B (2), were isolated from the aerial parts of Chloranthus japonicus. The structures of 1 and 2 were elucidated on the basis of spectroscopic analyses as well as TDDFT ECD calculations. Hitorins A (1) and B (2) might be biogenetically derived from eudesmane sesquiterpene and thujane monoterpene.


Hypatulins A and B, meroterpenes from Hypericum patulum

Two novel prenylated benzophenone related meroterpenes, hypatulins A (1) and B (2), were isolated from the leaves of Hypericum patulum. The structures of 1 and 2 were assigned by spectroscopic analysis, chemical conversion, and calculations of the ECD (electron circular dichroism) spectra. Hypatulin A (1) had a unique densely substituted tricyclic octahydro-1,5-methanopentalene core, while hypatulin B (2) possessed a bicyclo[3.2.1]octane moiety. Hypatulin A (1) exhibited antimicrobacterial activity against Bacillus subtilis. A possible biogenetic pathway of the new meroterpenes 1 and 2 from a prenylated benzophenone was presented.


Fermented Ginseng Contains an Agonist of Peroxisome Proliferator Activated Receptors and .

Peroxisome proliferator activated receptor (PPAR) is a nuclear receptor that is one of the transcription factors regulating lipid and glucose metabolism. Fermented ginseng (FG) is a ginseng fermented by Lactobacillus paracasei A221 containing minor ginsenosides and metabolites of fermentation. DNA microarray analysis of rat liver treated with FG indicated that FG affects on lipid metabolism are mediated by PPAR-. To identify a PPAR- agonist in FG, PPAR- transcription reporter assay-guided fractionation was performed. The fraction obtained from the MeOH extract of FG, which showed potent transcription activity of PPAR-, was fractionated by silica gel column chromatography into 16 subfractions, and further separation and crystallization gave compound 1 together with four known constituents of ginseng, including 20(R)- and 20(S)-protopanaxadiol, and 20(R)- and 20(S)-ginsenoside Rh1. The structure of compound 1 was identified as 10-hydroxy-octadecanoic acid by (1)H- and (13)C-NMR spectra and by EI-MS analysis of the methyl ester of 1. Compound 1 demonstrated much higher transcription activity of PPAR- than the other isolated compounds. In addition, compound 1 also showed 5.5-fold higher transcription activity of PPAR- than vehicle at the dose of 20 g/mL. In the present study, we identified 10-hydroxy-octadecanoic acid as a dual PPAR-/ agonist in FG. Our study suggested that metabolites of fermentation, in addition to ginsenosides, contribute to the health benefits of FG.


Erecricins A-E, prenylated acylphloroglucinols from the roots of Hypericum erectum

Six new prenylated acylphloroglucinols, erecricins A-E (1-5) and adotogirin (6), were isolated from the roots of Hypericum erectum (Hypericaceae). Their structures were assigned on the basis of spectroscopic evidences. Erecricins A-E (1-5) are bicyclic prenylated acylphloroglucinols possessing a chromane or a chromene skeleton. Adotogirin (6) is a simple achylphloroglucinol with an O-geranyl moiety. Antimicrobial activities of these acylphloroglucinols were also evaluated.


Acylated triterpene saponins from the stem bark of Acer nikoense

Three new acylated triterpene saponins, acernikoenosides A-C (1-3), were isolated from the stem bark of Acer nikoense, together with a known sterol glucoside. Their structures were elucidated on the basis of extensive spectroscopic analyses. This study provided the first example of triterpene saponins isolated from this plant. The anti-genotoxic activity of 1, 3 and 4 against ultraviolet irradiation was evaluated by comet assay.


Yezo'otogirins A-H, acylphloroglucinols and meroterpenes from Hypericum yezoense

Investigation of the methanolic extract from the aerial parts of Hypericum yezoense resulted in the isolation of three new acylphloroglucinols, yezo'otogirins D-F (1-3), and two new meroterpenes, yezo'otogirins G (4) and H (5). The structures of 1-5 were assigned on the basis of spectroscopic data. Yezo'otogirin D (1) is an acylphloroglucinol with a monoterpene moiety linked through an ether bond, while yezo'otogirins E (2) and F (3) are polyprenylated acylphloroglucinols possessing a tricyclic core. Yezo'otogirins G (4) and H (5) are linear meroterpenes with an enolized -diketone moiety. Yezo'otogirin E (2) exhibited antimicrobial activity against Escherichia coli and Staphylococcus aureus.


Preventive Effects of Houttuynia cordata Extract for Oral Infectious Diseases.

Houttuynia cordata (HC) (Saururaceae) has been used internally and externally as a traditional medicine and as an herbal tea for healthcare in Japan. Our recent survey showed that HC poultice (HCP) prepared from smothering fresh leaves of HC had been frequently used for the treatment of purulent skin diseases with high effectiveness. Our experimental study also demonstrated that ethanol extract of HCP (eHCP) has antibacterial, antibiofilm, and anti-inflammatory effects against S. aureus which caused purulent skin diseases. In this study, we focused on novel effects of HCP against oral infectious diseases, such as periodontal disease and dental caries. We determined the antimicrobial and antibiofilm effects of water solution of HCP ethanol extract (wHCP) against important oral pathogens and investigated its cytotoxicity and anti-inflammatory effects on human oral epithelial cells. wHCP had moderate antimicrobial effects against some oral microorganisms and profound antibiofilm effects against Fusobacterium nucleatum, Streptococcus mutans, and Candida albicans. In addition, wHCP had no cytotoxic effects and could inhibit interleukin-8 and CCL20 productions by Porphyromonas gingivalis lipopolysaccharide-stimulated human oral keratinocytes. Our findings suggested that wHCP may be clinically useful for preventing oral infectious diseases as a mouthwash for oral care.


Merohyperins A-C, meroterpenes from the leaves of Hypericum chinense


Tetrahydroxanthones from Mongolian medicinal plant Gentianella amarella ssp. acuta


Anti-bacterial and anti-inflammatory effects of ethanol extract from Houttuynia cordata poultice.

Houttuynia cordata (HC) has been commonly used as many traditional remedies in local areas of Japan. Although many pharmacological activities of HC have been reported, the mechanism underlying the effect of HC remains unknown. We conducted the interview survey in Japan to verify how HC was actually used. The interview survey revealed that HC poultice (HCP) prepared from smothering fresh leaves of HC was most frequently used for the treatment of purulent skin diseases including furuncle and carbuncle with high effectiveness. Ethanol extract of HCP (eHCP) showed anti-bacterial effects against methicillin-resistant Staphylococcus aureus (MRSA), and showed an anti-biofilm activity against MRSA. eHCP showed dose-dependent inhibition of S. aureus lipoteichoic acid (LTA)-induced interleukin-8 and CCL20 production in human keratinocyte without any cytotoxicity. These results suggest that HCP is effective for skin abscess and its underlying mechanism might be the complicated multiple activities for both bacteria and host cells.

Bioscience, Biotechnology, and Biochemistry


Acylated neo-clerodane type diterpenoids from the aerial parts of Scutellaria coleifolia Levl. (Lamiaceae).

Twenty new neo-clerodane type diterpenoids, scutefolides G1-S (1-20), were isolated from the 70 % aqueous acetone extract of the aerial parts of Scutellaria coleifolia. Their structures were elucidated by extensive spectroscopic analyses. The absolute configurations of 1, 2, 7, 8, 14 and 15 were determined by means of the CD exciton chirality method. Compounds 1, 2, 5, 7, 8, 12, 14, 15, 18 and 19 were evaluated for their cytotoxic activities against four human cancer cell lines, and anti-bacterial activities against methicillin-resistant Staphylococcus aureus.


A novel benzofuran, 4-methoxybenzofuran-5-carboxamide, from Tephrosia purpurea suppressed histamine H1 receptor gene expression through a protein kinase C--dependent signaling pathway.

Histamine H1 receptor (H1R) gene is upregulated in patients with allergic rhinitis (AR), and its expression level is strongly correlated with the severity of allergic symptoms. We previously reported isolation of the putative anti-allergic compound, 4-methoxybenzofuran-5-carboxamide (MBCA) from Tephrosia purpurea and its chemical synthesis (Shill et al., Bioorg Med Chem 2015;23:6869-6874). However, the mechanism underlying its anti-allergic activity remains to be elucidated. Here, we report the mechanism of MBCA on phorbol 12-myristate-13-acetate (PMA)- or histamine-induced upregulation of H1R gene expression in HeLa cells, and in vivo effects of MBCA were also determined in toluene-2,4-diisocyanate (TDI)-sensitized rats. MBCA suppressed PMA- and histamine-induced upregulation of H1R expression at both mRNA and protein levels and inhibited PMA-induced phosphorylation of PKCδ at Tyr(311) and subsequent translocation to the Golgi. Furthermore, MBCA ameliorated allergic symptoms and suppressed the elevation of H1R and helper T cell type 2 (Th2) cytokine mRNAs in TDI-sensitized rats. Data suggest that MBCA alleviates nasal symptoms in TDI-sensitized rats through the inhibition of H1R and Th2 cytokine gene expression. The mechanism of its H1R gene suppression underlies the inhibition of PKCδ activation.


The polyphenol (-)-epigallocatechin-3-gallate prevents apoA-IIowa amyloidosis in vitro and protects human embryonic kidney 293 cells against amyloid cytotoxicity

Apolipoprotein A-I (apoA-I) amyloidosis is either a non-hereditary form with deposits of wild-type apoA-I proteins in atherosclerotic plaques or a hereditary form with progressive accumulation of mutant apoA-I proteins in different tissues. Several small polyphenolic molecules reportedly inhibited formation of fibrillar assemblies of some amyloidogenic proteins and their cytotoxicity, but small molecules that inhibit apoA-I fibril formation have never been reported. Our methods included a thioflavin-T-binding assay, atomic force microscopy and dot blot and cell-based assays. We showed that (-)-epigallocatechin-3-gallate (EGCG), a tea-derived flavanol, inhibited in vitro fibril formation and disaggregated fibrils preformed by the N-terminal 1-83 fragments of wild-type (WT) apoA-I and the G26R point mutation of apoA-I (apoA-IIowa). We eliminated a common structure recognized by the anti-amyloid antibody OC by incubating apoA-IIowa with EGCG or treating apoA-IIowa fibrils with EGCG, which supported the above observation. In addition, EGCG rescued human embryonic kidney 293 cells from cytotoxicity and attenuated production of reactive oxygen species, which were induced by apoA-IIowa fibrils. Our results support the concept that EGCG inhibits amyloid fibril formation of various amyloidogenic proteins. Thus, EGCG may be a candidate for providing a structure to develop de novo inhibitors for amyloidosis treatment.


The isolation and synthesis of a novel benzofuran compound from Tephrosia purpurea, and the synthesis of several related derivatives, which suppress histamine H1 receptor gene expression.

A novel naturally occurring compound with a benzofuran skeleton was isolated from a plant, Tephrosia purpurea collected in Bangladesh. The chemical synthesis of this compound confirmed its structure, and preliminary biological results showed its suppressive activity towards histamine H1 gene expression. One isomer and four derivatives were also synthesized, and their suppression activity was investigated. Although only small quantities of this compound can be isolated from its natural source, a 10 g scale synthesis was demonstrated by the newly developed method.


Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin-4 genes.

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 Tyr(311) 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.


Coleifolides A and B, Two New Sesterterpenoids from the Aerial Parts of Scutellaria coleifolia H.Lév.

Coleifolides A and B (1 and 2), two new sesterterpenoids with a -methyl-,-unsaturated--lactone moiety, were isolated from the aerial parts of Scutellaria coleifolia H.Lév. (Lamiaceae), together with three known compounds. Their structures were elucidated by NMR and MS examinations. Coleifolides A and B were concluded to be partially racemic compounds by the HPLC analysis using a chiral column or introduction of chiral derivatizing agents. The absolute configuration of the major isomer was determined by analyses of the CD spectrum as well as NMR data of (R)- and (S)-2-NMA derivatives. Coleifolides A and B are structurally similar to manoalide derivatives, previously isolated from marine sponges, and appear to be the first examples of this type of compounds being isolated from higher plants.


Agelamadin F and tauroacidin E, bromopyrrole alkaloids from an Okinawan marine sponge Agelas sp.


A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy.

Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer.


Acylated neo-clerodanes and 19-nor-neo-clerodanes from the aerial parts of Scutellaria coleifolia (Lamiaceae).

Scutefolides A1 and A2, two acylated neo-clerodanes with a 19,18--lactone, scutefolides B1, B2 and C, three 19-nor-neo-clerodanes, together with scutefolides D, E1, E2 and F, four neo-clerodanes, were isolated from the EtOAc-soluble fraction of the aerial parts of Scutellaria coleifolia. Their structures were established on the basis of spectroscopic analysis. The absolute configurations of four of these compounds were elucidated by the CD exciton chirality method. Cytotoxic activities of scutefolides D-F against four cancer cell lines (KB, A549, HeLa, and MCF7) were also evaluated, but they were inactive.


Hepatoprotective effect of fermented ginseng and its major constituent compound K in a rat model of paracetamol (acetaminophen)-induced liver injury.

FG was shown to possess hepatoprotective activity against paracetamol (APAP)-induced liver injury better than FRG. Compound K might play an important role for an anti-inflammatory activity of FG by inhibiting JNK signalling in the liver.

The Journal of Pharmacy and Pharmacology


Miltiorins A-D, diterpenes from Radix Salviae miltiorrhizae

Constituents of the anti-influenza A neuraminidase (NA) active extract from Radix Salviae miltiorrhizae were investigated, resulting in the isolation of four new diterpenes, miltiorins A-D (1-4), together with eight known diterpenes. The structures of 1-4 were assigned by spectroscopic analysis. Miltiorins A-C (1-3) were abietane diterpenes possessing a 2-acetoxy group and a 12-hydroxy group in common, while miltiorin D (4) was a 11,12-seco-abietane diterpene with a -lactone ring. Miltiorin D (4) is the first example of a 11,12-seco-abietane diterpene from natural sources. Anti-NA activities of the isolated diterpenes were evaluated.


Algiolide A, secoiridoid glucoside from Mongolian medicinal plant Gentiana algida

A new secoiridoid glucoside, algiolide A (1), was isolated from the aerial parts of a Mongolian traditional herbal medicine Gentiana algida (Gentianaceae). The structure of 1 was elucidated on the basis of spec- troscopic analysis and chemical conversion as well as calculations of NMR and ECD spectra. Algiolide A (1) has a novel skeleton consisting of fused a,b-unsaturated-d-lactone and cyclopentene rings.


Antiparasitic effect of matrine and oxymatrine (quinolizidine alkaloids) on the ciliate Cryptocaryon irritans in the red sea bream Pagrus major.


Antiparasitic effects of Sophora flavescens root extracts on the ciliate, Cryptocaryon irritans


Agelamadins C-E, Bromopyrrole Alkaloids Comprising Oroidin and 3-Hydroxykynurenine from a Marine Sponge Agelas sp.

Three structurally unique bromopyrrole alkaloids, agelamadins C-E (1-3), were isolated from a marine sponge Agelas sp. Agelamadin C (1) possesses a hybrid structure of oroidin and 3-hydroxykynurenine connected through a dihydro-1,4-oxazine moiety. Agelamadins D (2) and E (3) are a C-9/C-10 diastereomer and a 10-epimer of 1, respectively. The structures of 1-3 were elucidated on the basis of spectroscopic analysis as well as application of a PGME method and a TDDFT ECD calculation. Antimicrobial activity of 1-3 was evaluated.


Hypelodins A and B, polyprenylated benzophenones from Hypericum elodeoides.

Two new polyprenylated benzophenones, hypelodins A (1) and B (2), were isolated from the aerial parts of the Chinese medicinal plant Hyperium elodeoides (Choisy). Their structures were elucidated on the basis of spectroscopic evidence. Hypelodin A (1) is a polyprenylated benzophenone having a tetrahydropyrane ring with three prenyl groups and one 4-methyl-1,3-pentadiene moiety, while hypelodin B (2) has a cage-like structure with a 6/6/5/7/6/5 hexacyclic ring system.


Agelamadins A and B, Dimeric Bromopyrrole Alkaloids from a Marine Sponge Agelas sp.

Two structurally unique dimeric bromopyrrole alkaloids, agelamadins A (1) and B (2), were isolated from a marine sponge Agelas sp. Agelamadins A (1) and B (2) have a structure consisting of an agelastatin-like tetracyclic moiety and an oroidin-like linear moiety in common. The structures of 1 and 2 were elucidated on the basis of spectroscopic analysis. The antimicrobial activity and cytotoxicity of agelamadins A (1) and B (2) were evaluated.


Prenylated Flavonoids from the Stems and Leaves of Desmodium caudatum and Evaluation of Their Inhibitory Activity against the Film-Forming Growth of Zygosaccharomyces rouxii F51.

In order to provide scientific evidence for the relationship between the traditional usage, stems and leaves of Desmodium caudatum being used for protecting miso from spoilage, and its Japanese name (miso-naoshi), phytochemical study on the stems and leaves of this plant was carried out. Seven new prenylated flavonoids (1-3, 15-18), together with 19 known compounds (4-14, 19-26), were isolated, and the structures of new compounds were elucidated by extensive spectroscopic analyses. The minimum inhibitory concentrations (MICs) of 28 flavonoids, including 17 compounds (1, 2, 4, 5, 7-14, 20-22, 24, 25) isolated in this study and 11 flavonoids (27-37) previously isolated from the roots of this plant, against the film-forming yeast of Zygosaccharomyces rouxii F51 were determined. Fifteen compounds (2, 4, 5, 11, 12, 14, 21, 22, 25, 27, 28, 32-35) inhibited the film-forming growth of Z. rouxii F51 (MIC values, 7.8-62.5 g/mL), among which 2'',2''-dimethylpyran-(5'',6'':7,8)-5,2'-dihydroxy-4'-methoxy-(2R,3R)-dihydroflavonol (11) demonstrated potent inhibitory activity with an MIC value of 7.8 g/mL.

Journal of Agricultural and Food Chemistry


Triterpenoids from the fruits of Azadirachta indica (Meliaceae).

Four new triterpenoids, indicalilacols A-D (1-4), were isolated from the MeOH extract of the fruits of Azadirachta indica, including a new 19(109)abeo-tirucallane derivative, two new tirucallane-type triterpenoids, and a new euphane-type triterpenoid, along with three known tirucallane-type triterpenoids. Their structures were elucidated on the basis of spectroscopic analyses. The absolute configuration of 2 was elucidated by the chemical conversion of 2 into 21-oxo-melianodiol 24,25-acetonide. Compounds 2, 6-8 exhibited moderate cytotoxicity against three human cancer cell lines, including multidrug-resistant (MDR) cancer cells (KB-C2). Although compound 5 was not cytotoxic against any of the tested cancer cell lines, 5 showed cytotoxicity against KB-C2 cells in the presence of 2.5 M colchicine, suggesting that 5 might have an MDR-reversal effect.


Conjugates of a secoiridoid glucoside with a phenolic glucoside from the flower buds of Lonicera japonica Thunb.

Secoiridoid glucosides, including two conjugates with a phenolic and two conjugates with a nicotinic acid derivative (3 and 4), together with seven known secoiridoid derivatives, were isolated from flower buds of Lonicera japonica. The structures were elucidated by spectroscopic analyses. Anti-influenza activities of six isolated compounds were also evaluated by plaque assay and neuraminidase inhibitory assay.


Rigenolide A, a new secoiridoid glucoside with a cyclobutane skeleton, and three new acylated secoiridoid glucosides from Gentiana rigescens Franch.

Rigenolide A (1), a new secoiridoid glucoside with a cyclobutane skeleton and three new acylated secoiridoid glucosides, 2'-(2,3-dihydroxybenzoyl)-gentiopicroside (2), 2'-(2,3-dihydroxybenzoyl)-swertiamarin (3), 3'-(2,3-dihydroxybenzoyl)-sweroside (4), along with two noriridoids (7 and 8) and two known secoiridoid glucosides (5 and 6), were isolated from Gentiana rigescens Franch. The structures of new compounds were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for DPPH free-radical scavenging activity.


Structural elucidation and biological fate of two glucuronyl metabolites of pelargonidin 3-O--D-glucopyranoside in rats.

A high proportion of pelargonidin 3-O--D-glucopyranoside (Pg3G) is metabolized to glucuronides and excreted in mammal urine after ingestion of strawberry fruit, suggesting that these metabolites play important functional roles in vivo. The aim of the present study was to elucidate the structures and determine the biological fate of the two dominant metabolites of Pg3G in rats to enable an accurate discussion of the biological properties of anthocyanins. Authentic Pg3G was orally administered to rats. One pelargonidin monoglucuronide and three Pg3G-monoglucuronides (glucuronides of the glucoside) were identified together with intact Pg3G in both blood plasma and urine samples. The structures of the two dominant metabolites were elucidated as pelargonidin 3-O--D-glucuronide (Pg3GlcA) and pelargonidin 3-O--D-glucuronyl-(12)--D-glucoside by means of (1)H and (13)C nuclear magnetic resonance spectroscopy and heteronuclear multiple-bond connective spectroscopy. The bioavailability of Pg3G in its intact form was 0.31% of the orally administered dose, and 0.65% was absorbed in the Pg3GlcA form.


New sesquiterpene lactone glucosides from the roots of Ferula varia.


Prenylated flavonoids from the roots of Desmodium caudatum and evaluation of their antifungal activity.

Two new prenylated flavonoids (1, 4) and two new prenylated C-methyl-flavonoids (6, 7), together with four known flavonoids (2, 3, 5, 8), were isolated from the roots of Desmodium caudatum. The structures of the new compounds were elucidated by extensive spectroscopic analyses including 1D-, 2D-NMR and MS. The antifungal activities of five compounds (1, 2, 4, 6, 8) as well as nine flavonoids (9-17) previously isolated from this plant against Aspergillus niger, Penicillium sp., Rhizopus sp., and Trichophyton sp. were evaluated. Compound 6 showed potent antifungal activity against Trichophyton sp. with a minimum inhibitory concentration (MIC) value of 1.95 µg/mL.


Prenylated flavonoids from Desmodium caudatum and evaluation of their anti-MRSA activity.

Seven prenylated flavonoids and a prenylated chromanochroman derivative, together with eight known flavonoids, were isolated from roots of Desmodium caudatum. The 15 structures were elucidated by extensive spectroscopic analyses. The antibacterial activity of many of other compounds was evaluated against methicillin-resistant Staphylococcus aureus (MRSA: COL and 5) by a disc diffusion method, and the minimum inhibitory concentrations (MICs) to MRSA were determined.


Quantification of phosphatidic acid in foodstuffs using TLC-imaging technique

Apical application of lysophosphatidic acid (LPA), a growth-factor-like phospholipid, was shown to prevent or restore gastrointestinal (GI) disorders, such as diarrhea and stomach ulcer, in experimental animals. Because LPA is formed from phosphatidic acid (PA) by the activity of digestive phospholipase A(2), PA is a potential component for dietary treatment of such GI disorders. Here, we quantified PA contained in 38 foodstuffs and 3 herbs by a thin-layer-chromatography-imaging technique. Vegetables belonging to Brassicaceae, such as cabbage leaves (700 nmol/g of wet weight) and Japanese radish leaves (570 nmol/g), contained higher amounts of PA than other foodstuffs. Amounts of PA in fruits, cereals, and starchy root vegetables were below 300 nmol/g. Animal foodstuffs contained low amounts of PA (<60 nmol/g). Interestingly, leaves of Mallotus japonicas, a Japanese edible herb used for treatment of stomach ulcer, had the highest PA (1410 nmol/g) among those examined. The data shown here will be useful for the development of dietary treatment for a damaged GI tract.


New α-glucosides of caffeoyl quinic acid from the leaves of Moringa oleifera Lam.

Two new caffeoyl quinic acid α-glucosides, together with three known caffeoyl quinic acids and five known flavonoid glucosides, were isolated from the leaves of Moringa oleifera Lam. The structures of the new compounds were elucidated as 4-O-(4'-O-α-D-glucopyranosyl)-caffeoyl quinic acid (1) and 4-O-(3'-O-α-D-glucopyranosyl)-caffeoyl quinic acid (2) by spectroscopic analyses.


Triterpenes and a triterpene glucoside from Dysoxylum cumingianum and their cytotoxicity.

Six triterpenes and a triterpene glucoside were isolated from the MeOH extract of the leaves of Dysoxylum cumingianum together with three known triterpenes. Their structures were elucidated by extensive spectroscopic analyses. In cytotoxicity assays against three human cancer cell lines, including a multi-drug resistant cancer cell line (KB-C2), compounds 1, 2 and 5 demonstrated significantly enhanced cytotoxicity against KB-C2 cells in the presence of 2.5 μM colchicine, as compared with those in the absence of colchicine. This result suggested that these triterpenes might show some MDR-reversing effects.


Spicachlorantins G-J, New Lindenane Sesquiterpenoid Dimers from the Roots of Chloranthus spicatus.

Four new lindenane sesquiterpenoid dimers, spicachlorantins G-J (1-4), were isolated from the roots of Chloranthus spicatus together with seven known compounds, including chloramultilide A, shizukaol B, shizukaol D, shizukaol F, shizukaol P, chlorahololide D, and cycloshizukaol A. The planar structures of the new compounds were established by 1D-, 2D-NMR, and MS analyses. The absolute configurations of these compounds were determined by analyzing rotating Overhauser enhancement and exchange spectroscopy (ROESY) and circular dichroism (CD) spectra.


Dyscusins AC, Three New Steroids From the Leaves of Dysoxylum cumingianum.

Three new steroids dyscusins A-C (1-3), including a stigmastane-type sterol and two pregnanes, together with two known steroids were isolated from the leaves of Dysoxylum cumingianum (Meliaceae). Their structures were elucidated on the basis of extensive spectroscopic analyses. In a cytotoxicity assay, compound 1 showed ten-fold enhanced cytotoxicity against multi-drug resistant cancer cells (KB-C2) in the presence of 2.5 µM colchicine as compared with the absence of colchicine. This notable finding indicated that 1 possessed a multi-drug resistant reversal effect.


Biflavonoids from Flowers of Butea monosperma (Lam.) Taub.


New 29-nor-cycloartanes with a 3,4-seco- and a novel 2,3-seco-structure from the leaves of Sinocalycanthus chinensis.

Eight new triterpenoids, including sinocalycanchinensins A-E (1-5) with a 3,4-seco-29-nor-cycloartane skeleton, sinocalycanchinensin F (6) possessing a novel 2,3-seco-29-nor-cycloartane skeleton, and 29-nor-cycloartanes, sinocalycanchinensins G and H (7 and 8), have been isolated from the leaves of Sinocalycanthus chinensis. Their structures were elucidated on the basis of spectroscopic examinations. The cytotoxicities of the isolated new triterpenes against a panel of human cancer cell lines, including multi-drug resistant (MDR) cancer cell lines, were also evaluated. Compound 5 demonstrated enhanced cytotoxicity against MDR KB cells in the presence of colchicine, although all the compounds showed moderate or no cytotoxicities.


Seven new dammarane triterpenes from the floral spikes of Betula platyphylla var. japonica.

Seven new dammarane-type triterpenoids, including two 20(S)-hydroxy-25-methoxy-dammar-23-enes (1 and 2), two 20(S),24(R)-epoxydammaranes (3 and 4), a cabralealactone (5), and two 20(S),25-epoxydammaranes (6 and 7), together with seven known triterpenes (8-14), were isolated from the floral spikes of Betula platyphylla var. japonica. The structures for all compounds were elucidated by the analyses of extensive spectroscopic data, as well as chemical examinations.


Four new glucosides from the aerial parts of Mediasia macrophylla

As part of our chemical studies on the medical plants in Uzbekistan aimed at searching for new drug leads, we have examined the aerial parts of Mediasia macrophylla. This has resulted in the isolation of four new glucosides, together with 30 known compounds. The structures of new compounds were elucidated as (1'S)-(4-hydroxyphenyl) ethane-1',2'-diol 2'-O-β-glucopyranoside (1), 3-(4'-methoxyphenyl)-propanol 1-O-β-glucopyranoside (2), 2-methoxy-3-hydroxy-5-(E)-propenyl-phenol 1-O-β-glucopyranoside (3), 1-O-angeloyl-β-glucopyranose (4), on the basis of spectral analysis.


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, and 60) exhibited potent anti-HIV activity at the submicromolar level, with EC(50) values ranging from 0.040 to 0.098muM in HIV-1(NL4-3) 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.


Petiolins J-M, prenylated acylphloroglucinols from Hypericum pseudopetiolatum var. kiusianum.

Four new prenylated acylphloroglucinols, petiolins J-M (1-4), were isolated from aerial parts of Hypericum pseudopetiolatum var. kiusianum, and the structures were elucidated by spectroscopic data and a single-crystal X-ray diffraction analysis. Petiolin J (1) exhibited antimicrobial activity.

Bioorganic & Medicinal Chemistry Letters


Consultation clinics for complementary and alternative medicine at Japanese university hospitals: An analysis at Tokushima University Hospital

Here, we report on a Consultation Clinic for Complementary and Alternative Medicine (CAM) which we established at Tokushima University Hospital in July of 2007 with the aim of providing person-to-person information on CAM, though not CAM therapy itself. In December of 2008, we received 55 applications for consultation, 37% concerning health foods, 37% Japanese herbal medicine (Kampo), and 26% various other topics. The consultants (nutritionists and pharmacists) communicated individually with 38 applicants; malignancies (26%) and cardiovascular disease (24%) were the main underlying concerns. To promote the quality of consultation, data was collected by means of focus group interviews concerning the perspective of the consultants. Safe and effective use of CAM requires a network of communication linking individuals, consultation teams, physicians, primary care institutions and university hospitals. To advance this goal, we plan to broaden the efforts described herein. Our findings indicate that the specific role of the consultation clinic in promoting the scientific use of CAM merits further study.


A new C14-polyacetylenic glucoside with an -pyrone moiety and four new C10-polyacetylenic glucosides from Mediasia macrophylla

Polyacetylenic glucosides (1-5) were isolated from the MeOH extract of Mediasia macrophylla, and their structures were established by spectroscopic analyses. Compounds 2-4 were the first examples of C(10)-polyacetylenic glucosides found in the family Umbelliferae, while compound 1 was a unique polyacetylenic glucoside possessing an alpha-pyrone moiety.


A Target-Based High Throughput Screen Yields Trypanosoma brucei Hexokinase Small Molecule Inhibitors with Antiparasitic Activity.

The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the gamma-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay. Exploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were approximately 20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03<or=EC(50)<3 microM) with parasite specificity of the compounds being demonstrated using insect stage T. brucei parasites, Leishmania promastigotes, and mammalian cell lines. Analysis of two structurally related compounds, ebselen and SID 17387000, revealed that both were mixed inhibitors of TbHK1 with respect to ATP. Additionally, both compounds inhibited parasite lysate-derived HK activity. None of the compounds displayed structural similarity to known hexokinase inhibitors or human African trypanosomiasis therapeutics. The novel chemotypes identified here could represent leads for future therapeutic development against the African trypanosome.


Papyriferic Acid Derivatives as Reversal Agents of Multidrug Resistance in Cancer Cells.

Forty-one derivatives of papyriferic acid were prepared based on our previous finding that methyl papyriferate (3) showed potent reversing effect on cytotoxicity of colchicine against multidrug resistance (MDR) human cancer cells (KB-C2), and evaluated for their cytotoxicity and effect on reversing P-gp-mediated MDR against KB-C2 cells. 3-O-(Morpholino-beta-oxopropanoyl)-12beta-acetoxy-3alpha,25-dihydroxy-(20S,24R)-epoxydammarane (37) significantly increased the sensitivity of colchicine against KB-C2 cells by 185-fold at 5microg/mL (7.4microM), and the cytotoxicity of colchicine was recovered to nearly that of sensitive (KB) cells. The other several new amide derivatives also exhibited potent reversal activity comparable to or more potent than methyl papyriferate and verapamil.


Biyouxanthones A-D, prenylated xanthones from roots of Hypericum chinense


Petiolins F-I, benzophenone rhamnosides from Hypericum pseudopetiolatum var. kiusianum.

Four new benzophenone-O-rhamnosides, petiolins F-I (1-4), were isolated from aerial parts of Hypericum pseudopetiolatum var. kiusianum, and the structures were elucidated by spectroscopic data and chemical means.


Xanthones from Hypericum chinense and their cytotoxicity evaluation.

A xanthonolignoid, 2-O-demethylkielcorin, and a phenylxanthone, chinexanthone A, were isolated from stems of Hypericum chinense together with four known xanthonolignoids and seven known xanthones. Their structures were established by spectroscopic analysis, as their optical properties and absolute stereochemistry determined. The cytotoxicities of the isolated xanthone derivatives as well as additional 32 xanthones against a panel of human cancer cell lines were also evaluated.


Acylphloroglucinol, biyouyanagiol, biyouyanagin B, and related spiro-lactones from Hypericum chinense.

Biyouyanagiol (1), an acylphloroglucinol-related compound having a unique cyclopenta-1,3-dione moiety, was isolated from a Japanese traditional medicinal plant, Hypericum chinense, together with three new spiro-lactone-related derivatives, biyouyanagin B (2), 5,6-dihydrohyperolactone D (3), and 4-hydroxyhyperolactone D (4). Their structures were established on the basis of spectroscopic evidence. In a cytotoxicity assay against human cancer cell lines including multidrug-resistant (MDR) cancer cell lines, several compounds demonstrated enhanced cytotoxicity against MDR KB cells in the presence of colchicine.


Spicachlorantins A and B, New Dimeric Sesquiterpenes from the roots of Chloranthus spicatus.


Petiolins D and E, phloroglucinol derivatives from Hypericum pseudopetiolatum var. kiusianum.


Chromone and chromanone glucosides from Hypericum sikokumontanum and their anti-Helicobacter pylori activities.

Chromone glucosides, takanechromones A-C (1, 2 and 5) and chromanone glucosides, named takanechromanones A and B (3 and 4), were isolated from the methanolic extracts of Hypericumsikokumontanum together with 27 known compounds. Their structures were established based on spectroscopic evidence. The isolated compounds and some chromone derivatives were assayed for antimicrobial activity against Helicobacter pylori and cytotoxicity against human cancer cell lines.


Spicachlorantins CF, hydroperoxy dimeric sesquiterpenes from the roots of Chloranthus spicatus.


Ent-3,4-seco-labdane and ent-labdane diterpenoids from Croton stipuliformis (Euphorbiaceae)

From a methanolic extract of the leaves of Croton stipuliformis, three ent-3,4-seco-labdanes (1-3) and an ent-labdane (4) together with the known compounds 6-hydroxynidorellol (5), maravuic acid, and sitosterol were isolated and identified from their spectroscopic data. The absolute stereochemistry of compound 4 was determined by application of Mosher's method in the NMR tube.


Tomoenones A-H, cytotoxic phloroglucinol derivatives from Hypericum ascyron

Phloroglucinol derivatives tomoeones A-H (1-8) and three known compounds were isolated from leaves of Hypericum ascyron. Their structures were established based on spectroscopic analyses. They are all acylphloroglucinol derivatives possessing a spiro skeleton with geminal isoprenyl groups and a monoterpene moiety, and they are stereoisomers to each other at C-4 and C-13. They appear to be a class of phloroglucinol derivatives. Cytotoxicities of the isolated phloroglucinol derivatives against human tumor cell lines, including multidrug-resistant (MDR) cancer cell lines, were evaluated. Tomoeone F (6) demonstrated significant cytotoxicity against KB cells with an IC50 value of 6.2 microM. Compound 6 was also cytotoxic against MDR cancer cell lines (KB-C2 and K562/Adr), which was more potent than doxorubicin.


Prenylated Phrologrucinol Derivatives from Hypericum perforatum var. angustifolium

Two new prenylated phloroglucinol derivatives and 15 known compounds were isolated from the aerial parts of Hypericum perforatum var. angustifolium. Their structures were determined on the basis of spectroscopic evidence.


Petiolins A-C, phloroglucinol derivatives from Hypericum pseudopetiolatum var. kiusianum

Two new phloroglucinol derivatives possessing chromane skeleton, petiolins A (1) and B (2), and a new phloroglucinol derivative containing a dihydrofuran ring, petiolin C (3), were isolated from aerial parts of Hypericum pseudopetiolatum var. kiusianum. The gross structures of 1-3 were elucidated by spectroscopic data, and the relative stereochemistry of 3 was elucidated by NOESY data. Petiolins A-C (1-3) showed modest cytotoxicity, while petiolin C (3) exhibited antifungal activity.


Monoterpene glycosides from Paeonia hybrida

Monoterpene glycosides (1-5, and 7), together with 14 known compounds, were isolated from the methanol extract of the roots of Paeonia hybrida. These compounds included a paeoniflorin-related glycoside with a hybrid structure of paeoniflorin and paeonovicinoside (1), a monoterpene glucoside biogenetically related to lactiflorin (2), a paeoniflorin-related monoterpene (3), arbiflorin-related monoterpenes (4 and 5), and a tymol-related monoterpene glycoside (7). Their structures were elucidated by extensive spectroscopic examinations.


Takaneones A-C, prenylated butylphloroglucinol derivatives from Hypercum shikokumontanum


New Alkaloid from the aerial parts of Condonopsis clematidea

A new codonopsine-related alkaloid and 13 known compounds were isolated from the aerial parts of Codonopsis clematidea (Campanulaceae). The structure of the new compound was elucidated by two-dimensional nuclear magnetic resonance and other spectral examinations.


Effect of Triterpenoids from the Floral Spikes of Betula platyphylla var. japonica on Glycoprotein Function

One of the major causes of multidrug resistance (MDR) in cancer cells is over-expression of P-glycoprotein (P-gp). We studied the effects of 20 triterpenes isolated from the floral spikes of Betula platyphylla var. japonica ( B. platyphylla) on P-gp function based on our previous finding that some of them showed MDR reversing effects. We evaluated accumulations and effluxes of rhodamine 123 as a P-gp substrate with P-gp over-expressing KB-C2 cells. Among the 20 triterpenes, compounds 3, 4, 8, 9, 13, 15, and 20 increased rhodamine 123 accumulations in KB-C2 cells, and three ( 8, 13, and 20) of them also inhibited efflux of rhodamine 123 out of cells. In addition, compounds 13 and 20 showed a weak inhibitory activity of P-gp ATPase. These results suggested that MDR reversing effects of compounds 13 and 20 are partly involved in inhibition of P-gp ATPase.


Sesquiterpene Lactone from the Roots of Ferula varia and Their Cytotoxic Activity,

The ethyl acetate-soluble fraction from a MeOH extract of the roots of Ferula varia gave six new sesquiterpene lactones (1-6) and five known sesquiterpenes (7-11). Their structures were established on the basis of spectroscopic evidence. The cytotoxic activities of 1-11 were evaluated against selected human cancer cell lines. Compound 4 showed significant selective cytotoxicity against multidrug-resistant cancer cells (KB-C2). The cytotoxicities of compounds 1, 3, 5, 8, and 11 against KB-C2 cells were enhanced in the presence of nontoxic concentrations of colchicine.


Inhibition of P-glycoprotein function by tannic acid and pentagalloylglucose.

We studied the effects of tannic acid and 1(beta),2,3,4,6-penta-O-galloyl-D-glucose (pentagalloylglucose), one of the components of tannic acid, on the P-glycoprotein (P-gp) function in multidrug-resistant P-gp over-expressing KB-C2 cells. Both tannic acid and pentagalloylglucose markedly elevated the accumulation of P-gp substrates, rhodamine 123 and daunorubicin, by inhibiting their efflux. A 19-fold increase in cellular rhodamine 123 was observed for tannic acid at 60 microM (85 microg mL(-1)) and a 21-fold increase was observed for pentagalloylglucose at 100 microM (94 microg mL(-1)). The increasing effects of these compounds in the accumulation were much larger than that of (-)epigallocatechin-3-O-gallate (EGCG), which has been revealed to have a prominent inhibitory effect on P-gp compared with other flavonoids. Analysis of verapamil-stimulated ATPase activity in membrane vesicles expressing human P-gp suggested that inhibition of P-gp function by tannic acid and pentagalloylglucose was at least partly due to ATPase inhibition of P-gp. The findings also suggested that the presence of a large number of galloyl groups in polyphenols strengthens the interaction with regulatory regions in P-gp.

The Journal of Pharmacy and Pharmacology


Triterpenoids from the Floral Spikes of Betula platyphylla var. japonica and Their Reversing Activity against Multidrug-Resistant Cancer Cells

Four new triterpenes, together with 16 known triterpenes, were isolated from the floral spikes of Betula platyphylla var. japonica in a search for compounds capable of reversing multidrug resistance in cancer cells. The structures of the new triterpenes were elucidated as 3,4-seco-olean-4(23),13(18)-dien-3-oic acid (1), 3,4-seco-urs-4(23),20(30)-dien-3-oic acid (2), 3-O-methylmalonylepiocotillol II (6), and 3-O-methylmalonylcabraleahydroxylactone (16) by spectroscopic examination. The cytotoxicity of the isolated triterpenes against human cancer cell lines as well as multidrug-resistant cancer cell lines was evaluated. Most of the isolated triterpenes showed very weak cellular toxicities. Although no discernible differences were found in the cytotoxicities for the tested compounds against sensitive and resistant cell lines, the cytotoxicities for several triterpenes against multidrug-resistant cancer cell lines (KB-C2 or K562/Adr) were enhanced in the presence of nontoxic concentrations of colchicine or doxorubicin. Compound 10 reversed the cytotoxicity of colchicine against KB-C2 cells at 8.1 microM and showed comparable potency to 5 microM verapamil.


Terpenoids from Juniperus polycarpus var. seravschanica

Two eudesmanes, two abietanes, two podocarpanes and other nine known compounds were isolated from the dried fruits of Juniperus polycarpus var. seravschanica. Their structures were established on the basis of analysis of spectroscopic evidence. Some of the isolated terpenoids showed antimalarial activity.


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

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 analogue 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 íM against NL4-3, 0.021 íM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 íM against FHR-2 (an HIV strain resistant to 8). Promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted.


Nasunin from Eggplant Consists of Cis-Trans Isomers of Delphinidin 3-[4-(p-Coumaroyl)-L-rhamnosyl (1 6)glucopyranoside]-5-glucopyranoside

Two major anthocyanins were isolated from the acidified methanolic extract of eggplant (Solanum melongena L.) by column chromatography and preparative high-performance liquid chromatography. These anthocyanins were interconvertible under room light illumination condition. By means of tandem time-of-flight mass spectrometry and nuclear magnetic resonance spectroscopy, their structures were identified and elucidated as delphinidin 3-[4-(cis-p-coumaroyl)-l-rhamnosyl(1-->6)glucopyranoside]-5-glucopyranoside (compound 1) and delphinidin 3-[4-(trans-p-coumaroyl)-l-rhamnosyl-(1-->6)glucopyranoside]-5-glucopyranoside (compound 2), respectively. The results indicated that nasunin comprised cis and trans isomers of the p-coumaric acid moiety in its structure.

Journal of Agricultural and Food Chemistry


Effect of Alkyl Gallates on P-glycoprotein Function

In this study, we examined the effects of the food antioxidants, alkyl gallates, on the function of P-glycoprotein (P-gp) and elucidated the importance of alkyl chains and gallic acid moieties on the activity of P-gp. We examined the effects of three alkyl (n-butyl, n-octyl and n-dodecyl) gallates and their related compounds on the cellular accumulation and efflux of rhodamine 123 and daunorubicin in P-gp overexpressing KB-C2 cells. Alkyl gallates increased the cellular accumulation of these P-gp substrates dependent on their alkyl chain lengths by inhibiting the efflux of the substrates. n-Dodecylresorcinol also increased the accumulation, but its effect was less than that of n-dodecyl gallate. However, either lauric acid or n-dodecyl-beta-d-maltoside, which does not have a phenol group, did not increase the accumulation. The results indicated that both the gallic acid moiety and a long alkyl chain play important roles in the modification of P-gp function. The cytotoxicity of daunorubicin was recovered in the presence of alkyl gallates possibly due to their inhibition of P-gp function.


Anti-HIV Benzylisoquinoline Alkaloids and Flavonoids from the Leaves of Nelumbo nucifera, and Structure-Activity Correlation with Related Alkaloids

(+)-1(R)-Coclaurine (1) and (-)-1(S)-norcoclaurine (3), together with quercetin 3-O-beta-D-glucuronide (4), were isolated from the leaves of Nelumbo nucifera (Nymphaceae), and identified as anti-HIV principles. Compounds 1 and 3 demonstrated potent anti-HIV activity with EC50 values of 0.8 and <0.8 microg/mL, respectively, and therapeutic index (TI) values of >125 and >25, respectively. Compound 4 was less potent (EC50 2 microg/mL). In a structure-activity relationship study, other benzylisoquinoline, aporphine, and bisbenzylisoquinoline alkaloids, including liensinine (14), negferine (15), and isoliensinine (16), which were previously isolated from the leaves and embryo of Nelumbo nucifera, were evaluated for anti-HIV activity. Compounds 14-16 showed potent anti-HIV activities with EC50 values of <0.8 microg/mL and TI values of >9.9, >8.6, and >6.5, respectively. Nuciferine (12), an aporphine alkaloid, had an EC50 value of 0.8 microg/mL and TI of 36. In addition, synthetic coclaurine analogs were also evaluated. Compounds 1, 3, 12, and 14-16 can serve as new leads for further development of anti-AIDS agents.


Protective role of Coptidis Rhizoma alkaloids agaist peroxynitrite-iduced damages to renal tubular epithelial cells

A study was conducted to elucidate and compare the protective activity of alkaloids from Coptidis Rhizoma (berberine, coptisine, palmatine, epiberberine, jatrorhizine, groenlandicine and magnoflorine) using an LLC-PK(1) cell under peroxynitrite (ONOO(-)) generation model. Treatment with 3-morpholinosydnonimine (SIN-1) led to an increase in cellular ONOO(-) generation in comparison with non-treated cells. However, Coptidis Rhizoma extract and its alkaloids, except for berberine, reduced the cellular ONOO(-) level. In addition, DNA fragmentation induced by SIN-1 was significantly decreased by the extract, and also by coptisine, epiberberine, jatrorhizine, groenlandicine and magnoflorine. Moreover, treatment with berberine, coptisine, palmatine and epiberberine exerted a protective effect against G(0)/G(1)phase arrest of cell cycle induced by SIN-1. The increase in cellular ONOO(-) generation, DNA damage and disturbance of the cell cycle by SIN-1 resulted in a decrease in cell viability. However, Coptidis Rhizoma extract, epiberberine, jatrorhizine, groenlandicine and magnoflorine significantly increased cell viability even at a concentration as low as 10 microg mL(-1). These findings demonstrate that Coptidis Rhizoma extract and its alkaloids can ameliorate the cell damage associated with ONOO(-) generation in renal tubular LLCPK(1) cells, and that the various alkaloids have distinctive mechanisms of action, such as ONOO(-) scavenging, protection from DNA damage and control of the cell cycle. Furthermore, the data suggest that among the Coptidis Rhizoma alkaloids, coptisine is the most effective for protection against SIN-1-induced cellular injury in terms of its potency and content.


3-O-Glutaryl-dihydrobetulin and related monoacyl derivatves as potent anti-HIV agents

3-O-Acyl-betulin and -dihydrobetulin derivatives were prepared and evaluated for anti-HIV activity. 3-O-Glutaryl-dihydrobetulin (17) demonstrated extremely potent anti-HIV activity with an EC(50) value of 2 x 10(-5) microM and a TI value of 1.12 x 10(6). 3-O-(3',3'-Dimethylsuccinyl)- and 3-O-(3',3'-dimethylglutaryl)-dihydrobetulins (15, 16) were also potent anti-HIV compounds with EC(50) values of 0.0017 and 0.0013 microM, respectively, and TI values of 16,160 and 19,530, respectively.

Bioorganic & Medicinal Chemistry Letters


Absorption and Metabolism of Delphinidin 3-O-β-D-Glucopyranoside in Rats

The absorption and metabolism of delphinidin 3-O-beta-d-glucopyranoside (Dp3G), which is the most potent antioxidant among the blueberry anthocyanins, were studied in rats. Dp3G rapidly appeared in the blood plasma within 15 min of oral administration (100 mg/kg body wt). The plasma level of absorbed Dp3G showed two peaks at 15 and 60 min after ingestion and then decreased time-dependently. However, the plasma level was maintained at approximately 30 nmol/l even after 4 h. Besides the Dp3G peak, a single major metabolite peak was detected by HPLC in the blood plasma obtained at 15 min. MS and NMR spectroscopy clarified that the chemical structure of the metabolite was 4'-O-methyl delphinidin 3-O-beta-d-glucopyranoside (methylation of the 4'-OH on the delphinidin B-ring). The present finding of this unique metabolite in anthocyanin metabolism strongly suggests that methylation of the 4'-OH on the flavonoid B-ring is a common metabolic pathway for flavonoids that carry the pyrogallol structure on the B-ring, as the same type of metabolite has been reported for other flavonoids such as epigallocatechin, but not for flavonoids carrying the catechol structure.


Coptidis Rhizoma: Protective effects against peroxynitrite-induced oxidative damage and elucidation of its active components

We have investigated the protective effects of Coptidis Rhizoma against peroxynitrite (ONOO(-))-induced oxidative damage and have elucidated the active components of this preparation. In an in-vitro system, Coptidis Rhizoma extract scavenged ONOO(-) and its precursors, nitric oxide (NO) and superoxide anion (O(2)(-)). This scavenging activity was more marked for ONOO(-) than its precursors. In addition, against 3-morpholinosydnonimine-induced cellular damage, this extract significantly reduced cellular ONOO(-) formation and increased cell viability. In an in-vivo lipopolysaccharide plus ischaemia-reperfusion system that generated ONOO(-), the administration of Coptidis Rhizoma extract at 50 and 100 mg kg(-1)/day for 30 days exerted greater inhibition of ONOO(-) than NO and O(2)(-). This suggested that it acted as a direct scavenger of ONOO(-) rather than as a scavenger of its precursors. Moreover, the suppression of the activities of the antioxidative enzymes superoxide dismutase, catalase and glutathione peroxidase was significantly attenuated by the administration of Coptidis Rhizoma extract. Furthermore, the extract ameliorated renal dysfunction judged by decreasing serum urea nitrogen and creatinine levels. To elucidate the active components of Coptidis Rhizoma extract, we evaluated and compared the effects of the phenol plus alkaloid and alkaloid fractions on ONOO-induced damage. We found that the alkaloid fraction consisting of berberine, palmatine and coptisine was the most effective at protecting against ONOO(-). We confirmed that berberine (10 and 20 mg kg(-1)/day for 10 days), the main and most active alkaloid in Coptidis Rhizoma extract, was also protective, exerting NO-, O(2)(-)- and ONOO(-)-scavenging activities. This study suggested that Coptidis Rhizoma could protect against ONOO(-)-induced oxidative damage and that this effect was mainly attributable to the constituent alkaloids, especially berberine. This study is the first to demonstrate an antioxidative effect of alkaloids, including berberine, against ONOO(-)-induced damage.

The Journal of Pharmacy and Pharmacology


Complete Assignment of Billberry (Vaccinium myrtillus L.) Anthocyanins Separated by Capillary Zone Electrophoresis

Capillary zone electrophoresis (CZE) mobilities of fifteen anthocyanins in bilberry extract were completely characterized. Four minor anthocyanins in bilberry extract (malvidin 3-O-alpha-L-arabinopyranoside (Mv 3-ara), peonidin 3-O-beta-D-galactopyranoside (Pn 3-gal), peonidin 3-O-alpha-L-arabinopyranoside (Pn 3-ara), and petunidin 3-O-alpha-L-arabinopyranoside (Pt 3-ara)) that remained unidentified in our previous CZE study were isolated from the bilberry extract, and the chemical structures were assigned by NMR and MS. Their CZE mobilities were then precisely examined together with those of other major anthocyanins in the extract. When the CZE mobilities of the fifteen anthocyanins assigned here were plotted against their molecular weight/numbers of free phenolic group, it was found that separation of anthocyanins by CZE is primarily determined by the type of conjugated sugar present, and secondly by the aglycon structure.


Plant-derived Terpenoids and Analogues as Anti-HIV Agents

The plant-derived terpenoids and analogues are reviewed with respect to their anti-HIV activity, structure-activity relationships, and mechanism of action. The active compounds include diterpenoid lactones, phenolic diterpenes, atisane and kaurane diterpenes, phorbol diterpenes, triterpene glycosides, friedelane triterpenes, taraxerane triterpenes, ursane triterpenes, lanostane triterpene, lupane triterpenes, seco-ring A triterpenes, degraded triterpenes, and cucurbitacin triterpenes. Positive new leads for drug development will be highlighted.


Anti-AIDS agents 49. Synthesis, anti-HIV, and anti-fusion activities of IC9564 analogues based on betulinic acid.

The betulinic acid derivative IC9564 inhibits human immunodeficiency virus (HIV)-1 entry. Among a series of IC9564 derivatives, 5 and 20 were the most promising compounds against HIV infection with EC(50) values of 0.33 and 0.46 microM, respectively. Both compounds inhibited syncytium formation with EC(50) values of 0.40 and 0.33 microM, respectively. The comparable EC(50) values in the two assays suggested that these compounds are fusion inhibitors. The structure-activity relationship data also indicated that a double bond in IC9564 can be eliminated and the statine moiety can be replaced with L-leucine while retaining anti-HIV activity.


Study on the Components of Luobuma with Peroxynitrite-Scavenging

The origin of the antioxidant activity of Luobuma aqueous extract was examined by measuring the peroxynitrite (ONOO^-)-eliminating activities of fractions of this extract obtained by Sephadex LH-20 column chromatography. Three of the four fractions obtained, i.e., those excluding the H_2O-eluted fraction, were found to possess ONOO^-eliminating activity. These three fractions were combined and fractionated again by Sephadex LH-20 column chromatography, which yielded five fractions. Seven different compounds were isolated from two of these five fractions with high activity. Epigallocatechin-(4β-8)-epicatechin showed the highest ONOO^- -eliminating activity.


Ellagitannins and hexahydroxydiphenoyl esters as inhibitors of vertebrate squalene epoxidase.

Ellagitannins isolated from various plant sources as well as newly synthesized n-alkyl (C(1)-C(18)) esters of hexahydroxydiphenyl (HHDP) dicarboxylic acid were evaluated as enzyme inhibitors of recombinant rat squalene epoxidase, a rate-limiting enzyme of cholesterol biosynthesis. Among the ellagitannins tested, pedunculagin (IC(50) = 2.0 microM) and eugeniin (IC(50) = 1.6 microM), both containing (S)-HHDP ester group(s), showed remarkable inhibition, which was more potent than those of previously reported substrate analogue inhibitors. Furthermore, ellagic acid (IC(50) = 2.0 microM), a bislactone formed by hydrolytic release of a HHDP group from ellagitannins, was also a good inhibitor of the enzyme. On the other hand, the synthetic HHDP esters with C(6) (IC(50) = 0.93 microM) and C(8) alkyl side chains (IC(50) = 0.83 microM) showed potent enzyme inhibition at the submicromolar concentration range, while esters with shorter chain lengths (C(1)-C(4)) and a C(18) ester exhibited moderate inhibition (IC(50) = 8-47 microM).


Anti-Human Immunodeficiency Virus Activity of YK-FH312 (a Betulinic Acid Derivative), a Novel Compound Blocking Viral Maturation

Betulinic acid, a triterpenoid isolated from the methyl alcohol extract of the leaves of Syzigium claviflorum, was found to have a potent inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Betulinic acid derivatives were synthesized to enhance the anti-HIV activity. Among the derivatives, 3-O-(3',3'-dimethylsuccinyl) betulinic acid, designated YK-FH312, showed the highest activity against HIV-induced cytopathic effects in HIV-1-infected MT-4 cells. To determine the step(s) of HIV replication affected by YK-FH312, a syncytium formation inhibition assay in MOLT-4/HIV-1(IIIB) and MOLT-4 coculture, a multinuclear-activation-of-galactosidase-indicator (MAGI) assay in MAGI-CCR5 cells, electron microscopic observation, and a time-of-addition assay were performed. In the syncytium formation inhibition assay or in the MAGI assay for de novo infection, the compound did not show inhibitory effects against HIV replication. Conversely, no virions were detected in HIV-1-infected cell cultures treated with YK-FH312 either by electron microscopic observation or by viral yield in the supernatant. In accordance with a p24 enzyme-linked immunosorbent assay of culture supernatant in the time-of-addition assay, YK-FH312 inhibited virus expression in the supernatant when it was added 18 h postinfection. However, Western blot analysis of the cells in the time-of-addition assay revealed that the production of viral proteins in the cells was not inhibited completely by YK-FH312. These results suggest that YK-FH312 might affect the step(s) of virion assembly and/or budding of virions, and this is a novel mechanism of action of an anti-HIV compound.


Influence of Natural and Synthetic Compounds on Cell Surface Expression of Cell Adhesion Molecules, ICAM-1 and VCAM-1

Various natural and synthetic compounds including alkaloids, terpenoids and phenolics were tested for inhibition of the cell surface expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), both of which are crucial in the regulation of immune response and inflammation. Of 40 compounds tested, two compounds significantly downregulated the expression of VCAM-1 on murine endothelial cells (F-2) and ten compounds that of ICAM-1 on mouse myeloid leukemia cells (M1). Sanguinarine chloride (5) and isoliquiritigenin (13) were capable of lowering the levels of both ICAM-1 and VCAM-1. The structure-activity relationships study on chalcone and flavone derivatives related to 13 suggested that the inhibitory activity of the chalcone derivatives is attributable to the 4-hydroxy group as well as the possible coplanarity between the phenyl ring and the adjacent conjugated ketone.


3,28-Di-O-(Dimethylsuccinyl)-Betulin Isomers as Anti-HIV Agents

Four isomers of 3,28-di-O-(dimethylsuccinyl)-betulin were prepared and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. 3-O-(3',3'-Dimethylsuccinyl)-28-O-(2", 2"-dimethvlsuccinyl)-betulin (11) was the most potent anti-HIV compound with an EC5, value of 0.00087 microM and a TI value of 42,400.

Bioorganic & Medicinal Chemistry Letters


Isolation of Rhododaurichromanic Acid B and the Anti-HIV Principles Rhododaurichromanic Acid A and Rhododaurichromenic Acid from Rhododendron dauricum


Sesquiterpene Glucosides from Anti-Leukotriene B4 Release Fraction of Taraxacum officinale

Chemical examination of the MeOH extract of the root of Taraxacum officinale, which exhibited inhibitory activity on the formation of leukotriene B4 from activated human neutrophils, has resulted in the isolation of 14-O-beta-D-glucosyl-11,13-dihydro-taraxinic acid (1) and 14-O-beta-D-glucosyl-taraxinic acid (2). The absolute stereostructure of 1 has been established by X-ray chrystallographic examination.

Journal of Asian Natural Products Research


つるぎ町一宇地区の民間薬調査

つるぎ町一宇地区の民間薬調査


三好市東祖谷地区の民間薬調査

三好市東祖谷地区の民間薬調査